High Blood Glucose Levels Ebook

Blood Sugar Miracle

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Hyperglycemia And Pericyte Channels

With epidemiological studies indicating that hyperglycemia is a critical factor in the development of diabetic retinopathy (35), investigators have assessed the effects of glucose on the function of ion channels in pericytes that were isolated from normal animals, maintained in culture and exposed to high concentrations of glucose. In these studies, the activities of certain calcium-activated potassium channels (36, 37) and VDCCs (38)

Mechanisms Of Hyperglycemiainduced Pkc Activation

Cellular DAG content can also be increased by agonist-stimulated hydrolysis of PI or PC such as PLC or PLD (11-13). Because inositol phosphate products are not increased by hyperglycemia in aortic cells and glomerular The activation of PKC by hyperglycemia may be tissue specific because it was noted in the retina (16), aorta, heart (17), and glomeruli (8,18) but not clearly demonstrated in the brain (16) and peripheral nerves (30) (Table 1). Similar increases in DAG levels and PKC activation have also been shown in multiple types of cultured vascular cells in response to increased glucose levels (Table 1) (8,16,22,31). Thus, it is likely that the DAG-PKC pathway is activated by the hyperglycemic-diabetic state in all vascular- cells. Among the various PKC isoforms in vascular cells, PKC (3 and 8 isoforms appear to be preferentially activated as shown by immunoblotting studies in aorta and heart of diabetic rats (17) and in cultured aortic smooth muscle cells exposed to high levels of...

Role Of Membrane Transporters In The Normal And Diabetic Lens

Dysfunction of volume regulation is an initiating factor in diabetic cataract. Confocal images of equatorial sections taken from rat lenses made diabetic by injection with streptozotocin. (A) One month post-injection, a distinct zone of tissue liquefaction in the outer cortex of the lens, surrounded by relatively normal fibre cells is evident. (B) At one week post-injection, a higherpower image of cells located in this zone indicates that tissue liquefaction is initiated by the swelling of individual fibre cells. (C) A schematic of some of the biochemical mechanisms that may contribute to diabetic cataract. In hyperglycemia an increase in the conversion of glucose to the impermeable osmolyte sorbitol by aldose reductase (AR), induces osmotic stress. Since this increase in AR activity consumes reducing equivalents (NADPH), the regeneration of oxidized glutathione (GSSH) by glutathione reductase (GR) to its reduced form (GSH) is decreased. The fall is GSH compromises the...

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...

Biological Properties Medicinal Applications Of Laminaria

As discussed under the chemical properties, a dietary supplement, Laminaria, is rich in several constituents that can be very beneficial to the health. Its high iodine content proves to be a great natural boon for the thyroid gland to prevent goiter. Apart from its high calcium, potassium, magnesium, iron, and trace minerals such as manganese, copper, selenium, and zinc, it provides vitamins B1 and B2 as well as chromium which is instrumental in blood sugar control and helps to keep diabetes in check. In Europe, Laminaria is basically harvested for a main source of alginate in the food industry, an emulsifying and binding agent used in the production of many foods like ice cream, toothpaste, cereals, and cosmetics as well as in paints and films (www.montereybayaquarium.org).

L Protease Inhibitors PIs

Each of the protease inhibitors that have been studied to date has a low incidence of side effects that appear to be class related (Kaul et al., 1999). These rare adverse reactions include hyperlipidemia, lipodystrophy, hemo-lytic anemia, hyperglycemia, and spontaneous bleeding in hemophiliacs. Each reaction has been associated with each of the protease inhibitors. The PI-associated hyperlipidemia is usually an elevation of the triglycerides. In PI-associated lipodystrophy, patients develop aberrant fat deposits around their waists and on the back of their necks (''buffalo humps''). This problem is more cosmetic than medical and may resolve with discontinuation of the PI. PI-associated hyperglycemia can be mild or can present as ketoacidosis with new onset diabetes mellitus.

Neurotrophins In Diabetic Neuropathy

Diabetes is associated with increases in oxidative stress in humans and in experimental animal models. Chronic hyperglycemia per se results in autoxi- dative glycation oxidation and lipid peroxidation (54-56), and hyperglycemia alone will cause lipid peroxidation of peripheral nerve in vitro (57).

Changes In Anesthetic Requirements In Animal Models With Altered Pmca Activity

Because chronic hyperglycemia inhibits PMCA in cells from several tissues, diabetic rats could manifest chronic inhibition of brain synaptic PMCA and thus provide a model for testing the hypothesis that synaptic PMCA plays a role in IA pharmaco-dynamics. We found that PMCA pumping was about 10 less frequent in cerebral SPM from rats with STZ-induced diabetes (duration 13 days) than in SPM from normoglycemic rats. (As noted below, a further decrease in PMCA activity occurred with prolongation of the diabetic state.) The halothane requirement for STZ-hyper-glycemic rats was dramatically reduced to about 65 of control. Halothane and xenon MEDs correlated strongly with percent glycated hemoglobin (GHb) in all treatment groups. When PLM was evaluated in SPM taken from diabetic rats 2 weeks after STZ injection, PLMT I activity was enhanced nearly 30 compared with normoglycemic controls. Thus PLMT I activity was also shifted in the expected direction in this rat model with reduced anesthetic...

