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Reverse Diabetes Now

Reverse Diabetes Now by Matt Traverso is a program that encourages people to follow healthy lifestyle by eating well and performing exercises frequently to get in shape and manage the blood sugar levels well. This remedy will teach users how to eat right with healthy foods and the best time to eat for preventing the increase of blood sugar levels. This diabetes healing program provides users with natural remedies for diabetes that are proven totally safe to apply. In fact, the author has research thousands of websites; read dozens of magazines, books, diet plans, and brochures out there to find out how to reverse diabetes for good. This treatment offers the tools that are proven effective by many people in many areas all over the world. Reverse Diabetes Today PDF is an extremely comprehensive treatment that encourages people to make positive changes in daily habits, more concretely, dieting, regularly exercising, and weight managing routines to reverse diabetics. More here...

Reverse Diabetes Now Overview

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Oxidative Stress and Antioxidants The Antioxidant Network aLipoic Acid and Diabetes

In this introductory chapter, oxidative stress in diabetes and implications of antioxidant treatment are considered. It is thought that free radicals may play a major role in aging and disease. Free radicals arise from radiation, environmental chemicals, cigarette smoke, and various other environmental sources. In addition, all through our life, we have a fire burning inside of us our own body metabolism, which generates free radicals. Finally, many environmental substances (as well as drugs and alcohol) are metabolized in our body, generating free radicals through cytochrome P450-mediated oxidations. Many free radicals can be cytotoxic.

On the Possible Role of Inflammation in Obesity and Type 2 Diabetes in Schizophrenia

It is well known that genetic and environmental factors interact to favor weight gain, changes which disrupt metabolism. The body fat stores are normally maintained within a narrow range by energy homeostasis. This process is controlled by the brain regions, such as hypothalamus, that control appetite and energy balance in addition to peripheral signaling systems that monitor energy stores. Glucose, free fatty acids, insulin and leptin are examples of the signaling molecules that activate the hypothalamus thereby controlling the metabolic rate and the desire to eat. Obesity does not simply arise from the passive accumulation of excess body weight but is an active adaptation to the elevation of body fat. Clearly, the genetic background of the individual contributes to the variation in the response to elevated body fat which helps to explain why some individuals are protected against weight gain while the majority is not despite the fact that they live in the same environment and eat...

An Overview Of Metabolic Syndrome A Precursor Of Diabetes Heart Disease And Stroke

(4) lowered sensitivity to insulin Individuals who have two or more of these symptoms are at higher risk of developing cardiovascular disease and type 2 diabetes (i.e., non-insulin dependent), especially if there is a family history of these illnesses. The symptoms of metabolic syndrome often occur concurrently because they arise from multiple, tightly-coupled biochemical abnormalities.2 PART II. TYPE 2 DIABETES because they accumulate in the body, leading to diminished insulin sensitivity. Thus, although glucose is a critical fuel for the body, it must be tightly controlled. Adipose cells function not only as energy storage vessels but also as sources of regulatory molecules. One such regulator is the small protein leptin, which after secretion by fatty tissue travels to the brain where it normally induces a signal to decrease food intake. Another regulator is adiponectin, which increases insulin sensitivity, decreases glucose production in the liver, and increases glucose uptake by...

Sex Differences in Insulin Resistance

Insulin resistance can vary between sexes and across a women's reproductive life cycle. For example, some studies have suggested that girls through adolescence are inherently more insulin resistant than boys, but this relationship is thought to reverse after puberty 3, 4 . In adults, fat distribution patterns favor the development of IR in men, as men are more likely to develop abdominal obesity. Abdominal fat tissue is a major source of free fatty acids and cytokines and is associated with IR 5 . Premenopausal adult women more frequently develop peripheral obesity with subcutaneous fat accumulation, whereas men and postmenopausal women are more prone to central or abdominal obesity. After the menopause, concentrations of lipoproteins as well as body fat distribution shift to a more male pattern 5 . Pregnancy is also a time of elevated peripheral IR for women. During pregnancy, there is an approximate 50 reduction in insulin sensitivity by the third trimester such changes are thought...

Vitamin E In Diabetes

About one-half of the total plasma vitamin E is a constituent of circulating LDL. Interindividual variations in plasma vitamin E are closely related to those in LDL (24,25). The concentration of vitamin E per LDL particle is rather low (i.e., in the order of 5-9 molecules compared with 2200 molecules of cholesterol and 170 molecules of triglycerides) (26). Nevertheless, the level of vitamin E in LDL is an independent factor that influences susceptibility of LDL to oxidation. The lagtime of in vitro LDL oxidation was found to be related to the level of vitamin E in LDL when diabetic patients were supplemented with vitamin E (27,28). For persons with usual nutritional habits, the corresponding relationship was observed in two studies (29,30) but not in others (3,31,32). There are several publications on vitamin E concentrations in the plasma of diabetic patients. The assumption that the oxidative stress in diabetes is due to deficient vitamin E in plasma could not be confirmed. In most...

HT2CR Mutant Mice Demonstrate a Metabolic Syndrome Consistent with Type II Diabetes

Prior to the development of obesity (but in the context of ongoing hyperphagia), young constitutive 5-HT2CR - Y mice have normal serum glucose, insulin, triglyceride, free fatty acid, corticosterone, and leptin concentrations. A separate study revealed no phenotypic differences in hepatic expression of peroxisome proliferator-activated receptor (PPAR) a and g, two transcription factors with key roles regulating lipid metabolism and energy balance (Memon et al. 2000). By 9 months of age, constitutive 5-HT2CR - Y mice are significantly more obese than wild-type littermates and demonstrate increased hepatic expression of both PPAR-a and PPAR-g. In these mice, no differences were noted in serum glucose, insulin, triglyceride, free fatty acid, corticosterone, or leptin concentrations. However, constitutive 5-HT2CR - Y mice older than 9 months are much less responsive to 3 days of leptin treatment, showing less blunting of food intake and less short-term decline in body weight. These...

Vitamin A In Diabetes

The level of vitamin A in diabetes has found much attention in recent literature. Vitamin A deficiency may cause blindness. Poorly controlled diabetes mellitus is attributed to a decreased availability of retinol carrier protein and subsequently to depressed vitamin A levels in blood. The impaired vitamin A status may not be improved by vitamin A supplementation but by insulin administration (51). In persons with well-controlled NIDDM without insulin deficiency, the metabolism of vitamin A appears not to be impaired. Interestingly, persons with impaired glucose tolerance show increased (2.5 (imol L) vitamin A versus persons with normal glucose tolerance (2.1 imol L) (46). Most studies demonstrated lowered levels in IDDM, the difference being significant in six studies. Significantly lowered levels in NIDDM were found in two studies (Table 3). The weighed mean values are similar for control subjects and NIDDM and lower for IDDM (control subjects 1.95 0.23 imol L, IDDM 1.52 0.46 nmol L,...

Diabetes And The Pericytecontaining Retinal Microvasculature

Diabetes is the most important disease that affects the function of the retinal micro-vasculature. With the accelerating incidence of diabetes, the number of people at risk for the sight-threatening complications of diabetic retinopathy is increasing at an alarming rate (17). For this reason, there is keen interest in elucidating the mechanisms by with diabetes disrupts vascular function in the retina. Recent experimental studies indicate that ion channels and transporters play important roles in the responses of the retinal microvasculature to diabetes. For more than four decades, attention has focused on the effects of diabetes on the pericyte-containing retinal microvasculature whose loss of mural cells is one of the earliest histopathological signs of diabetic retinopathy (18). More recently, investigators observed that apoptotic death, not only of pericytes, but also of endothelial cells within microvessels of the diabetic retina (19). Unsurprisingly, functional changes in the...

The Effect Of Diabetes On P2x7 Purinoceptors

Kir channels are not the only types of microvascular channels affected by insulin-deficient diabetes. We recently found that the function of the ligand-gated P2X7 purino-ceptors is also altered in microvessels of the diabetic retina (24). These purinoceptors are involved in the vasoconstrictive response of retinal microvessels to extracellular adenosine triphosphate (ATP) (3), which is likely to be a glial-to-vascular signal in the retina. However, in addition to this physiological role, activation of P2X7 purinoceptors can have a pathological effect due to their peculiar ability to cause large transmembrane pores to form (32, 33). These pores, which are permeable to molecules of less than 900 Da, can cause microvascular cell death by disrupting ionic gradients and or by providing pathways for an efflux of vital intracellular molecules (32). Of potential relevance to diabetes, the concentration of P2X7 ligand needed to open pores and to trigger apoptosis is decreased approximately...

Carbonyl Stress In Diabetes

The increase in lipoxidation and glycoxidation products in diabetes is the direct result of an increase in carbonyl precursors however, not all of these intermediates are derived from oxidative reactions. 3DG, for example, is formed nonoxidatively from Amadori compounds (34) or fructose-3-phos-phate (35) and is also increased in diabetes, along with increases in both pyrra-line and 3DG-arginine imidazolone (36) adducts that are derived from 3DG by nonoxidative mechanisms. MGO adducts to protein, including CEL and MOLD, are also increased in diabetes (37,38). Like 3DG, MGO is formed by anaerobic mechanisms, either enzymatically as an intermediate in amino acid catabolism or by (3-elimination reactions of triose phosphates (39,40). However, MGO may also be produced during the oxidative chemistry of both lipids and carbohydrates, so that its precise origin in vivo is unknown. In any case, the increase in 3DG, and possibly MGO, and their adducts to proteins suggests that limitations in...

The Role of Insulin in Glucose Metabolism

Diabetes mellitus (DM) is defined as a disease that results in chronic hypergly-caemia due to an absolute or relative lack of insulin and or insulin resistance, which in turn impairs glucose, protein and lipid metabolism, and finally entrains the characteristic secondary complications.17 According to the definition of WHO, DM is generally classified as either insulin-dependent (IDDM, type 1) or non-insulin-dependent (NIDDM, type 2).18 To treat NIDDM several synthetic organic therapeutics have already been clinically used involving sul-phonylureas, sulphonamides, biguanides and triglydazone, which has recently been developed. However, IDDM can be controlled only by daily injections of insulin. Insulin is a signalling hormone, which is essential for the metabolism of both carbohydrate and fat. It is secreted by the pancreas in response to elevated levels of glucose in the bloodstream. The increased insulin level then normally promotes glucose uptake by the liver and gut as well as by...

Therapeutic Use of Insulin

3 Application of 6.1.3 Treatment of Insulin-induced Hypoglycaemia 58 6.4 Insulin 6.4.3 Treatment of Insulin Allergy 63 6.5 Anti-insulin Antibody 6.5.1 Insulin Autoantibody Hypoglycaemia Syndrome 65 6.6 Insulin 6.6.1 Forms of Insulin 6.6.2 Management of Insulin Resistance 66 6.6.3 Biochemical Defects Causing Insulin Resistance 67 7 Clinical Studies of Insulin-replacement Therapy 69 7.2 Type-I Diabetes 7.2.8 Intraperitoneal Insulin Application 74 7.2.9 Insulin Analogues in Type-I Diabetics 74 7.2.10 Nasal Absorption of Insulin 74 7.3 Type-II Diabetes Insulin is used for the treatment of Type-I and for Type-II diabetes mellitus, when other therapeutic measures, i.e. appropriate diet and oral antidiabetics, are not sufficient to produce normoglycaemia. The physiological actions of insulin including recent advances in our knowledge on signal transduction have been discussed above (chapter 4). Since treatment of diabetes with insulin attempts only to supplement inadequate insulin secretion,...