The Regulated Production of Superoxide by Nadph Oxidase Isoforms

The cardiovascular NAD(P)H oxidase isoforms are induced by hormones, hemodynamic forces, or local metabolic changes 54 . Angiotensin II stimulates NAD(P)H-dependent superoxide production in vascular smooth muscle cells and fibroblasts. Thrombin, platelet-derived growth factor (PDGF), and tumor necrosis factor-a (TNF-a) stimulate NAD(P)H-dependent superoxide production in vascular smooth muscle cells. Interleukin (IL)-1, TNF-a, and platelet-activating factor (PAF) stimulate NAD(P)H-dependent superoxide production in fibroblasts (reviewed in Ref. 54), and minimally oxidized low-density lipoprotein (LDL) was shown to activate NADPH oxidase in vascular endothelial cells 158 . The increased vascular superoxide formation under conditions of chronic hyperglycemia appears to result from the fact that high glucose increases mRNA expression of the oxidase subunit p22PHOX 28 . In most of these cases, Rac1 is involved in the induction of NAD(P)H oxidase activity 80,81,192 . Redox factor-1 APE was...

Oxidative Stress In Patients With Diabetes Mellitus

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 increasing the production of free radicals (35-39). A close relationship of oxidative stress with glycemic control has been described, showing a significant positive correlation between malondialdehyde (MDA) and both fasting blood sugar and glycosilated hemoglobin (40)....

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...

Artificial cells containing islets

Typical results obtained by a number of groups showing that heterologous islets inside artificial cells are not immuno-rejected. They continue to function for various lengths of time in maintaininga normal blood glucose level. However, the results are not always reproducible especially in the duration of function after implantation. Fig. 8.2. Typical results obtained by a number of groups showing that heterologous islets inside artificial cells are not immuno-rejected. They continue to function for various lengths of time in maintaininga normal blood glucose level. However, the results are not always reproducible especially in the duration of function after implantation.

Role of Oxidative Stress and Antioxidants on Adhesion Molecules and Diabetic Microangiopathy

Each cell can mobilize an armory of antioxidant defense systems. Under normal metabolic conditions, the production of free radicals and the antioxidant capacity are balanced. Hyperglycemia in diabetes mellitus is associated with an increased production of free radicals. Furthermore, observational studies indicate lower levels of antioxidants like vitamin E, vitamin C, carotene, ascor-bate, and thiols in patients with diabetes mellitus (1,2). Imbalance between free radical production and the antioxidant defense system leads to oxidative stress. In diabetic patients, oxidative stress can be demonstrated by increased levels of lipid peroxidation products (3-8). There is a body of evidence that vascular and neurological complications in patients with diabetes mellitus are a consequence of oxidative stress (9-12).

Endotheliumdependent Vasodilation

In physiological terms, hyperglycemia increases blood pressure and leads to endothelial dysfunction with impaired vascular reactivity (23). Hypoxia is accompanied with an influx of calcium, which might activate nitric oxide (NO) synthase followed by vasodilation and hyperemia (11) (Fig. 5). In diabetes, increased free radicals might quench NO, leading to ischemia (11,24). In vitro acetylcholine-induced vasodilation of vasculature from diabetic animals is impaired (25,26). The rate of NO synthesis in vivo compared with the rate of NO quenching is unclear. We measured the blood flow of the arteria iliaca in diabetic and nondiabetic rats. The NO-mediated stimulation by acetylcholine was impaired in diabetic rats, but in contrast to in vitro experiments, treatment

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 Figure 6 Changes in blood sugar are associated with changes in blood flow....

Analysis of Mutant Mice Selectively Lacking M3 mAChRs in Pancreatic b Cells

Type 2 diabetes (T2D) has emerged as one of the major threats to human health world-wide (Zimmet et al. 2001). A pathophysiological hallmark of T2D is that pancreatic p cells fail to release sufficient amounts of insulin in order to maintain normal blood glucose levels (p cell dysfunction). Drugs that can promote insulin release from pancreatic p cells are therefore considered useful for the treatment of T2D (Kahn 1994). In order to study the importance of p-cell M3 mAChRs in maintaining normal blood glucose levels in vivo, we employed Cre loxP technology to generate mutant mice lacking M3 receptors in pancreatic p cells only (p-M3-KO mice Gautam et al. 2006b). Studies with isolated islets showed that muscarinic agonist-induced phosphatidylinositol (PI) hydrolysis was greatly reduced in islets prepared from p-M3-KO mice, as compared to islets obtained from control littermates (Gautam et al. 2006b). Consistent with this observation, the ability of the muscarinic agonist, oxotremorine M...

Painful Polyneuropathies

Diabetic peripheral neuropathy is a late complication of diabetes mellitus resulting from decreased blood flow and high blood sugar levels. Population-based studies indicate that diabetic neuropathies are common among patients with diabetes, affecting up to 66 of patients with insulin-dependent diabetes mellitus and 59 of patients with noninsulin-dependent diabetes mellitus. Several types of diabetic neuropathy have been identified including focal

PK Parameter Area Under the Curve Vs Peak Concentration

Release in response to hyperglycemia is achieved by amplification of these high-frequency pulses (5). This pattern of insulin secretion has been shown to be abnormal in subjects with type 2 diabetes and in patients at risk of developing type 1 diabetes. As the magnitude of insulin pulses is decreased in patients with type 2 diabetes (6), it is likely that the liver of these patients is exposed to even more attenuated oscillations in insulin pulse amplitude, which may contribute to the hepatic insulin resistance characteristic of this disease.

Vascular Blood Flow

Abnormalities in hemodynamics have been clearly documented to precede diabetic nephropathy (51,52). Elevated renal glomerular filtration rate (GFR) and modest increases in renal blood flow are characteristic findings in insulin-dependent diabetes mellitus (IDDM) patients (51,52) and experimental diabetic animals (53). Diabetic glomerular hyperfiltration is likely to be the result of hyperglycemia-induced decreases in arteriolar resistance, especially at the level of afferent arterioles (54,55), resulting in an elevation of glomerular filtration pressure. Multiple mechanisms have been proposed to explain the increases in GFR and glomerular filtration pressure, including an enhanced activity of angiotensin (56) and culturation in prostinoid productions (57-59). It is possible that the activation of DAG-PKC may also play a role in the enhancement of angiotensin actions because angiotensin mediates some of its activity by the activation of the DAG-PKC pathway (57). In addition, increases...

Vascular Permeability and Neovascularization

In the kidney, the expression of transforming growth factor-P (TGF-P) has been shown to be increased in the glomeruli of diabetic patients and experimental animals. Similar increases of TGF-p have also been reported in cultured mesangial cells exposed to high glucose levels (9). Because TGF-P can directly cause the overexpression of extracellular matrix, PKC inhibitors have been shown both to inhibit TGF-P expression by hyperglycemia and to prevent the mesangial expansion observed in diabetic nephropathy (7,9,11).

Extracellular Matrix Components

(3 antibodies significantly reduced collagen synthesis and gene expression of type (IV) collagen and fibronectin in the renal cortex of diabetic rats and in cultured mesangial cells exposed to high glucose levels. Because PKC activation can increase the production of extracellular matrix and TGF-(3 expression, it is not surprising that several reports have shown that PKC inhibitors can also prevent hyperglycemia- or diabetes-induced increases in extracellular matrix and TGF-(3 in mesangial cells or renal glomeruli (32).

Comparison of CR and the KD on Epileptogenesis in EL Mice

Body weight prior to the analysis (41). We found that the mild 15 CR diet was more effective than the KD in delaying seizure onset and in reducing seizure susceptibility (Figure 7). Our comparative analysis of CR and the KD was restricted to juvenile mice because the AL-fed KD does not inhibit seizure susceptibility in adult EL mice (74). In contrast to CR, which lowers blood glucose levels (Figure 5A), the AL-fed KD does not lower blood glucose levels in the juvenile EL mice (27).

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). 1. Hyperglycemia Hyperglycemia has been strongly implicated in the development of diabetic complications, an effect also known as glucose toxicity. The mechanisms of glucose toxicity are the subject of extensive investigation and include glucose

Can Oxidative Stress Cause Insulin Resistance

The first prospective population study undertaken to address the role of free radical stress and antioxidants in relation to the incidence of diabetes examined whether low vitamin E concentrations are a risk factor for the incidence of type 2 diabetes (92). The authors computed the levels of plasma vitamin E and the incidence of developing diabetes over a 4-year period in 944 men aged 42-60 who were determined not to have diabetes at baseline examination (92). Type 2 diabetes was defined by either a fasting blood glucose concentration of S 6.7 mM, a blood glucose concentration > 10.0 mM 2 h after a glucose load, or by a clinical diagnosis of diabetes with either dietary, oral, or insulin treatments. Forty-five men developed diabetes over the 4-year follow-up period (92). However, these 45 men also had a raised baseline body mass index, elevated blood glucose and serum fructosamine concentrations, a higher ratio of saturated fatty acids to the sum of monounsa-turated and...

Drug Interactions And Glucose Metabolism

Many drugs can cause hypoglycemia or hyperglycemia or alter the response of diabetic patients to their existing therapeutic regimens. Aside from insulin and oral hypoglycemic drugs, drug-induced hypoglycemia is most often caused by ethanol, fi adrenergic receptor antagonists, and salicylates. The primary action of ethanol is to inhibit gluconeogenesis. In diabetics, fi adrenergic receptor antagonists pose a risk of hypoglycemia because of their capacity to inhibit cate-cholamine effects on gluconeogenesis and glycogenolysis. These agents also may mask the autonomic symptoms associated with hypoglycemia (e.g., tremor and palpitations). Salicylates enhance fi-cell sensitivity to glucose and potentiate insulin secretion and also have a weak insulin-like action in the periphery. A number of drugs have no direct hypoglycemic action but may potentiate the actions of sulfonylureas (see below). An equally large number of drugs may cause hyperglycemia in normal individuals or impair metabolic...

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.

Rational Design of Protein Hormones Tomorrow Is Here

Physiologic insulin secretion has two elements. There is a continuous basal secretion of insulin that serves to regulate hepatic gluconeogenesis. In addition there are peaks of insulin secretion that occur upon eating. Efforts at insulin replacement therapy have attempted to mimic these elements by combining intermediate or long-acting insulin, such as NPH or UltraLente, with more rapidly acting regular insulin. Unfortunately, release of longer-acting insulins from the injection site is not constant, and onset of action of regular insulin after injection lags behind postprandial hyperglycemia. Therefore insulin injection

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...