Clinical Studies on Insulin Lispro 151 Pharmacokinetics and GHucodynamics

Howey and coworkers at the Lilly Clinic in Indianapolis administered the first dose of insulin lispro to humans on July 11, 1990 (90). Immediately, there was great excitement about the potential for this new innovative insulin to make a difference in the lives of people with diabetes. Its more rapid absorption and shorter duration of action compared to regular human insulin was impressive and highly suggestive that insulin lispro could provide better postprandial glucose control at a more convenient injection time (91). These seminal studies were soon followed by numerous other clinical pharmacology investigations comparing insulin lispro with regular human insulin. In their review on the pharmacokinetics and glucodynamics of insulin lispro, Heinemann and Woodworth (92) note that after subcutaneous administration of a clinically relevant range of doses, insulin lispro consistently has a more rapid absorption and elimination profile than regular human insulin. Both insulins are...

Insulin Lispro In Continuous Subcutaneous Infusion Therapy

Insulin treatment regimens designed to mimic natural physiologic responses to meals (bolus insulin) coupled with the need to suppress hepatic glucose production between meals (basal insulin) are very demanding and imprecise. Continuous subcutaneous insulin infusion, or CSII, via programmable external infusion pumps, is an alternate method for insulin administration and theoretically provides the opportunity for more ideal basal bolus therapy. The advent of insulin lispro has stimulated investigations comparing this new insulin analogue with regular human insulin in CSII regimens (102-106). Zinman et al. (102) studied 30 patients with type 1 diabetes in a double-blind crossover study (3 months each insulin) in which the before-meal boluses of both insulins were given immediately before breakfast, lunch and supper. The 1-hour postprandial blood glucose levels were lower during insulin lispro therapy and HbAic was significantly reduced when compared to regular human insulin (8.00 0.16...

Insulin Lispro and Improved Quality of Life

The more rapid onset and shorter duration of action of insulin lispro provides for more convenient insulin therapy. This characteristic is vital for lifestyle benefits. Being able to inject insulin closer to meals not only gives patients better postprandial glucose control, it also allows flexibility to a person's lifestyle. A major quality-of-life study was conducted by Kotsanos et al. (114) comparing health-related quality-of-life parameters in patients receiving either insulin lispro or regular human insulin. Primary analyses showed that treatment satisfaction scores and treatment flexibility scores were higher for insulin lispro in patients with type 1 diabetes. Similar results were obtained in a smaller study by Desmet et al. (115).

Oxidative Stress And Antioxidant Treatment Effects On Neurovascular Function In Experimental Diabetes

Figure 2 Effects of diabetes and antioxidant treatment with a-tocopherol on endo-thelium-dependent relaxation of phenylephrine-precontracted aortas to acetylcholine in vitro. Groups ( 14-17) nondiabetic control (O) 8-week streptozotocin-diabetic ( ) a-tocopherol (1 g kg day) treated from diabetes induction ( ). (From Ref. 39.) Figure 2 Effects of diabetes and antioxidant treatment with a-tocopherol on endo-thelium-dependent relaxation of phenylephrine-precontracted aortas to acetylcholine in vitro. Groups ( 14-17) nondiabetic control (O) 8-week streptozotocin-diabetic ( ) a-tocopherol (1 g kg day) treated from diabetes induction ( ). (From Ref. 39.) In rats, the diabetes-induced decrease in sciatic nutritive blood flow was accompanied by a reduction in mean endoneurial oxygen tension, which was prevented by probucol treatment (49). In nondiabetic rats, prooxidant treatment with the antimalarial drug primaquine mimicked the reductions in blood flow, endoneurial oxygen tension, and NCV...

Application of Insulins

The particular insulin employed, such as human or animal, the type of formulation, the route of administration, and the frequency of administration must be chosen to suit the needs of the individual patient. The dose must also be determined for each patient, and, although a precise dose range cannot be given, a total dose in excess of about 80 units daily would be unusual and may indicate the presence of a form of insulin resistance (Martindale, 1989). The short-acting insulins are usually injected between 30 and 45 min before meals. The intermediate-acting insulins should be given once a day before breakfast or twice a day, the long-lasting insulins are given three times on the first day as a loading dose and then as one or two injections per day, the dosage being adapted as required to maintain near normoglycaemic blood glucose levels (Kahn and Schechter, 1990).

Diabetes and Pre Diabetes in the General Population

Diabetes (DM) type 2 is highly prevalent worldwide in 2008 and will have increasing prevalence through until at least 2025 coincident with a global obesity epidemic 2 . Diabetes type 1 is a very different disorder that is predominantly genetically inherited and in which obesity is not an important risk factor. Worldwide there are substantial regional variations with Africa having the lowest prevalence. In Europe, prevalence will increase from around 6 in 2008 to 8 in 2025 in the 20-79 age group and in some regions will increase to over 10 2 . The worldwide prevalence of DM was 5.1 in 2003 and will rise to 6.3 by 2005. In the UK it is estimated that by 2010 DM will be diagnosed in 7 of men and 5 of women 3 . In addition, impaired glucose tolerance (IGT) will rise from 8.2 in 2003 to 9 in 2005. The sheer relevance of these data is encapsulated in the single statistic that in 2007 3.8 million deaths will be due to DM globally 4 . Complications of DM are of concern on many levels in that...

Clinical Studies of Insulinreplacement Therapy

Clinical studies concerned with recent advances in the understanding of insulin effects predominantly applied knowledge on the physiology of insulin regulation as a prerequisite for achieving near normoglycaemic status in diabetic patients. There is now compelling evidence that a relationship exists between good metabolic control and development of late diabetic complications (DCC Trial, 1993). Other major points of interest in clinical trials are hyperinsulinaemia and insulin resistance as a common denominator of the metabolic syndrome, hyperinsulinaemia as an independent predictor of coronary heart disease, and the efficacy of new insulin analogues.

Typeii Diabetes Mellitus

In IDDM, insulin is needed, by definition, to preserve life. It is generally agreed that near-normoglycaemia can be achieved only by MDI of short- and intermediate-acting insulin. There is less consensus with regard to non-insulin-dependent (Type-II) diabetic patients about when to use what medication, and particularly at what point insulin therapy is appropriate. The natural history in obese Type-II diabetes patients usually starts with both impaired B-cell function and insulin resistance and or basal hyperinsulinaemia resulting in elevated fasting blood glucose levels. Reaven (1988) suggested that insulin resistance might be a common denominator for obesity, Type-II diabetes hypertension and hyperlipidaemia (metabolic syndrome) and should be treated rigorously to avoid coronary heart disease, the most common cause of morbidity and mortality in Type-II diabetes mellitus. However, it still remains to be proven that effective blood glucose control will reduce the mortality of the...

Laminaria japonica as a Food for the Prevention of Obesity and Diabetes

Diabetes 205 B. Antidiabetic effects of seaweeds 205 food additives, and foodstuffs in many countries, especially those in Asia. The seaweed Laminaria jap nica (LJ) is popular as kombu in Japanese cuisine. Laminaria sp. is one of the most important marine medicinal foodstuffs, as its biological functions have been widely investigated in both in vitro and in vivo experiments. This chapter introduces recent reports on the ability of Laminaria to prevent obesity and diabetes, and some approaches for effectively using the bioactivities found in Laminaria. The inhibitory effects of Laminaria sp. on triglyceride absorption were investigated in triglyceride-loaded mice and in mice with high-fat-diet-induced obesity. Shaved Laminaria, known as tororokombu, showed more effective activities in

Oxidative Stress In Patients With Diabetes Mellitus

Several studies have shown that increased production of reactive oxygen species and antioxidant depletion occurs in patients with diabetes mellitus (1 -11). Oxidative stress may lead to endothelial cell damage and vascular dysfunction through various mechanisms (12-32). Lately, considerable effort has been devoted to gain insights into the role of oxidative stress in the development and progression of late micro-and macrovascular complications in diabetes (17,23,27,28,31-34). Although hyperglycemia is an acknowledged pathogenic factor in diabetic complications, it is not known through which mechanism an excess of glucose results in tissue damage. Accumulating data support the hypothesis that oxidative stress might play an important role in the pathogenesis of late diabetic complications. Several pathways are leading to oxidative stress associated with acute or chronic hyperglycemia, such as the polyol pathway, prostanoid synthesis, glucose autoxidation, and protein glycation by...

Role of ROS in the Regulation of Insulin Receptor Tyrosine Kinase Activity

Signaling by insulin involves autophosphorylation of the insulin receptor kinase domain at Tyr1158, Tyr1162, and Tyr1163. In line with the oxidative inhibition of tyrosine phosphatases by (approximately millimolar concentrations of) hydrogen peroxide or other strong oxidants (see previous section), it was found that similar strongly oxidative conditions enhance the tyrosine phosphorylation of the insulin receptor h-chain in an insulin-independent fashion. Lower and physiologically relevant concentrations (< 100 M) of hydrogen peroxide, in contrast, do not induce phosphorylation in the absence of insulin but enhance the response to insulin in a synergistic fashion 146 . More recent experiments have shown that the stimulatory effect of hydrogen peroxide can be demonstrated on highly purified preparations of the insulin receptor kinase domain, indicating that the insulin receptor kinase domain serves by itself as a redox-sensitive signaling compound (W. Droge, unpublished observation)....

Antidiabetic effects of seaweeds

Vaugelade et al. (2000) investigated the possible effects of algal poly-saccharides on postprandial blood glucose and insulin responses in pig. Three seaweed fibers of different viscosities, extracted from Palmaria palmata (PP), Eucheuma cottonii (EC), or LD, were compared with purified cellulose (CEL). The addition of LD to the diet resulted in a dramatically reduced glucose absorption balance, accompanied by a higher amount of starch left in the small intestine. This study demonstrated that highly viscous alginates could affect the intestinal absorption of glucose and the insulin response. Related studies on the bioactivity of LJ have also been reported. Jin et al. (2004) investigated the preventive effects of LJ aqueous extract (LJE) on alterations in the activity of hepatic xanthine oxidase and oxidative stress in streptozotocin-induced experimental diabetes. Pretreatment with LJE at 100 mg kg orally for 5 days significantly reduced blood glucose levels and hepatic lipid...