Pharmacology and pharmaceutics

Clinical pharmacology Insulin is secreted by the beta cells of the pancreas. Insulin deficiency results in marked reduction in the rate of transport of glucose across cell membranes, resulting in hyper-glycemia there is also a reduction in the enzyme system that catalyzes the conversion of glucose to glycogen, and an abnormally high rate of conversion of protein to glucose. Insulin stimulated endogenously or administered exogenously stimulates carbohydrate metabolism and facilitates transfer of glucose into cardiac muscle, skeletal muscle, and adipose tissue and converts glucose to glycogen.

Streptozotocin Diabetic

Much less information regarding the oxidant antioxidant status is presently available for the obese Zucker rat. It should be stressed that this animal model displays only mild fasting hyperglycemia, with more severe abnormalities observed when the animal is presented with a glucose load (27,37,38). Nevertheless, Nourooz-Zadeh (39) reported that the isoprostane 8-cpi-PGF2 , a marker of oxidative stress, is elevated in the plasma of the diabetic Zucker rat compared with lean controls. Interestingly, these elevated levels of oxidative stress are significantly reduced with antioxidant treatment, such as a-tocopherol (39). These results concerning oxidative stress in the diabetic Zucker rat are consistent with observations of human type 2 diabetes. During a euglycemic hyperinsulinemic clamp, a significant inverse relationship has been observed between insulin action on nonoxidative glucose disposal and plasma superoxide ion, and a significant positive relationship has been seen between...

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) 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 damage resulting from autoxidation of glucose, glycated proteins, inflammatory processes, and impaired antioxidative defense...

Diabetes Mellitus Type

The question remains whether dietary vitamin E intake is related to the risk of diabetes in healthy individuals. Insulin resistance precedes the development of type 2 diabetes and it is associated with an increase in oxLDL and circulating lipid peroxidation products in healthy, nondiabetic individuals at an early, preclinical stage as well as in patients with glucose intolerance (87-89). In a clinical trial, insulin-mediated glucose disposal was inversely related to self-reported dietary intake of vitamin E (90). In another study with apparently healthy volunteers, blood vitamin E levels were higher in insulin-sensitive subjects than in insulin-resistant subjects, and a significant negative association between plasma vitamin E and lipid hydroperoxides was observed (91). Thus, vitamin E likely plays a beneficial role in the prevention of type 2 diabetes. Furthermore, a beneficial role for vitamin E (alone or in combination with other antioxidants) was suggested in the prevention of...

Vitamin E and Pregnancy

Preterm delivery, and or birth defects such as fetal malformations and growth retardation, respiratory distress, and vascular complications (93-96). This teratogenicity results from fetal hyperglycemia, hyperlipidemia, hyperinsulinemia, and chronic fetal hypoxia due to reduced maternal blood flow. Oxidative stress during diabetic pregnancy is also reflected in fetuses and is an important determinant of fetal injury (97,98). A study in mothers with gestational diabetes and their newborns (fetal age 34-39 wk) revealed increased lipid peroxidation and protein oxidative damage in erythrocytes of both mother and fetus compared with controls (99).

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

Lithium treatment in patients with BD has been associated with weight gain in numerous studies 64-68 and has been found to range from 5 kg within 1-2 years to 4.5-15.6 kg over 2 years 69, 70 . A recent animal study found that lithium increased gastrointestinal weight of male and female rats but only increased total body weight in females 71 . The mechanisms for lithium-induced weight gain remain unclear despite several conjectures. Lithium appears to exert insulin-like activity on carbohydrate metabolism, leading to increased glucose absorption in adipose tissue 72-75 . Lithium may also have direct effects on the hypothalamus to stimulate appetite and or thirst and can also result in increased fluid retention 76 . Although lithium treatment can result in significant weight gain and or hypothyroidism, long-term lithium treatment does not appear to be associated with IR or increased risk of developing diabetes mellitus 66 . In fact, one study suggested that lithium exerts anti-diabetic...

O Newer Agents For The Treatment Of Hiv Infection

There is an important caution for the use of PIs. As a class, they cause dyslipidemia, which includes elevated cholesterol and triglycerides and a redistribution of body fat centrally to cause the protease paunch buffalo hump, facial atrophy, and breast enlargement. These agents also cause hyperglycemia.

Endogenous Glucoregulatory Peptide Hormones and Dipeptidyl Peptidase IV DPP4 Inhibitors

In view of the essential role of DPP4 in the control of GLP-1 activity and glucose homeostasis, it seemed an obvious step to search for small molecule inhibitors of DPP4, which would increase the half-life of active GLP-1 and prolong the glucor-egulatory effect of this incretin. Several small molecule inhibitors of DPP4 were designed and have proved effective in preventing degradation of GLP-1 in vivo, lowering blood glucose in the first preclinical studies 5 . Subsequently, proof-of-concept (PoC) for the efficacy of DPP4 inhibitors as antidiabetic agents in humans was provided with NVP DPP728, a first-generation small molecule inhibitor 6 .

Pathways of Glucose Mediated Oxidative Stress in Diabetic Neuropathy

Diabetic distal symmetric sensorimotor polyneuropathy (DPN), the most common peripheral neuropathy in developed countries (1-3), affects up to 6070 of diabetic patients (4) and is the leading cause of foot amputation (5). The typical slowing of nerve conduction and the advancing distal symmetrical sensorimotor deficits are thought to reflect an underlying slowly progressive distal axonopathy of the dying-back type primarily affecting sensory nerve fibers (6). Improved blood glucose control substantially reduces the risk of developing DPN in insulin-dependent (type 1) diabetes (7,8), thereby strongly implicating hyperglycemia as a causative factor.

Inborn Errors of Metabolism

There are no specific anatomical brain abnormalities associated with GLUT1 deficiency syndrome, and brain imaging is usually normal or may show nonspecific findings. Electroencephalograph (EEG) changes include both focal and generalized epileptiform discharges and slowing, which may be reversible with food intake (47). Hypoglycorrhachia (low cerebral spinal fluid CSF glucose concentration) in the presence of a normal blood glucose (or a CSF blood glucose ratio < 0.4) is the hallmark of the disease. The lumbar puncture should be performed during the metabolic steady state, such as 4-6 h after the last meal. In children, blood glucose should be determined before the lumbar puncture to avoid stress-related serum hyperglycemia. The CSF should be examined for cells, glucose, protein, and lactate and pyruvate concentrations. In GLUT1 deficiency syndrome, CSF concentrations of lactate are usually low to normal. For other causes of hypoglycorrhachia (meningitis, subarach-noid hemorrhage,...

Therapeutic Uses Of Ace Inhibitors And Clinical Summary

Other Adverse Effects Dysgeusia, an alteration in or loss of taste, can occur. It may be more frequent with captopril and is reversible. Neutropenia is a rare but serious side effect of ACE inhibitors it occurs predominantly in hypertensive patients with collagen-vascular or renal parenchymal disease. If the serum creatinine concentration is 2 mg dL or greater, the dose of ACE inhibitor should be kept low, and the patient should be counseled to seek medical evaluation if symptoms (e.g., sore throat, fever) develop. Glycosuria in the absence of hyperglycemia is an exceedingly rare and reversible side effect whose mechanism is unknown. Hepatotoxicity, usually of the cholestatic variety, also is exceedingly rare and reversible. The mechanism again is unknown.

Yoshitaka Kajimoto Yoshimitsu Yamasaki Takaaki Matsuoka Hideaki Kaneto and Masatsugu Hori

We have found that the insulin gene promoter is rather sensitive to oxidative stress caused by the induction of glycation. Results of reporter gene analyses using 3-cell-derived HIT-T15 cells revealed that approximately 50 and 80 of the insulin gene promoter activity was lost when the cells were kept for 3 days in the presence of 40 and 60 mM D-ribose, respectively. The addition of 1 mM aminoguanidine or 10 mM N-acetylcysteine prevented this phenomenon. In agreement with the suppression of promoter activity, a decrease in the insulin mRNA and insulin content was observed in glycation-induced cells. Such a decrease in promoter activity was not observed at all with the control 3-actin gene. Because protein glycation occurs in pancreatic 3 cells when kept under chronic hyperglycemia, the oxidative stress-mediated suppression of the insulin gene transcription may cause a decline in insulin secretion from pancreatic 3 cells accompanied by a decrease in the insulin content of the cells and...

Route of administration Novo Log

Recommended dosage and monitoring requirements The dosage of NovoLog should be individualized and determined in accordance with the needs of the patient. The total daily individual insulin requirement is usually between 0.5 and 1.0 units kg per day. In a meal-related treatment regimen, NovoLog may provide 50 to 70 of this requirement and the remainder by an intermediate-acting or long-acting insulin. Patients may require more basal insulin in relation to bolus insulin and more total insulin when using NovoLog compared to regular human insulin to prevent premeal hyperglycemia. Additional basal insulin injections may be necessary. Because of the fast onset of action, the injection of NovoLog should immediately be followed by a meal. Because of the short duration of action of NovoLog, patients with type 1 diabetes also require a longer-acting insulin to maintain adequate glucose control.

Toxic Side Effects of As2O3

Instead, As2O3 induces leukocytosis in about 50 of patients.11,13,36 The leuko-cytosis can resolve in all cases without chemotherapy.87 The APL patients on As2O3 can also develop retinoic acid syndrome (RAS)-like symptoms such as fever, skin rash and edema, which can be readily relieved by steroid administra-tion.88 Other mild effects were reported in about 40-50 of relapsed patients, including fatigue, fever, edema, nausea, anorexia, diarrhea, emesis, headache, insomnia, cough, dyspnea, dermatitis, tachycardia, pain, hypokalemia, hypo-magnesemia and hyperglycemia. The most common (> 10 ) Grade 3 and 4 adverse events were abdominal pain, epistaxis, dyspnea, hypoxia, bone pain, thrombocytopenia, neutropenia, hypokalemia and hyperglycemia.11,36,89 In a clinical trial, prolonged QT intervals (the time intervals for the contraction of the ventricle from the beginning of the Q wave to the end of T wave a prolonged QT interval indicates cardiac toxicity) were observed in all patients...

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

Oxidative Damage to Carbohydrates

Reactive carbonyl species also react with DNA 119 , causing mutations both in nDNA and mtDNA 120, 121 , and inhibit complex I, increasing free radical leakage 122 . Moreover, hyperglycemia stimulates inflammatory processes 123 through the activation ofspecific receptors for AGE products called RAGE (receptors for advanced glycoxidation end products).