Formation of AGEs in Diabetes

AGE formation proceeds slowly under normal glycemic conditions but is enhanced in the presence of hyperglycemia, oxidative stress, and or conditions in which protein and lipid turnover are prolonged. For example, V-epsilon-(carboxymethyl)lysine (CML), one of the various AGE structures postulated to date, has been found to be a product of both glycoxidation (combined non-enzymatic glycation and oxidation) and lipid peroxidation reactions (53). CML and pentosidine have been shown to accumulate in diabetic kidneys in colocal-ization with a marker of lipid peroxidation (MDA), suggesting an association of local oxidative stress with the etiology of diabetic glomerular lesions (54). Evidence for an age-dependent increase in CML accumulation in distinct localizations and acceleration of this process in diabetes has been provided by immunolocalization of CML in skin, lung, heart, kidney, intestine, intervertebral discs, and particularly in arteries (55). In diabetic kidneys, AGEs were...

Antioxidant Vitamins and CoQ10 in Diabetes in Relation to Vascular Disease

The evidence concerning the role of antioxidants and free radicals in human diabetes is limited (Oberley, 1988 Packer, 1993 Wolff, 1993). A low intake and plasma level of vitamins C and E and p-carotene has been observed in patients with diabetes compared to control subjects (Tables 16.1-16.4). Oxidative stress seems to play an important role in the development of diabetes and CVD. In several of our clinical and epidemiological studies, we have reported that plasma levels of lipid peroxides are significantly higher among patients with diabetes and CHD compared to healthy subjects (Tables 16.1-16.3). Those diabetics with vascular complications tend to have higher lipid peroxide levels compared to diabetics without such complications (Table 16.4). Bambolker and Sainani (1995) also reported greater oxidative stress in diabetics with complications compared to those with uncomplicated diabetes. There is increased utilization of antioxidant vitamins and ubiquinol in diabetes. Plasma copper...

Risks For Obesity Diabetes And Cardiovascular Disease 41 Obesity

Obesity is a major public health problem in the United States, with an increasing prevalence in both adults (37,38) and children (39). Obesity increases the risk of morbidity and mortality from associated diseases such as diabetes, hypertension, coronary heart disease, and cancer (40-42). Diets have been the traditional approach to dealing with excessive weight. Robert Atkins (43) popularized the use of the ketogenic diet to deal with weight gain. This type of ketogenic diet is a low-carbohydrate but high-protein formulation and consequently is fundamentally different from diets used for seizure control. The Atkins diet is based on the premise that control of insulin is essential for weight loss and associated beneficial effects in reduction of diabetes and cardiovascular risk. By reducing carbohydrate intake to a negligible level, the diet attempts to eliminate insulin fluctuations that might occur after a typical meal. It is important to note that while this diet does not limit...

Ischemiareperfusion In Diabetes Mellitus

Microvascular dysfunction has been studied extensively in animal models. One of the most widely used models is streptozotocin-induced diabetes in the rat. In this model, rats are treated with a single toxic dose of streptozotocin, which destroys the islets of Langerhans (27). The effect of hyperglycemia on the microvasculature is then evaluated after 4-12 weeks (21,28-37). Gly-cemic control by insulin treatment can prevent the microvascular dysfunction. In diabetic humans, metabolic status is not stable, and episodes of normogly-cemia are followed by phases of hyper- and hypoglycemia. Thus, blood sugar levels vary considerably, and in consequence to the pathophysiological changes presented above, the status of oxidative stress changes and blood flow will go up and down. Therefore, it is reasonable to assume that under realistic conditions, a diabetic patient undergoes episodes of ischemia and reperfusion during the time until manifestation of microangiopathy. The time intervals of the...

Pharmacokinetic And Pharmacodynamic Case Example In Insulin

IN administration of insulin provides an attractive option for a noninvasive diabetes treatment. Currently, marketed prandial (meal time) insulin products are dosed by injection immediately before each meal, posing a barrier among patients and physicians to initiate therapy. The rapid PK profile of IN insulin also offers the potential to reduce postmeal hypoglycemia caused by longer halflife insulin preparations. To identify promising IN formulations, an in vitro model system was employed to monitor reduction in transepithelial electrical resistance (TER), cellular toxicity, and permeation. From this HTS process, formulations that provided up to 105-fold increase in in vitro permeation relative to a simple formulation devoid of enhancers were identified. We have previously reported (104) the assessment of PK parameters following instillation (15 pL kg) of IN insulin formulations in New Zealand white rabbits. IN insulin provided 9 to 19 bioavailability relative to SC NovoLog injection...

Exocytosis of Insulin from the Pancreatic Pcell 1611 Introduction

Blood glucose concentrations are tightly regulated in the healthy indi- control of blood glucose vidual. This is accomplished through the fine tuning of insulin secretion by insulin from the (3-cells in the pancreatic islets and the subsequent action of insulin on its target tissues. Failure of the (3-cells to release insulin promptly during food intake, as well as resistance to the action of the hormone, lead to various forms of diabetes mellitus (Polonsky, 1995, Turner et a ., 1995). Insulin is stored in crystals in secretory vesicles (secretory granules), of which only a small proportion is liberated even under maximal stimulation. The secretory process, rather than the biosynthesis of the hormone, therefore constitutes the primary determinant of the concentration of insulin in the circulation. The secretion rate is the result of the dynamic interactions of a large number of stimulatory and inhibitory modulators. Glucose and leucine, as well as certain other nutrients, are...

Modulation of Insulin Secretion via Adenylate Cyclase and Phospholipase C PLC

As discussed in section 3, insulin secretion is initiated through depolarization and subsequent opening of L-type Ca2+ channels. It has also been suggested that here insulin secretion and Ca2+ uptake may be modulated by nutrient metabolism, especially glucose, probably by changing islet nicotinamide nucleotide thiol redox status. Other possibilities for modulation of insulin release come from factors affecting the adenylate cyclase and PLC systems through activation of protein kinases and release of Ca+ from intracellular stores. The modulating agents include hormones from the entero-insular axis, neurotransmitters and neuropeptides from pancreatic nerves and last but not least intraislet hormones (see also section 2). Similar to other tissues, insulin-producing cells possess an adenylate cyclase-cAMP system including stimulatory and inhibitory G-proteins and phosphodiesterases. It is generally agreed that the role of cAMP in insulin secretion is not an initiating one, but, by...

Role of Ca2 and Rab3A in Insulin Exocytosis

The Ca2+-and phospholipid-binding protein synaptotagmin is also expressed in insulin-secreting cells (Lang and Wollheim, unpublished, Jacobsson et al., 1994). It should be noted that the affinity for Ca2+ of neurotransmitter exocytosis (S dhof, 1995) is two orders of magnitude lower than the 1 -2 iM Ca2+ affinity reported for insulin exocytosis (Bokvist et al., 1995, Vallar et al., 1987, Ullrich et al., 1990). The latter process is similar to the slow secretion of peptide neurotransmitters stored in LDCVs. As with LDCVs, insulin secretory granules are not clustered at active zones, as is the case for synaptic vesicles. The short distance between the N-type Ca2+ channels and the synaptic vesicles is thought to explain the high Ca2+ concentrations required for the fast synaptic release. The greater distance between L-type Ca2+ channels and the LDCVs, as well as insulin secretory granules, allows for buffering of Ca2+ following channel gating, and would explain the higher affinity of the...

Potential Role of Antioxidant Supplementation on Complications of Diabetes

Our body is continuously generating ROS, collectively called oxidative stress. If not detoxified, ROS can result in oxidative cellular damage and impaired body functions. For example, increased oxidative stress can cause oxidative modification of plasma lipoproteins, associated with an increased risk of atherosclerosis and CVD. A number of studies have provided increasing evidence that elevated glucose levels can generate ROS such as superoxide, hydroxyl and hydrogen peroxide in cell-free systems, endothelial cells and RBC (Jain, 1989 Jain et al., 1989b, 1991 Rajeshwari et al., 1991). Oxidative stress is increased in different tissues in both experimental diabetes and in diabetic patients. Long-term effects of diabetes include glycation of proteins, increased risk of CVD, atherosclerosis, retinopathy, nephropathy and neurological dysfunctions. A similar abnormality can be induced in vitro or in animal models under conditions of increased oxidative stress, which suggests that increased...

Vitamin E Supplementation and CVD Risk Factors in Diabetes

Clinical trials in type II diabetic patients have shown that supplementation with pharmacological doses of vitamin E (900-2000 IU day-1 for 2-4 months) results in both a decrease (Ceriello et al., 1991 Paolisso et al., 1993 Jain et al., 1996) and no effect (Reaven et al., 1995 Fuller et al., 1996) on blood glycosylated haemoglobin (GHb) a decrease (Bierenbaum et al., 1985) and no effect on blood glucose (Ceriello et al., 1991 Paolisso et al., 1993 Reaven et al., 1995 Jain et al., 1996a) a decrease (Bierbaum et al., 1985 Ceriello et al., 1991 Jain et al., 1996a) and no effect (Reaven et al., We have recently carried out the first trial on type I diabetic patients. We examined the effects of daily supplementation with vitamin E on blood GHb, glucose, TG and cholesterol levels. Since blood GHb can be affected by the red cell count, we also determined the effect of vitamin E on red cell indices, not previously examined in any of the clinical trials with diabetic patients. In a randomized...

Concept of Initiation and Modulation of Insulin Secretion

A hypothetical scheme for the machinery of insulin release assuming coupling of initiation and modulation to the process of granule movement-exocytosis is given in Fig. 20. Fig. 20. Hypothetical model of how insulin secretion is regulated. The most important event is the depolarization of the B-cell which causes Ca+ influx along L-type Ca2+ channels and subsequent increase in cytosolic Ca+. Depolarization is produced by nutrient (glucose) metabolism via an increase in B-cell ATP and or ATP ADP ratio which closes KAXP channels. Also, sulphonylureas, at a distinct location, close KATP channels. The increase in Ca + j activates CaCaMK. Ca uptake appears to be modulated by nutrient metabolism (redox state of NAD(P)H and GSH). Insulin release in response to depolarization is also modulated by factors affecting PLC and adenylate cyclase. Here, production of IP3 leads to release of stored Ca2+ from the endoplasmic reticiulum. DAG activates PKC whereas cAMP activates PKA. CaMK, PKC and PKA...

Oral Human Insulin Expectations Vs Challenges

Among protein and peptide drugs, the oral delivery of insulin has received the widest attention. The development of oral insulin has long been regarded as the Holy Grail of drug delivery, as developers search for a replacement to daily injections, particularly for young diabetic children who often have problems with injections. An oral insulin product would have tremendous benefits by decreasing the number of injections for diabetic patients and reducing the incidence of side effects (42,43). The development of oral insulin has been at different stages for different companies and covered a broad spectrum, from preclinical testing to phase II clinical trials (44). A notable advancement is the completion of phase II trials in two oral insulin products Nobex's oral HIM2 (45) and Emisphere's oral Eligen insulin pill (46). The carrier-enhanced insulin permeability across the GI membrane barrier makes the drug absorption possible, while the drug available for transport is site and time...