Experimental Diabetic Neuropathy Oxidative Stress and Antioxidant Therapy

Glucose, by a process of autooxidation in the presence of decompartmenta-lized trace transitional metals, can cause lipid peroxidation (6). We have evaluated the role of hyperglycemia in lipid peroxidation in vitro, using an in vitro lipid peroxidation model, with an ascorbate-iron-EDTA system. The addition of 20 raM glucose to the incubation medium increased lipid peroxidation fourfold, confirming rapid and marked glucose-mediated autooxidative lipid peroxidation (7). Glucose autooxidation results in the production of protein reactive ketoaldehydes, hydrogen peroxide highly reactive oxidants, and the fragmentation of proteins (free radical mechanisms). Glycation and oxidation are simultaneous and inextricably linked (8).

Hypoglycemic Agent Pharm Chem

For a time, tolbutamide, chlorpropamide, and acetohexamide were the only oral hypoglycemic agents. Subsequently, a second generation of these drugs became available. Although they did not present a new method of lowering blood glucose levels, they were more potent than the existing drugs. Glipizide and glyburide are the second-generation oral hypoglycemic agents.

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).

Conclusions

Taken together, there is good evidence that short- and long-term hyperglycemia cause an activation of NADPH oxidase and the formation of ROI. The endothelium has been demonstrated as one of the major sources of ROI generation. Experimental data from in vitro and in vivo studies clearly show that these ROIs are able to induce a thrombogenic transformation of the vessel wall and to be the cause for the endothelial dysfunction observed in diabetes but also in hypertension and hypercholesterolemia. Whether these cytotoxic effects are exerted by superoxide anions directly or are mediated by peroxynitrite depends on the local environment and the type of vasculature regarded. Our current knowledge is summarized in the hypothesis shown Figure 6 Current hypothesis formation of ROI by hyperglycemia and the effects of ROI on the vessel wall as cause for the development of vascular complications in diabetes. Figure 6 Current hypothesis formation of ROI by hyperglycemia and the effects of ROI on...

Conclusion

Proteins (glycoxidation), supporting the concept of increased oxidative stress in diabetes. Indeed, the newly introduced drug troglitazone may exert some of its protective effects by its antioxidant capacity (95). Further work is required using modern biomarkers to evaluate the extent to which agents beneficial in the treatment of diabetes, including lipoic acid (see other chapters in this volume), act by suppressing oxidative stress. Another exciting area is the prevention of the teratogenic effects of hyperglycemia Studies in rats have shown that vitamin E (96) and overexpression of CuZnSOD (97) can be beneficial.

Antioxidant Supply

In diabetic mellitus, it is expected that hyperglycemia restricts the supply of vitamin C to the retina due to inhibition of GLUT1. Indeed, 14C DHA uptake by TR-iBRB cells was inhibited by D-glucose and 3-OMG in a concentration-dependent manner with an IC50 of 5.56 and 16.9 mM, respectively (Fig. 3B) (30). The Kinretina of 14C DHA was reduced by 66 in streptozocin-induced diabetic rats compared with normal rats (Fig. 3A) (31). Accordingly, diabetic patients may experience enhanced oxidative stress and metabolic perturbations in the retina following a reduction in the influx transport of DHA, leading to the hypothesis that diabetic retinopathy involves a dysfunction of DHA influx transport at the BRB.

Diabetes

Minimizing the oxidative damage from overproduction of ROS in diabetic hyperglycemia. In the three main pathways of pathogenesis of hyperglycemic damage, normalizing levels of SOD2 in bovine aortic endothelial cells prevented the pathogenesis.60 These results suggest that therapy with SOD mimetics warrant further investigation.

Introduction

Neuropathy is a common complication of diabetes mellitus. Studies in patients and animal models have shown that endoneurial hypoxia, caused by impaired nerve blood flow, is a major factor in the etiology of diabetic neuropathy (l-4). Changes in vascular function, particularly of the endothelium, occur early after diabetes induction in experimental models, and in some preparations, this may even be partially mimicked by acute exposure to hyperglycemia (5,6). In streptozotocin-induced diabetic rats, sciatic nerve blood flow is reduced by approximately 50 within a week of diabetes induction (7,8), and this precedes changes in nerve conduction velocity (NCV). Large diameter sensory and motor fibers are particularly susceptible to endoneurial hypoxia in experimental diabetes (9,10).

Meal Composition

Greater in women compared with the decline previously described in men 35 . Glucose load leads to a rapid rise in insulin levels in nondiabetics, and thereby to an increased transport of tryptophan into the central nervous system. This is followed by an increased synthesis of serotonin, which is known to have a stimulatory influence on the HPA axis at the hypothalamic level 41 . Following Trier Social Stress Test subjects with high blood glucose levels showed the well-established response pattern of a twofold increase in free cortisol levels 42, 43 . Human studies suggest that ready availability of energy is a prerequisite for significant acute stress responses of the HPA axis 12 .

Nad Nadh

Figure 3 Hyperglycemia activates the sorbitol pathway. Sorbitol oxidation increases cytosolic NADH NAD+. Increased NADH NAD+ ratios increase prostaglandin synthesis, leading to free radical production. In the mitochondria, the superoxide radical is generated by oxidation of NADH in the electron transport chain. Hyperglycemia Sorbitol pathway activity

Perspective

The ketogenic diet (KD) is both a therapy and a tool for investigating the mechanisms of seizures and, perhaps, epilepsy. Despite our ignorance of the mechanisms by which the KD acts to alter seizures, the observation that seizure threshold can vary widely depending on what an animal eats suggests that seizure threshold is a (patho)physiological variable. The general hypothesis underlying experimental studies of the KD is that, by understanding the physiological changes consequent to a switch from a carbohydrate-based metabolism to one based on fats, we might gain insight into fundamental processes that affect ictogenesis. If a person whose seizures are controlled by a KD abandons the diet abruptly and suffers a seizure, then we might consider elevated blood glucose (or decreased ketonemia) to be ictogenic. Because central nervous system (CNS) metabolism is normally based entirely on glucose, the success of KDs in treating seizures and epilepsies presents interesting questions and...

NaK ATPase

Na+-K+ ATPase, an integral component of the sodium pump, is involved in the maintenance of cellular integrity and functions such as contractility, growth, and differentiation (5). It is well established that Na+-K+ ATPase activity is generally decreased in the vascular and neuronal tissues of diabetic patients and experimental animals (5,86-88). However, studies on the mechanisms by which hyperglycemia inhibited Na+-K+ ATPase activity have provided some conflicting results regarding the role of PKC. Phorbol esters, activators of PKC, have been shown to prevent the inhibitory effect of hyperglycemia on Na+-K+ ATPase (5), which suggested that PKC activity might be decreased in diabetic conditions. Recently, however, we showed that elevated glucose level (20 mM) will increase PKC and cPLA2 activities, leading to increases of arachadonic acid release and PGE2 production resulting in decreases in Na+-K+ ATPase activity. Inhibitors of PKC or PLAo prevented glucose-induced reduction in...

Discussion

In interpreting the results of this study, it is important to note both the composition of the sample and the criteria used to define MetS. Although large and diverse, the sample did not represent all ages or ethnicities. All subjects were inpatients at the time of assessment, and a number of characteristics of the sample suggest that these patients may be more severely and or chronically ill than those included in previous studies. Not all data were available on all patients, and reliable information was not available about smoking status, diet or exercise. The pharmaco-therapy for these patients may not be representative of all clinical settings, and type and duration of medication exposure prior to the baseline assessment are not known. All patients were being treated for MDD, but diagnosis was not independently verified by the investigators. The variable 'diabetic medication', following the NHANES methodology 4 , grouped all of the available pharmacotherapies for hyperglycemia....

Summary

The results presented above are consistent with the activation of the DAG-PKC signal transduction pathway in diabetes. The initiating factors are chiefly metabolic with hyperglycemia as the main triggering element. Other metabolic changes such as those associated with free fatty acids are also potentially involved. The finding that the secondary metabolic products of glucose such as glycation products and oxidants can also increase DAG-PKC suggest that the activation of DAG-PKC could be a common downstream mechanism by which multiple byproducts of glucose are exerting their adverse effects. It is not surprising that changes in the DAG-PKC pathway can play a role in diabetic microvascular complications as this signal transduction pathway is known to regulate many vascular actions and functions as described above (11,12). It is also likely that hyperglycemia and diabetes may affect other signal transduction pathways besides the DAG-PKC pathway because a number of these other pathways...

Enzymes

L-Asp has minimal effects on bone marrow and GI mucosa. Its most serious toxicities result from its antigenicity and its inhibition of protein synthesis. Hypersensitivity reactions occur in 5-20 of patients and may be fatal. These reactions are heralded by the appearance of circulating neutralizing antibody in some, but not all, hypersensitive patients. In these patients, pegas-pargase is a safe alternative, and the Erwinia enzyme may be used with caution. Other toxicities result from inhibition of protein synthesis in normal tissues and include hyperglycemia due to insulin deficiency, clotting abnormalities due to deficient clotting factors, and hypoalbuminemia. The clotting problems may take the form of spontaneous thrombosis, or less frequently, hemor-rhagic episodes. Brain magnetic resonance imaging (MRI) studies should be considered in

Insulin Resistance

Hyperglycemia (NIDDM) The levels of expression of the GLUT4 glucose transporter have been analyzed in a variety of animal models of type 2 diabetes and in tissue from individuals with type 2 diabetes (for review see 18,19). GLUT4 protein content is markedly diminished in adipose tissues of human and most animal models. It has been found that GLUT4 expression in adipocytes decreases as diabetes develops in older Zucker rats (18,19), and adipose cells taken from humans with type 2 diabetes also show a reduction in GLUT4 content (20). However, this change in GLUT4 levels is restricted to adipose tissue and is not seen in skeletal muscle of these animal models of type 2 diabetes as normal expression of GLUT4 is observed in muscle of db db mice and Zucker rats (21-24). Muscle biopsies taken from individuals with type 2 diabetes also show normal skeletal muscle GLUT4 content (25). However, a small number of studies have examined the amount of GLUT4 protein on the plasma membrane of muscle...

Antiglucocorticoids

Developed nations are witnessing a striking increase in the prevalence of diabetes mellitus (DM), predominantly related to lifestyle changes and the resulting surge in obesity. The metabolic consequences of prolonged hyperglycemia and dyslipidemia, including accelerated atherosclerosis, chronic kidney disease, and blindness, pose an enormous burden on patients with DM and on society. Improvements in our understanding of the pathogenesis of diabetes and its complications and in the prevention and therapy of diabetes are critical to meeting this challenge.