Specific Considerations for the Study of Insulin Secreting Cells

Insulin-secreting cells do not express the receptors required for entry of the neurotoxins. Consequently, the cells need to be permeabilized before the addition of the neurotoxins. SLO has been shown to produce holes in the plasma membrane of several cell types that allow the passage of molecules up to 150 kDa. The permeabilization procedure with SLO described above yields reproducible results in insulin-secreting cells and is, therefore, the method of choice to test the effect of neurotoxins in these cells. Thus, if the stimulation of the cells is delayed by 30min, Ca2+-induced exocytosis is greatly reduced. Therefore it is necessary to find a compromise to ensure adequate cleavage of VAMPs while preserving appropriate exocytotic responses of the cells. For our experiments we chose an 8min TeTx pretreatment of the cells. In insulin-secreting cells, 8min was found to be sufficient for 50 nM TeTx to digest between 80 and 90 of VAMP-2 and cellubrevin (VAMP-1 is not expressed at...

Inconsistencies in the Research Literature Regarding the Putative Brattleboro Diabetes Insipidus Retention Deficit

Colombo et al. (1992) used a delayed alternation T-maze task, with varying intertrial intervals, to assess ability to retain spatial information in memory using a recently developed VP-deficient strain of rat. Relative to M520 NO rats, M520 DI rats exhibited diabetes insipidus and were significantly impaired in memory on this task. M520 HZ rats did not display diabetes insipidus and their task performance was intermediate between that of M520 DI and M520 NO rats.

Oxidative Stress and Pancreatic pCell Destruction in Insulin Dependent Diabetes Mellitus

Insulin-dependent diabetes mellitus (IDDM) is considered to be an autoimmune disease (1,2). Recent reports suggest that reactive oxygen species (ROS) participate in the development of IDDM (3,4). Thioredoxin (TRX) is a small (12 kDa) reduction oxidation (redox) protein (5,6) and has protective effects on cells against oxidative stress by scavenging ROS (5-7), by repairing DNA and proteins damaged by ROS (5-8), and by blocking apoptosis induced by ROS (6,9). Nonobese diabetic (NOD) mice are well known as an excellent animal model for human IDDM (10-12). To elucidate the roles of oxidative stress in autoimmune diabetes, we generated NOD transgenic mice overex-pressing TRX exclusively in pancreatic 3-cells. Spontaneous diabetes was prevented or delayed in the NOD transgenic mice. The results indicate that ROS in pancreatic P-cells may play an essential role in the development of IDDM.

B A Role for Decreased mtDNA Transcription in Diabetes Associated Mitochondrial Dysfunction

Studies of liver mitochondrial function in diabetic animals provide evidence for chronic, progressive impairment of the mitochondrial gene expression system in vivo. It has been known since the 1950s that uncontrolled type I diabetes can lead to frank defects in respiration rates and respiratory control ratios (Hall et al., 1960 Mackerer et al., 1971 Harano et al., 1972 Rinehart et al, 1982 Churchill etal., 1983 Pierce and Dhalla, 1985 Rogers et al., 1986 Bedetti etal., 1987 Grinblat etal., 1988 Brignone etal., 1991 Tanaka et al., 1992 Mokhtar et al, 1993 Memon et al, 1995). A role for the loss of transcription in overt mitochondrial respiratory failure is supported by observations of decreased protein synthesis in diabetic mitochondria (Rinehart et al, 1982 Memon et al, 1995). The diabetic model was therefore used to test whether mtDNA transcription decreases at or before the stage of disease in which overt respiratory dysfunction begins. Studies indicate that the transcription of...

Preventive Effects Of Trx Overexpression Against Autoimmune Diabetes In Vivo

To directly assess the roles of oxidative stress in (3-cell destruction in autoimmune diabetes, we generated NOD transgenic mice overexpressing TRX exclusively in p-cells. The incidence of diabetes in NOD transgenic mice was b. Insulin contents of pancreas remarkably reduced compared with their negative littermates. Although the incidence of diabetes was reduced, the severity of insulitis before overt diabetes was not significantly different between NOD transgenic mice and their negative littermates. To study the protective effects of TRX against ROS-generating agents, we produced (NOD X C57BL 6J (B6)) F1 transgenic mice and injected the ROS-generating agent STZ into them (Fig. 3). The elevation of blood glucose levels in (NOD X B6) F1 transgenic mice was reduced and the reduction of insulin contents was suppressed compared with their negative littermates. These results suggest that ROS play pivotal roles in (3-cell destruction, in autoimmune diabetes and in STZ-induced diabetes.

Insulin Resistance A Key Factor In Type 2 Diabetes

Insulin is the predominant hormone responsible for the maintenance of glucose homeostasis through its regulation of metabolic activit s in muscle, liver, and adipose tissue. Insulin causes an increase in glucose uptake into peripheral tissues, specifically muscle and fat cells conversely, in the liver, the hormone decreases gluconeogenesis, thereby reducing hepatic glucose output. Insulin is also responsible for the promotion of protein synthesis. These effects result from both rapid and long-term metabolic actions of the hormone (1). One hundred million people worldwide suffer from type 2 diabetes (2), yet despite intense research, the primary lesion(s) responsible for type 2 diabetes remains unknown. The genetic susceptibility of this disease fails to follow simple Mendelian inheritance but is of a polygenic nature with superimposed environmental influences (3). An aggregation of small genetic effects rather than the effect of one single gene, gene-to-gene, and gene-to-environment...

Molecular Basis of Insulin Action and Insulin Resistance in Peripheral Tissues

To understand the molecular basis of insulin resistance (whether primary or secondary) in muscle and fat cells, it is imperative to gain knowledge of the normal mechanisms of insulin action. In these tissues, insulin stimulates glucose uptake by rapidly mobilizing preexisting glucose transporters (primarily the GLUT4 isoform) from an intracellular storage organelle (or vesicle) to the plasma membrane (5,6). This is achieved by a series of signals elicited from the receptor, which are detected in an unknown fashion by the intracellular organelle. The latter is then free to find and interact with docking sites on the plasma membrane (7) that will ultimately enable fusion of the two membranes to provide functional glucose transporters. Detailed knowledge has emerged on the signals emanating from the receptor that are essential for GLUT4 translocation and the nature of the proteins engaged in vesicle docking and fusion with the plasma membrane. The signaling events involved in the...

Factors That May Trigger Insulin Resistance

It has been suggested that circulating and metabolic factors could play an important role in the etiology of insulin resistance. This is supported by the observation that insulin resistance of in vitro muscle preparations can be reversed by incubation in solutions of normal insulin and glucose levels (40). Circulating factors, such as tumor necrosis factor-a (TNF-a) and free fatty acids (FFA), and intracellular metabolites, such as glucosamine, can induce an insulin-resistant state in vitro and may contribute to the development of insulin resistance in vivo. The level of expression of adipose tissue TNF-a, a multifunctional cytokine, rises as a consequence of obesity. It is also closely correlated with circulating insulin levels, which serve as an index of insulin resistance, (41) and is expressed in increased levels in skeletal muscle of individuals with insulin resistance (42). Mice homozygous for a targeted null mutation in the TNF-a gene were significantly less insulin resistant...

Aldose Reductase Inhibitors as New Antidiabetic Drugs

8.4 Effect on Diabetic Increased aldose reductase activity is observed in tissues which are affected by complications of diabetes mellitus. The possible participation of the polyol pathway in the pathogenesis of these complications led to detailed evaluation of the role of this system both to improve the understanding of diabetes mellitus and to open up new therapeutic possibilities in the prevention of complications. The underlying therapeutic idea is to prevent lesions caused by high glucose concentrations. This seems to be possible for those tissues with insulin-independent glucose uptake and high activity of the polyol pathways (for a detailed review on aldose reductase see Sarges, 1989).

Origin of Oxidative Stress in Type 2 Diabetes

Suspected causative agents of the increased level of oxidative stress associated with type 2 diabetes are hyperglycemia, hyperinsulinemia, and an alteration of serum antioxidant activity (Fig. 3). Figure 3 How oxidative stress may arise in diabetes. The characteristic high levels of glucose and insulin observed in type 2 diabetes may contribute to oxidative stress through the production of free radicals, protein oxidation, and by depletion of intracellular reductants and antioxidants. This increased level of oxidative stress may be attributed to the increased levels of glucose oxidation, glycation, increased activity of the polyol pathway, sympathetic nervous system overdrive, and elevated nonesterified free fatty acid (NEFA) concentrations resulting from high levels of glucose and insulin.

Can Oxidative Stress Cause Insulin Resistance

The question of precedence between hyperinsulinemia and oxidative stress into the subsequent development of diabetes remains unanswered (64). The studies mentioned above suggest that at least the secondary hyperinsulinemia could plausibly precede or cause increased free radical production and the resulting oxidative stress. Further studies are necessary to address whether oxidative stress, as a result of hyperinsulinemia-mediated increased free radical production, could precede insulin resistance and lead to the onset of diabetes. To date there is no evidence that primary insulin resistance is linked to oxidative effects. The following sections analyze two emerging lines of study in this direction. 1. Oxidative Stress, Antioxidants, and Insulin Resistance In Vivo There is little evidence for a role of antioxidant therapy in the prevention of insulin resistance and type 2 diabetes. Serum of individuals with type 2 diabe tes have a lower vitamin E level and a higher GSH GSSG ratio...

D aLipoic Acid Stimulation of Glucose Uptake via Components of the Insulin Signaling Pathway

A-Lipoic acid has been shown in vitro to stimulate glucose utilization in isolated rat diaphragms (115), to enhance insulin-stimulated glucose metabolism in insulin-resistant skeletal muscle of obese Zucker rats (116), and to stimulate glucose transport activity in skeletal muscle isolated from both lean and obese Zucker rats (117). In streptozotocin-diabetic rats, chronic a-lipoic acid treatment reduced blood glucose concentrations by enhancement of muscle GLUT4 content and increased muscle glucose utilization (118). In addition, acute and repeated parenteral administration of a-lipoic acid improved insulin-stimulated glucose disposal in individuals with type 2 diabetes (110,119), strengthening its therapeutic value as an antidiabetic agent. Estrada et al. (120) established the ability of a-lipoic acid to stimulate glucose uptake into the insulin-responsive L6 skeletal muscle cells and 3T3-L1 adipocytes in culture. The naturally occurring (R)+ isoform of lipoic acid was shown to have...

Glucagon In Diabetes Mellitus

Plasma glucagon concentrations are elevated in poorly controlled diabetic patients. Because it enhances gluconeogenesis and glycogenolysis, glucagon exacerbates the hyperglycemia of diabetes. However, this abnormality of glucagon secretion appears to be secondary to the diabetic state and is corrected with improved control of the disease. Although somatostatin-mediated inhibition of glucagons secretion does not restore glucose metabolism to normal, it significantly slows the rate of development of hyperglycemia and ketonemia in insulin-deficient subjects with type 1 DM. In normal individuals, glucagon secretion increases in response to hypoglycemia, but this important defense mechanism against insulin-induced hypoglycemia is lost in type 1 DM.

Diabetes And Retinal Vitamin C Status

Diabetes is associated with hyperglycemia and glucose-induced generation of reactive oxygen species. Both of these factors are directly relevant to the transport and biologic functions of vitamin C. The neural retina relies on the transfer of DHAA from the peripheral circulation across the inner blood-retinal barrier, as well as across the outer blood-retinal barrier, to meet its requirements for ascorbate. In both cases, the transfer process is mediated by GLUTI. Since this transporter handles glucose as well as DHAA, diabetes-associated hyperglycemia is likely to interfere with the transfer of DHAA into neural retina, due to increased competition with DHAA by glucose for the transport process. Therefore, it is likely that the delivery of vitamin C to the neural retina is impaired in diabetes. At the same time, glucose-induced production of reactive oxygen species in diabetes increases the oxidative burden on the retina, and consequently enhances the requirements for ascorbate for...

Iiinsulin Resistance In Diabetes

Insulin resistance is defined as a reduced ability of insu, n to activate specific insulin-dependent biological processes in cells of target organs. In poorly controlled type 1 diabetes, insulin resistance is thought to be a secondary effect of the dyslipidemic state (elevated free fatty acids) and the prolonged hyperglycemic state. In type 2 diabetes, insulin resistance of skeletal muscle glucose disposal is generally considered to be a primary factor in the etiology of this disease. In this latter state, the skeletal muscle insulin resistance is often accompanied by a variety of other metabolic abnormalities, including obesity, dyslipidemia, hypertension, and atherosclerosis (17-19), a condition referred to variously as syndrome X (18,19) or the insulin resistance syndrome (17). The link among these disorders has been attributed to hyperinsulinemia, a consequence of the insulin resistance (17). Indeed, the increased cardiovascular mortality associated with this condition has been...

Metabolic Disorders Diabetes Mellitus

Diabetes comprises a group of metabolic disorders characterized by a defect in insulin secretion and or insulin insufficiency leading to a disturbed glucose homeostasis and to hyperglycemia. The current classification of diabetes distinguishes among (i) type 1 diabetes, which is the result of p-cell destruction leading to absolute insulin deficiency (formerly insulin-dependent diabetes) (ii) type 2 diabetes, characterized by insulin resistance with relative insulin deficiency (formerly noninsulin-dependent diabetes) (iii) gestational diabetes, which has its time of first recognition during pregnancy, and (iv) other types of diabetes (44). In subjects with undiagnosed or poorly controlled diabetes, chronic hyper-glycemia causes micro- and macroangiopathies with subsequent dysfunction and multiple organ failure of primarily the visual, kidney, nerve, and cardiovascular systems. A number of hypotheses exist on the origin of these complications apart from hyper-glycemia, such as oxidative...

Diabetes Mellitus Type

Low vitamin E status is regarded as a potential risk factor for the development of type 1 diabetes (53) this is likely because oxidative stress plays a role in the autoimmune processes leading to destruction of the p cells in the pancreas (54). Vitamin E has proven beneficial for patients with type 1 diabetes, ameliorating several disease parameters. In diabetic children, supplementation with vitamin E (100 iu d for 3 mo) significantly lowered malondialdehyde (MDA) and increased glutathione (GSH) levels in erythrocytes the intervention also reduced hemoglobin Alc (HbAlc) levels in erythrocytes, which is a marker for protein glycation and severity of disease (55). In another trial with type 1 diabetic patients, vitamin E (750 Iu d for 1 y) did not significantly change antioxidant capacity and blood viscosity or lipid composition of ery-throcytes however, an improvement in the susceptibility of lipoproteins to oxidation was observed (56). Vitamin E supplements also improve vascular...

Oxidative Stress And Insulin Sensitivityclinical Observations

Paolisso et al. (25) demonstrated close correlations between the presence of (K and insulin sensitivity in an elderly nondiabetic population. Epidemiological studies found a close correlation between low levels of antioxidants, such as vitamin E or vitamin C, and a high risk of developing frank type 2 diabetes (26,27). Several groups report a higher prevalence of radical oxygen species in prediabetic individuals who had an impaired oral glucose tolerance test (17-19). An increase in plasma thiobarbituric acid reactive substance (TBARS) was found in healthy subjects when free fatty acids (FFA) were experimentally kept elevated by an infusion of intralipid and heparin (28) under these experimental conditions, insulin sensitivity was markedly reduced (28). It could thus be speculated that the elevation of FFA seen in patients with type 2 diabetes or with insulin resistance (29) could be a source for such an augmented oxidative stress.

Role Of Impaired Insulin Action In The Pathogenesis Of Type 2 Diabetes Mellitus

In type 2 diabetes mellitus, plasma glucose levels are elevated as a result of an impairment of several metabolic pathways (29-31) (Table 1). Skeletal muscle is the principal organ for postprandial glucose uptake (29,30). In the pathogenesis of diabetes mellitus type 2, reduced insulin-stimulated glucose disposal (insulin resistance) plays a key role (21,29). When clearance of plasma glucose is impaired, blood glucose after a meal will remain slightly elevated Table 1 Metabolic Alterations in Type 2 Diabetes Diminished insulin-mediated peripheral glucose disposal and metabolism (insulin resistance) Impaired insulin secretion (reduced first-phase response, prolonged second phase) Decreased insulin-mediated inhibition of lipolysis Increased gluconeogenesis and will thus induce hyperinsulinemia to overcome resistance (Fig. 1). Hyper-insulinemia, however, will evoke an alteration of the insulin-signaling cascade, which will further augment insulin resistance, thus leading to a vicious...

Homocysteine NO and Insulin Sensitivity

Homocysteine levels were found to be significantly higher in patients with coronary artery disease and in those with diabetes mellitus (50-54). Elevated homocysteine levels induce oxidative stress and reduce NO availability (55) this can contribute to endothelial dysfunction. It seems possible that hyperho-mocysteinemia could also alter insulin sensitivity by this mechanism. Therefore, it remains to be clarified whether there are any interactions between elevated homocysteine levels and the development of insulin resistance in nondiabetic subjects. The interesting observation of an augmented oxidative stress, insulin resistance, and elevated homocysteine levels in smokers (14,23,24,50) suggests some interactions. However, this still remains to be evaluated.

Mood Stabilizers and Impact on Insulin Resistance in Women with Bipolar Disorder

Women with BD are often treated with psychotropic agents, including mood stabilizers, atypical antipsychotics, and antidepressants, whose effects on reproductive function and IR are not fully understood. Medications may impact weight and endocrine abnormalities in a variety of ways that contribute to IR. For example, it has been theorized that valproate can influence the development of menstrual abnormalities by decreasing estrogen levels, increasing luteinizing hormone and increasing testosterone 54 . The increase in testosterone can lead to an arrest in maturation of ovarian follicles, leading to the development of polycystic ovaries. Additionally, valproate may cause an increase in leptin resulting in increased body weight 54 , or lead to glucose-stimulated insulin secretion by pancreatic cells 55 . Weight gain itself, not specific to valproate use, may lead to menstrual abnormalities or IR. In our studies, we demonstrated a correlation between BMI and both testosterone and insulin...

Propylene Glycol Diabetic Insulin

Conversely, salting out results from interfacial effects of strongly hydrated ions near the protein essentially removing water molecules and desolvating the surface. For example, the solubility of human insulin-like growth factor (hIGF) in 140 mM benzyl alcohol and 145 mM NaCl increased aggregation and decreased solubility (Fransson et al., 1997 Kim and Dordick, 1997). Usually, as the ionic strength increases, first a slight salting in effect is observed, followed by a salting out effect. Stoichiometric ratios of anionic detergents, such as sodium dodecyl sulfate (SDS), have been used to complex peptides and increase their partition coefficient into non-polar solvents by two- to four-fold (Powers et al., 1993). For example, insulin was complexed with SDS and resulted in a ten-fold increase in solubility in 1-octanol. The insulin remained in its native conformation with increased thermal stability (Tm), when compared with water (Powers et al., 1993 Manning et al., 1995). Insulin (pH...

Antidiabetic effects

Diabetes mellitus is a chronic metabolic disorder which can damage many systems in the body, such as blood vessels and nerves. It is one of the world's most serious health concerns, developing increasingly with the dietary patterns and age. The control of blood glucose levels is very important in hyperglycemic patients, and a-glucosidase inhibitors are a cost-effective means to preventing the progression of diabetes. Fucodiph-loroethol G (IC50 19.52 pM), dieckol (IC50 10.79 pM), 6,6'-bieckol (IC50 22.22 pM), 7-phloreckol (IC50 49.49 pM), and phlorofucofuroeckol A (IC50 19.71 pM) from E. cava have shown significant inhibition of a-glucosidase (Lee et al., 2009). Several other studies have conducted to investigate in vivo antidiabetic effects by feeding phlorotannin extracts to diabetic mouse models. Ecklonia stolonifera extracts have shown strong inhibition of a-glucosidase in noninsulin dependent diabetic mice (Iwai, 2008). Feeding with E. cava extract (Kang et al., 2010) and I....

Insulin Lispro Humalog

Key words Insulin, insulin analogues, insulin lispro, lispro, Humalog, diabetes, diabetes mellitus, rapid acting insulin. Abstract Initially discovered in 1921, insulin was first made commercially available in 1923. Up until the early 1980s, all insulin preparations used medically were obtained by direct extraction from the pancreatic tissue of animals. In 1982, Humulin (recombinant human insulin) became the first recombinant therapeutic product to gain marketing approval. By the mid-1980s, efforts to develop insulin analogues displaying improved therapeutic properties were well underway. Insulin LISPRO (Humalog(R)) is such an analogue which has gained regulatory approval for general medical use. It is identical to human insulin except that the Pro-Lys amino acid sequence at positions B28 and B29 of the native molecule are reversed. Insulin lispro has a more rapid onset of activity and a shorter duration of action when compared to regular human insulin while maintaining equal glucose...

Modified Version of Plimstex for Insulin Selfassociation

To obtain data similar to that from PLIMSTEX, the concentration of insulin in solution is varied and amide exchange is initiated, followed by quenching the exchange, and injecting the ice-cold solution into the ESI source of a mass spectrometer. After the quench, the oligomers dissociate into monomers, but the increase in mass of the monomer (compared to the control) gives a weighted average of the increase in mass of the various oligomers. These data can be used to obtain a species-specific deuterium number for each oligomer and to calculate the association constants for the oligomerization. For fitting the insulin self-association The insulin amide exchange during the self-association shows that the number of exchangeable hydrogens decreases with increasing concentration of insulin, demonstrating that, as the self-association occurs, fewer amide hydrogens undergo exchange. The AD values in the case of insulin represent changes in the solvent accessibility of the oligomer compared to...

Manufacturing Process for Insulin Lispro

Lilly's experience in manufacturing human insulin in E. coli using rDNA technology is well documented (6, 23, 50-54). Commercial recombinant human insulin was initially made by a chain combination procedure (28), then four years later in 1986 via the proinsulin route (24). In this latter process a 277-residue chimeric fusion protein (Trp LE'- Methionine-Human Proinsulin) is expressed in E. coli followed by chemical cleavage at methionine with cyanogen bromide to release human proinsulin mixed disulphides. Human insulin is obtained subsequent to appropriate folding, enzymatic transformation, large-scale purification and crystallisation (55, 56). Insulin lispro is manufactured in essentially the same manner as human insulin with a few exceptions. The expression product from fermentation is a smaller precursor molecule with a shorter amino terminal extension that is removed enzymatically to yield Lys Pro -human proinsulin. Insulin lispro is liberated from proinsulin by hydrolysis with...

Application of the Snare Hypothesis to Insulin Exocytosis

Several of the proteins which, it has been suggested, regulate neurotransmitter release have recently been identified in the (3-cell, and for a number of them a function in insulin exocytosis has been established. The ubiquitous fusion factor NSF is present in the insulin-secreting cell line HIT-T15. In addition, aSNAP, also present in these cells, appears to be one of the factors in cytosol required for Ca2+-triggered insulin exocytosis (Kiraly-Borri et at., 1996). The v-SNARE VAMP-2 was localized to insulin secretory granules (Jacobsson et a ., 1994). It is also expressed on the SLMVs in the (3-cell, as demonstrated by its colocalization with synaptophysin, a synaptic vesicle membrane protein (Regazzi eta ., 1995). Clostridial neurotoxins have been used to investigate the functional importance of several of the SNARE proteins. As insulin-secreting cells do not express the ganglioside receptors for the clostridial neurotoxins on the cell surface, the toxins were introduced into the...

Effects Of Diabetes On Microvascular Kir Channels

The recent development of a technique to isolate viable pericyte-containing microvessels from the retinas of normal and diabetic rats has facilitated the quest to elucidate the mechanisms by which diabetes alters microvascular function. With freshly isolated microvessels, it is feasible to monitor pericyte currents via patch-pipettes, measure pericyte calcium levels with fura-2, and visualize pericyte contractions and lumen constrictions using time-lapse photography. Thus, retinal microvessels can be studied from the level of ion channels to pericyte function. Recent analyses of freshly isolated retinal microvessels reveal that insulin-deficient diabetes significantly affects the function of inwardly-rectifying potassium (KIR) channels and P2X7 purinoceptors (23, 24).

Type 2 Diabetes Mellitus

Type II non-insulin-dependent diabetes (T2DM) is one of the most common age-associated diseases (diabetes of the elderly) and is characterized by a variety of severe complications which can be responsible for disability and eventually death. Diabetic patients not only live shorter lives but also have longer periods of disability. The pathogenesis of T2DM is complex, and a large literature indicates that inflammation and oxidative stress play an important role. In particular, TNF-a and its polymorphic variants as well as IL-6 are associated with an increased risk of developing the disease. The genetics of type 2 diabetes is still unclear, although in most cases several nuclear genes appear to be involved (complex genetic disease). Recent data suggest that oxidative stress can play an important role in the pathogenesis of T2DM. Indeed, increased production of ROS and decreased levels of antioxidant enzymes and vitamins could explain, at least in part, the damage observed in a number of...

And Familial Nephrogenic Diabetes Insipidus

Nephrogenic diabetes insipidus (NDI) is characterized by renal tubular resistance to the antidiuretic effect of arginine vasopressin (AVP). NDI may be inherited as an autosomal dominant or X-linked recessive disorder. The autosomal dominant form of NDI results from mutations of the aquaporin 2 gene (AQP2). AQP2 encodes a water channel of the renal collecting duct. Its disruption causes autosomal dominant NDI (113,114) and occasionally recessive forms of the disease. The gene encoding the V2 vasopressin receptor (AVPR2), located in the Xq28 region (115), is responsible for the X-linked nephrogenic diabetes insipidus. AVPR2 belongs to the cyclic nonapeptide-binding GPCR subfamily that also includes the V1a and V1b vasopressin receptors and the oxytocin receptor. AVPR2 is expressed predominantly in the distal convoluted tubule and collecting ducts of the nephron. Its primary role is to respond to the pituitary hormone AVP by stimulating mechanisms that concentrate the urine and maintain...

Applications of Polysaccharide Nano Microparticles in Diabetes Therapy

Diabetes is a group of metabolic diseases in which a person has high blood sugar, either because the body does not produce enough insulin or because cells do not respond to the insulin that is produced. One of the most important difficulties that are met in diabetes treatment is represented by the poor gastrointestinal uptake of poorly absorbable drugs such as insulin. Polysaccharides (like those that are contained in black tea) may benefit people with diabetes because they help retard absorption of glucose, but also polysaccharides like starch, CS, alginates and glucomannan are intensively studied for being used as carriers for diabetic drugs. However, the oral delivery of many diabetic drugs, like insulin which is a peptide, still remains an unresolved challenge because of the large size, hydrophilicity and instability. The potential utility of CS, related to its mucoadhesive properties and to the fact that it can facilitate drug absorption by localising drug concentration around...

Selfassociation of Insulin A Protein Protein Interaction

Protein-protein interactions mediate the majority of life processes. An understanding of these interactions is critical to understanding cell regulation 66 and to preventing human disease that can arise from errors in protein-protein interactions 67 . A clear understanding of these interactions points the way to developing new targets and discovering new drugs 68 . Insulin, a protein with 51 residues in two chains 69 , is a good model system for testing whether a PLIMSTEX-like approach can determine protein self association. Oligomerization of insulin also has implications in the treatment of type I diabetes. The large size of the hexamer, which contains two Zn2+, of insulin prevents its efficient absorption into the blood stream 70 , whereas aggregation is prevented by using analogs of insulins that are stable in monomeric form 71 . PLIMSTEX can be used to study the self-association properties of various insulins 33 and may be a promising method for investigating protein-protein...

Antidiabetic activity

Diabetes mellitus is a chronic metabolic disorder characterized by high blood glucose levels. Diabetes without proper treatments can cause many complications. Acute complications include hypoglycemia, diabetic ketoacidosis, or nonketotic hyperosmolar coma. Serious long-term complications include cardiovascular disease, chronic renal failure, and retinal damage. Hence, antidiabetic agents are urgently required. It has been reported that fucosterol from P. siliquosa have antidiabetic activity. Fucos-terol at a dose of 100 and 300 mg kg reduced hyperglycemic effect by 25-33 in epinephrine-induced diabetes mouse model. Moreover, fucosterol at a dose of 100 and 300 mg kg was shown to decrease the glycogen degradation of mouse liver by 23-29 . Hence, it was suggested that fucosterol from marine alga P. siliquosa has potential in development of antidiabetic agent (Lee et al., 2004).

Tyrosine Phosphorylation And The Insulin Action Cascade

Receptors for insulin and IGF-1 belong to the family of receptor tyrosine kinases, and tyrosine kinase activity is essential for insulin signaling (Figure 60 2). The activated receptors undergo autophosphorylation, which activates their tyrosine kinase activity toward other substrates, principally the four insulin receptor substrates IRS-1, 2, 3, and 4 and Shc Tyrosine phosphorylated IRS proteins recruit signaling cascades via the interaction of SH2 domains with phosphotyrosines, recruiting such proteins as SHP2, Grb2, and SOS and resulting in the activation of MAP kinases and PI3K, which transduce many of insulin's cellular effects. The IGF-1 receptor resembles the insulin receptor and uses similar signaling pathways furthermore, the two receptors bind each other's ligand, albeit with lower affinity. In addition, IGF-1 and insulin-receptor heterodimers can combine to form hybrid heterotetramers. Diabetes Mellitus and the Physiological Effects of Insulin DM consists of a group of...

Initiation of Insulin Secretion

Initiators of insulin secretion switch on the secretory machinery. Thereafter modulators derived from nutrient metabolism, hormones peptides and neurotransmitters determine how fast or slow the machine will run. It is now well accepted that initiation of insulin release in response to glucose and other nutrients is caused by depolarization of the B-cell as a first step followed by subsequent Ca2+ influx.

Sensitivity Of Insulin Gene Promoter To Glycation And Oxidative Stress

Among reducing sugars that potentially induce glycation, D-ribose is outstanding for its very potent activity and thus is often used in in vitro studies as an inducer of glycation (Franklin and Higgins, 1981 Hasegawa et al., 1995). We therefore used D-ribose to evaluate the effects of glycation on insulin gene transcription (Matsuoka et al., 1997). According to the results of reporter gene analyses, the insulin gene promoter but not the 3-actin gene promoter or RSV-LTR promoter was sensitive to the induction of glycation. When HIT-T15 cells were kept for 72 hr with D-ribose, the activity of the insulin gene promoter was suppressed down to 48-18 of the control (Table I Matsuoka et al., 1997). No significant changes were observed with the 3-actin gene promoter, and an increase was observed with the RSV-LTR promoter in the presence of 40 and 60 mM D-ribose (Table I). Interestingly, the promoter-suppressing effects were neutralized, at least in part, with the addition of aminoguanidine...

Diabetes

Schematic of the effects of diabetes on the function of P2X7 purinoceptors, voltage-dependent calcium channels (VDCC), inwardly rectifying potassium (KIR) channels and gap junctions in a pericyte-containing retinal microvessel. AGEs, advanced glycation endproducts SPM, spermine PKC, protein kinase C. Experimental evidence indicates that insulin-deficient diabetes (i) inhibits KIR channels by a mechanism involving an increase in spermine, (ii) increases the transition from activated P2X7 purinoceptors to opened transmembrane pores, (iii) inhibits VDCC activity secondary to the formation of advanced glycated end-products, and (iv) inhibits microvascular gap junctions by a PKC-dependent mechanism (28). Fig. 3. Schematic of the effects of diabetes on the function of P2X7 purinoceptors, voltage-dependent calcium channels (VDCC), inwardly rectifying potassium (KIR) channels and gap junctions in a pericyte-containing retinal microvessel. AGEs, advanced glycation endproducts SPM,...

Insulin Assays

The most prominent manifestation of insulin activity, an abrupt decrease in blood glucose, was the basis for biologic assay from the time of its first clinical use. The procedure, although relatively cumbersome, has the great merit of accurately reflecting the effect on the diabetic patient. The advent of practical yet sophisticated physicochemical methods (e.g., liquid chromatography) to measure insulin potency quantitatively has resulted in a more accurate and precise compendial test for insulin and insulin products. However, the bioidentity of insulin and insulin products cannot be assessed by these methods. Thus, a qualitative test in rabbits is included in this chapter, and its use is called for in the appropriate monographs. The Rabbit Blood Sugar Method Quantitative is used to determine the potency of Insulin Reference Standards, for the validation of the stability of new insulin preparations, and to determine the specific activities of insulin analogs.

Type 1 diabetes

Type 1 (insulin-dependent) diabetes results from the autoimmune destruction of the insulin-producing pancreatic -cells. Supplementation studies in animals indicate that increasing pancreatic zinc levels reduce the severity of chemically induced type 1 diabetes.49 Evidence that higher zinc intakes are protective against type 1 diabetes in humans is very limited. A case-control study in Sweden50 and an ecological study in the UK51 found that higher concentrations of zinc in the drinking water were associated with a significantly lower incidence of type 1 diabetes, but an ecological study in Finland found no such relationship.52 Increased urinary zinc excretion (hyperzincuria) and decreased plasma zinc concentrations have been observed in patients with type 1 diabetes in some53,54 but not all studies.55,56 However, there is no evidence in humans that higher zinc intakes are beneficial in the management of type 1 diabetes. In fact, one study found that supplementation with 50 mg day of...

Insulin Sensitivity

A number of studies have suggested that perturbation of insulin metabolism is associated with AD 24,110-113 . In the past decade, large studies have found that individuals with Type 2 diabetes are twice as likely to develop AD when compared to gender matched healthy subjects 114-119 . Insulin resistance and hyperinsulinemia, two characteristics of type II diabetes, have been shown to have a high correlation with memory impairment and risk for AD. There is substantial evidence establishing a role of insulin in cognition. Insulin can pass the blood-brain barrier and enter the CNS via a receptor-mediated transport process. Insulin receptors in the mammalian brain have a very specific pattern of expression and are localized to the hippocampus and medial temporal cortex, both are areas associated with memory. In addition, brain insulin receptor signaling has been reported to be significantly reduced in AD, an indication of insulin resistance 120,121 . Furthermore, an acute increase in...

Insulin Resistance

Insulin release (P-cell Dysfunction) Figure 2 Schematic diagram of the glucose transporter translocation hypothesis. Insulin-responsive tissues, specifically adipose tissue and skeletal muscle, contain intracellular stores of glucose transporter proteins (GLUT). The binding of insulin and the subsequent increase in tyrosine kinase activity of the insulin receptor initiates a signaling cascade, which results in the tyrosine phosphorylation of insulin receptor substrates (IRS 1 -n), their binding to the enzyme phosphatidylinositol 3-kinase (PI 3-kinase), and the resultant activation of PI 3-kinase to produce phosphorylated phosphoinositides. This signaling cascade leads to the mobilization and insertion of stored glucose transporters into the plasma membrane, allowing for increased glucose influx into the cell in response to insulin. insulin signals, defects in detecting transducing the signal, a reduction in the total amount of glucose transporters, and or inability of the transporters...

Type 2 Diabetes

Type 2 diabetes, in many ways like cancer, arises from a complex interplay of environmental and genetic factors that lead to a broad spectrum of conditions characterized by chronic high levels of glucose. While glucose levels are the common denominator for diagnosis of the disease, the simplicity of this mea- surement actually masks a complex set of problems that vary among individuals. Some people are beset primarily with dysfunctional pancreatic beta cells, while others may have more significant issues in muscle or liver tissues. Being able to determine the underlying nature of an individual's diabetes will help best determine the proper course of treatment.

Insulin

One of the major triumphs of the 20th century occurred in 1922, when Banting and Best34 extracted insulin from dog pancreas. Advances in the biochemistry of insulin have been reviewed with emphasis on proinsulin biosynthesis, conversion of proinsulin to insulin, insulin secretion, insulin receptors, metabolism, effects by sulfonylureas, and so on.35-38 Insulin is synthesized by the islet jS-cells from a single-chain, 86-amino-acid polypeptide precursor, proinsulin.39 Proinsulin itself is synthesized in the polyribosomes of the rough endoplasmic reticulum of the jS-cells from an even larger polypeptide precursor, preproinsulin. The B chain of preproinsulin is extended at the NH2-terminus by at least 23 amino acids. Proinsulin then traverses the Golgi appara tus and enters the storage granules, where the conversion to insulin occurs. The subsequent proteolytic conversion of proinsulin to insulin is accomplished by the removal of the Arg-Arg residue at positions 31 and 32 and the Arg-Lys...

Insulin Aspart

Indications Treatment of adult patients with diabetes mellitus, for the control of hyperglycemia A. General description Insulin aspart (rDNA origin) is a rapid-acting human insulin analogue. It is homologous with regular human insulin with the exception of a single substitution of the amino acid proline by aspartic acid in position B28, and is produced by recombinant DNA technology utilizing Saccharomyces cerevisiae (baker yeast) as the production organism. It has a molecular weight of 5.8 kDa. B. Indication NovoLog is indicated for the treatment of adult patients with diabetes mellitus, for the control of hyper-glycemia. Because NovoLog has a more rapid onset and a shorter duration of action than human regular insulin, it should normally be used in regimens together with intermediate or long-acting insulin.

Insulin Glargine

Indications Treatment of adult and pediatric patients with type 1 diabetes mellitus or adult patients with type 2 diabetes mel- litus who require basal (long-acting) insulin for the control of hyperglycemia A. General description Insulin glargine is a recombinant human insulin analogue with a long duration of action (up to 24 hours). It is produced by recombinant DNA technology utilizing a laboratory strain of Escherichia coli as the production organism. Insulin glargine differs from human insulin in that the amino acid asparagine at position A21 is replaced by glycine and two arginines are added to the C-terminus of the B-chain. It has a molecular weight of about 6.1 kDa. B. Indications and use Lantus is indicated for once-daily subcutaneous administration at bedtime in the treatment of adult and pediatric patients with type 1 diabetes mellitus who are at least 6 years old or adult patients with type 2 diabetes mel-litus who require basal (long-acting) insulin for the control of...

Insulin Lispro

Indications Treatment of diabetes mellitus A. General description Humalog (insulin lispro, rDNA origin) is a rapid-acting human insulin analog. Chemically it is Lys(B28), Pro(B29) human insulin analogue (molecular weight 5.8 kDa), created when the amino acids at positions 28 and 29 on the insulin B-chain are reversed. Humalog is synthesized in a laboratory strain of Escherichia coli bacteria that has been genetically altered by the addition of the gene for insulin lispro. B. Indications and use Humalog is an insulin analogue that is indicated in the treatment of patients with diabetes melli-tus for the control of hyperglycemia. It has a more rapid onset and shorter duration of action than human regular insulin.

Bernard Testa Urs A Meyer

ANTIDIABETIC AGENTS RECENT ADVANCES IN THEIR MOLECULAR AND CLINICAL PHARMACOLOGY This book tries to give an overview on present knowledge about pharmacological and clinical aspects of antidiabetic drugs. In this connection it was found to be important to include chapters on the regulation of glucose homoeostasis and pathophysiology of Type-I and Type-II diabetes mellitus. Since diabetes mellitus is a disease of inadequate insulin secretion and inadequate action of insulin, especially in Type-II diabetes mellitus, special emphasis has been put on the molecular basis of insulin secretion and insulin actions. Several experts have contributed different topics. The clinical part was written by H. Laube, and insulin action by H. U. Haring, M. Kellerer and L. Mosthaf. The secretory machinery and mechanisms of sulphonylurea actions were contributed by H. P. T. Ammon. The author of pharmacodynamics of other antidiabetic drugs, side effects and drug interactions is E. J. Verspohl and finally M....

Induction Of Aox Enzymes

Relevance to Diabetes Both steady-state levels of 80HdG in blood monocytes (46) and urinary excretion of 80HdG (47) have been reported as elevated in diabetic patients. Gas chromatography mass spectrometry has recently shown elevated levels of a wide range of base oxidation products in DNA from white blood cells of diabetic patients. The pattern of base damage was diagnostic of increased OH formation in vivo (48). Lipid peroxidation is important in vivo for several reasons, in particular because it contributes to the development of atherosclerosis (49-51), a process known to be accelerated in diabetic patients (6). Lipid peroxides and other end products of the peroxidation process may be toxic to vascular endothelium in diabetics (6,52). Many assays are available to measure lipid peroxidation, but the simpler ones, such as the TBA test and diene conjugation, are notoriously unreliable when applied to human tissues and body fluids (reviewed in Ref. 53), although the TBA test can be...

Plasma Vitamin E Status In Healthy And Diabetic Subjects

Data are conflicting on the a-tocopherol status in diabetic subjects. Some studies report no changes, others a decrease, and still others an increase (23-25). One problem with the previous studies was a failure to standardize a-tocopherol for lipid concentration, which would produce misleading results in hyper-lipidemic patients. We have found that absolute plasma a-tocopherol levels in diabetic subjects were slightly, but significantly, lower than those of the control subjects (Table 1). Plasma a-tocopherol levels between the two groups differed markedly when a-tocopherol levels were expressed per unit of cholesterol. No difference was found in absolute plasma or cholesterol-standardized a-tocopherol in the diabetic patients with and without complications (Table 2). These findings have recently been confirmed by Borcea et al. (22). Further studies are needed to address the question whether the low plasma oc-tocoph-erol in the diabetic patients is related to increased oxidative stress...

Relationship Between Rooh And Glycemic Control

INFLUENCE OF INSULIN THERAPY ON PLASMA ROOHs Little information is available on the effect of glycemic control on plasma markers of oxidative stress. Berg et al. (26) compared the effect of continuous intensified insulin treatment (CUT) and conventional insulin treatment (CIT) on plasma lipid peroxides as measured by the FOX assay. Plasma ROOHs in patients receiving CIIT fell by 31 as compared with baseline over a period of 24 months. HbAlc fell by 15 during the same period (Fig. 4). By contrast, no difference was seen in patients receiving CIT over the same period. Faure et al. (27) also examined the effect of CIIT on plasma lipid peroxides using the TBA assay. They too reported a marked reduction in TBARs after CIIT as compared with the baseline level (2.42 0.25 vs. 3.03 0.27 (imol L n 16) over a period of 7 years (27). These observations provide further support for the hypothesis of a beneficial effect of insulin therapy on lipid peroxidation brought about by decreasing...

Characteristics Of Niddm

NIDDM is a heterogeneous disorder that may be initiated by a defect in insulin action. A reduction in glucose clearance is one of the earliest abnormalities. At that time, the early phase of insulin secretion tends to be reduced, priming the insulin target tissues, primarily the liver, that are responsible for the maintenance of glucose homoeostasis. As the first phase of insulin secretion is impaired, the resulting postprandial hyperglycaemia initiates a hyperinsulinaemia, returning blood glucose to normal. In NIDDM, with a fasting glucose concentration up to 120mg 100ml, insulin secretion is increased to twice normal with a fasting glucose concentration of 80 mg 100 ml. As the pancreatic exhaustion continues, insulin response becomes insufficient and the absolute amount of insulin decreases. Basal blood glucose begins to rise. Once the fasting blood glucose concentration exceeds 120 mg 100 ml there is a further progressive decline in reactive insulin release in response to glucose....

Materials And Methods

Barrier-sustained cesarean-delivered male Wistar rats (Charles River, Wilmington, MA), body weight 250-300 g, were fed a standard rat chow diet (ICN Biomedicals, Cleveland, OH) and had ad libitum access to water. Diabetes was induced by a single intraperitoneal injection of streptozotocin (Upjohn, Kalamazoo, MI, 55 mg kg body weight, IP, in 0.2 mL of 10 mM citrate buffer, pH 5.5) to animals that were fasted overnight. Blood samples for measurements of glucose were taken from the tail vein 48 h after streptozotocin injection and the day before they were killed. The rats with blood glucose 3 250 mg dL were considered diabetics, and the treatments were started 48 h after streptozotocin injection. Three experiments were performed. In experiment 1, the experimental groups included control, 6-week diabetic, and 6-week diabetic rats treated with dl-a-lipoic acid (Sigma, 100 mg kg body weight day, IP, 5 days a week). Experiment 2 was performed in control, 3-week diabetic, and 3-week diabetic...

Antioxidant Enzymes

Free radical defenses of peripheral nerve are reduced relative to brain and liver, especially involving glutathione (GSH)-containing enzymes (9). Cuprozinc superoxide dismutase (SOD) is reduced in sciatic nerve of experimental diabetic neuropathy, and this reduction is improved by insulin treatment (10). Glutathione peroxidase (GSH-Px) is reported to be further reduced in experimental diabetic neuropathy in alloxan diabetic mice 7-21 days after induction of diabetes, and enzyme activity inversely regresses with glucose level (11). We recently evaluated the gene expression of the antioxidant enzymes, GSH-Px, SOD (cuprozinc czSOD and manganese mnSOD separately), and cata-lase (CAT) in L4-L6 dorsal root ganglia (DRG) and superior cervical ganglion (SCG) of rats that had been diabetic for 3 and 12 months (Kishi et al unpublished data). cDNA fragments for rat GSH-Px, czSOD, mnSOD, CAT, and cyclophilin was obtained by reverse transcriptase polymerese chain reaction of rat DRG RNA using...

Glucose Uptake And Energy Metabolism

A-Lipoic acid has a number of actions in addition to its antioxidant properties. These include its effect on glucose uptake. We therefore evaluated glucose uptake, nerve energy metabolism, and the polyol pathway in EDN induced by streptozotocin. Control and diabetic rats received lipoic acid at various doses (0, 10, 25, 50, and 100 mg kg). Duration of diabetes was 1 month, and a-lipoic acid was administered intraperitoneally 5 times during the final week of the experiment. Nerve glucose uptake was reduced to 60 , 37 and 30 of control values in the sciatic nerve, L5 DRG, and superior cervical ganglion, respectively, in EDN. a-Lipoic acid supplementation had no effect on glucose uptake in normal nerves at any dose but reversed the deficit in EDN, with a threshold between 10 and 25 mg kg.

Summary And Conclusions

Studies on antioxidant treatment have shown that ROS makes a marked contribution to the etiology of nerve dysfunction in experimental diabetes. Effects on vasa nervorum predominate in the short term ROS cause dysfunction of vascular endothelium which at the very least reduces NO-mediated vasodilation and increases local vasoconstrictor production and reactivity. The effects of oxidative stress are crucial, complex, and far reaching, causing basic changes in cell signaling such as PKC and NF-kB that affect a plethora of systems involved in the maintenance of vascular control and integrity. ROS effects also impinge on prostanoid and EDHF systems, further exacerbating a diabetic deficit of substrate availability in the former. The result is reduced nerve perfusion, causing endoneurial hypoxia, which in turn is responsible for NCV and other functional deficits. Autooxidation of glucose and its metabolites and other transition metal-catalyzed reactions such as advanced glycation are...

Neurotrophins In Diabetic Neuropathy

Decreased capture and retrograde transport of iodinated NGF in the sciatic nerve was observed in diabetic rats many years ago (34). Reduced retrograde transport of iodinated NGF in ileal mesenteric nerves has also been demonstrated (35). These observations imply that even in the absence of any deficit in production of NGF in diabetes, a deficit in the amount delivered to the cell body might be expected. In diabetic rats, there are reduced levels of NGF in the submandibular gland, superior cervical ganglion, and sciatic nerve (3638). NGF levels have also been shown to be decreased in the serum of diabetic patients with symptomatic peripheral neuropathy (39). Work in our laboratory has shown that with increasing duration of diabetes, progressive reductions in NGF mRNA appear in leg muscle and sciatic nerve followed by reductions in skin. There is a profound reduction in the retrograde transport of NGF in the sciatic nerve, which can be reversed by intensive insulin treatment, and...

Studies In Healthy Volunteers

Physiologically, insulin, C-peptide and glucagon are released in a pulsatile fashion in metabolically healthy people (Hansen et al., 1982) with a periodicity of pulses ranging from 8 to 30min. The insulin release in the basal state ranges from 14 to 17 mU min the concentration in peripheral venous blood from 10 to 20mUr', while portal insulin concentration is three times higher. Following an oral glucose load, a total of 0.9 U insulin per 150 min and 10 g ingested glucose are secreted (1.35 U per 12 g carbohydrate). Pulsatile insulin is more effective in suppressing hepatic glucose production while it exhibits an equipotent effect on glucose utilization (Bratusch-Marrain et al., 1986). The application of pulsatile insulin may thus reduce free insulin levels (Waldhausl et al., 1985) and insulin resistance and may contribute more effectively to a reduction in hormone load in insulin-treated diabetic patients. To shorten periods of hyperinsulinaemia in insulin-treated diabetic patients,...

Effect Of Thioctyl7linolenic Acid On The Activation Of Stressactivated Protein Kinases

Recently, among this large family of MAP kinases, a family of stress-activated protein kinases (SAPKs), including JNK and p38, have been delineated and characterized (see Ref. 100 for review). JNK exits in three forms in mammalian cells JNK1, JNK2, and JNK3 of 46, 54, and 56 kDa molecular weight, respectively. JNK has been found to be activated by a variety of different stimuli, including inflammatory cytokines such as interleukin-1 and tumor necrosis factor a, y-irradiation, ultraviolet irradiation, and oxidative stress (101). Once activated, JNK phosphorylates a number of different substrates, including c-jun and ATF2. Both of these transcription factors can form part of the AP-1 transcription factor complex, which is known to regulate the transcription of many different genes (reviewed in Ref. 98). Because oxidative stress, as part of the dysmetabolism of diabetes mellitus, seemed an excellent candidate for activation of SAPKs, we included measurement of activation of these...

Role Of Oxidative Stress In Diabetic Neuropathy Clinical And Experimental Evidence

A growing body of evidence suggests that oxidative stress resulting from enhanced free radical formation and or defects in antioxidant defense is implicated in the development of various disorders, including neurodegenerative diseases (7) and diabetic complications (8,9). Increased free radical formation and changes in hemostatic variables related to endothelial damage have been found in Type 2 diabetic patients with microalbuminuria (10). Impaired endo-thelium-dependent vasodilation is improved by administration of vitamin C, suggesting that nitric oxide inactivation by increased oxygen free radical activity contributes to abnormal vascular reactivity in diabetes (11). Furthermore, impaired cellular scavenging activity against oxidative stress (12) and elevated levels of plasma hydroperoxides in conjunction with a trend to lower vitamin E levels (13) have recently been demonstrated in patients with Type 2 diabetes. free radical scavenger (14), results in prevention of neurovascular...

Oxidative Stress NFkB Activation and Late Diabetic Complications

Oxidative stress is widely believed to play a central role in the pathogenesis of late diabetic complications. Recently, the understanding of oxidative stress in diabetes has been improved by the availability of assays exactly determining defined products of reactive oxygen species. These studies have revealed oxidative stress to occur before diabetic complications are present, further supporting the concept that oxidative stress is pivotal for the development of diabetic complications. Studies looking at the oxidative stress-activated transcription factor NF-kB help to understand the cellular consequences of oxidative stress at the molecular level. However, the occurrence of oxidative stress and oxygen species-mediated secondary end products are not sufficient proof for the hypothesis of oxidative stress-dependent diabetic complications. It has to be demonstrated that antioxidant therapy does not only reduce plasmatic markers of oxidative stress and subsequent NF-kB activation but...

Cagerage Interactions

Inhibition of AGE formation prevents diabetic peripheral nerve dysfunction (67) Accumulation of AGEs in the kidney of diabetic patients (56,60) Injection of AGE-albumin in normal rats induces symptoms of diabetic nephropathy (68) An induction of endothelial RAGE expression has been shown on vessels from patients with arteriosclerosis, diabetes, uremia, and vasculitis (77-79). Binding of AGEs to their cellular binding sites results in generation of oxygen free radicals and depletion of antioxidants such as glutathione and ascorbate (32,80). The consequently enhanced cellular oxidative stress leads to activation of the redox-sensitive transcription factor NF-kB in endothelial cells, smooth muscle cells, mesangial cells, and monocytes macrophages (23,25,32,78-81).

Activation Of NfkB

Activation of NF-kB and induction of increased binding activity of NF-kB are believed to have a pivotal role in the pathogenesis and progression of chronic diseases, such as diabetes and atherosclerosis (39,86,91,92). Accumu- lating data indicate a close link between hyperglycemia, oxidative stress, formation of AGEs, and induction of NF-kB to the etiology of late diabetic complications. Increased glucose concentration has been shown to induce NF-kB activation in endothelial cells (38) and to increase NF-kB binding activity in peripheral blood mononuclear cells isolated from diabetic patients with poor glycemic control (37), suggesting that NF-kB activation is an early event in response to elevations in glucose contributing to diabetes-induced endothelial cell injury.

Route by which Initiators and Modulators Reach the BCell

A very important factor, which may give us some idea how external initiators modulators reach their target cells and how communication between islet cells occurs, is the direction of the intraislet blood flow. Studies performed by Samols and Stagner (1988) and Samols et al. (1988) suggest that the arterial circulation first reaches the centre of the islets where B-cells are localized and from there supplies A- and D-cells in the mantle (Fig. 15). This means that B-, A- and D-cells receive information from the bloodstream and that by this route A- and D-cells also obtain messages from B-cells but not vice versa. Communication of A- and D-cells with the B-cell is assumed to occur in a paracrine manner along interstitial routes. In addition, the action of freshly released hormone on the hormone-releasing cells (i.e. direct feedback inhibition of insulin release) is possible. Fig. 15. Hypothetical model of how initiators and modulators that affect insulin release may reach A-, B- and...

Inhibition Of Diabetic Complications By Antioxidant Treatment

In patients with diabetes mellitus, oxidative stress is increased by enhanced production of free radicals and by antioxidant depletion, resulting in an increased susceptibility to oxidative damage and possibly development of late diabetic complications. Endogenous antioxidant proteins such as superoxide dismutase, glutathione peroxidase, and metal-binding proteins may protect the body against the effect of prooxidant reactions. Multiple antioxidants, including a-lipoic acid, vitamins C and E, urate, carotenoids, flavonoids, the amino acid methionine, and protein-bound zinc and selenium, are interacting addi-tively in these biological systems. In vitro and in vivo studies using antioxidants support the concept of radical-mediated diabetic complications.

Diabetes 2

Diabetes 2

Diabetes is a disease that affects the way your body uses food. Normally, your body converts sugars, starches and other foods into a form of sugar called glucose. Your body uses glucose for fuel. The cells receive the glucose through the bloodstream. They then use insulin a hormone made by the pancreas to absorb the glucose, convert it into energy, and either use it or store it for later use. Learn more...

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