Daily Requirements

In type 1 DM patients, the average dose of insulin is usually 0.6-0.7 units kg day, with a range of 0.2-1 units kg day. Obese patients generally require more (about 2 units kg day) because of resistance of peripheral tissues to insulin. As in nondiabetics, the daily requirement for insulin can be divided into basal and postprandial needs. The basal dose (usually 40-60 of the total daily dose) suppresses lipolysis, proteolysis, and hepatic glucose production. The dose necessary for disposition of nutrients after meals usually is given before meals. Insulin often has been administered as a single daily dose of intermediate-acting insulin, alone or in combination with regular insulin. This rarely achieves true euglycemia since hyperglycemia is the major determinant of long-term diabetic complications, more complex regimens that include combinations of intermediate-or long-acting insulins with regular insulin are used to reach this goal. Several commonly used dosage regimens that include...

Type 1 Diabetes

The most widely used animal model of type 1 diabetes is the streptozotocin-induced diabetic rat. Streptozotocin is a compound that causes hypersecretion of insulin from the pancreatic P-cells, resulting in their eventual dysfunction and leading to a hypoinsulinemic state (23). The streptozotocin-diabetic rat is characterized by marked postprandial hyperglycemia and by an elevation in free fatty acids without ketoacidosis (23). Skeletal muscle from the streptozotocin-diabetic rat is markedly insulin resistant for stimulation of glucose transport (24,25) and expresses a significantly reduced protein expression of the GLUT4 glucose transporter isoform (24,25).

Pancreatic bCells

Pancreatic p-cells play a major role in the regulation of glucose homeostasis by secreting insulin in response to elevated blood glucose. In pancreatic p-cells, SIRT1 enhances glucose-stimulated insulin secretion and improves glucose tolerance, at least in part, by repressing the expression of uncoupling protein 2 (UCP-2), an inner mitochondrial membrane protein (Bordone et al. 2006 Moynihan et al. 2005). UCP-2 functions as a proton transporter, whose activity has the effect of uncoupling the electron transport chain and ATP biosynthesis. Suppression of UCP-2 by SIRT1 increases ATP production, inducing glucose-stimulated insulin secretion. Indeed, islets isolated from beta cell-specific Sirtl -overexpressing (BESTO) transgenic mice exhibit increased ATP production in response to glucose. Interestingly, both pancreata and islets of BESTO mice show the enhancement of insulin secretion not only by glucose, but also by KCl-induced depolarization, suggesting that SIRT1 might also regulate...

SIRT1 and T2D

T2D has a complex pathology consisting of defects in insulin secretion and action that together result in hyperglycemia (Bell and Polonsky 2001 Cavaghan et al. 2000). SIRT1 plays an important role in promoting insulin secretion by pancreatic b-cells and protecting against insulin resistance in the liver, skeletal muscle, and adipose tissue. These findings support the notion that SIRT1 is important for the maintenance of glucose homeostasis and the prevention of T2D. Indeed, under diabetogenic HFD conditions (Kraegen et al. 1991 Kubota et al. 1999 Surwit et al. 1988), the activity and or protein expression of SIRT1 are reduced in several tissues (Deng et al. 2007 Escande et al. 2010 Qiao and Shao 2006). Moreover, increasing SIRT1 by genetic manipulation prevents metabolic disorders induced by HFD feeding. It has been reported that whole-body Sirt1 -overexpressing transgenic mice improves glucose tolerance by decreasing hepatic glucose production without changes in body weight or fat...

Spine Injections

Cervical Facet Joint Referred Pain

A wet tap or neurologic injury is increased. The effects of the steroid usually occur within 2448 h and reach their maximum potential benefit by 7-10 days. They may be repeated monthly up to three times per year without significant systemic side effects from the steroids. Diabetics may experience elevated blood glucose levels for up to several weeks.

Insulin Aspart

Indications Treatment of adult patients with diabetes mellitus, for the control of hyperglycemia 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.

Mutant Mice2C

Double mutant mice constitutively lacking both 5-HT2CRs and the adipocyte hormone leptin (htr2c Y, ob- ob-) provide particularly convincing evidence that signal integration at the POMC neuron plays a vital role in control of ingestive behaviors. Young double mutant mice had many hallmarks of significant diabetes, including hyperphagia and marked polydipsia, obesity, hyperglycemia, aberrant glucose tolerance tests, glucosuria, and hyperinsulinemia (Wade et al. 2008). Double mutant mice also had markedly elevated serum concentrations of the antiinsulin counterregulatory hormones corticosterone and glucagon. While there were no phenotypic differences appreciated in the above outcomes for young mice carrying a single constitutive 5-HT2CR deletion, addition of the 5-HT2CR mutation on top of the ob- ob- genetic background markedly increased the size of each of these deficits well above the baseline ob- ob- phenotype.

Glucagon

Diabetic hyperglycemia SC, as directed by physician 15-30 minutes before meals up to t.i.d. or q.i.d. Attention has been focused on glucagon as a factor in the pathology of human diabetes. According to Unger et al.,62 the following observations support this implication of glucagon elevated glucagon blood levels (hyperglucagonemia) have been observed in association with every type of hyper-glycemia when secretion of both glucagon and insulin is suppressed, hyperglycemia is not observed unless the glucagon levels are restored to normal by the administration of glucagon the somatostatin-induced suppression of glucagon release in diabetic animals and humans restores blood sugar levels to normal and alleviates certain other symptoms of diabetes. trations of glucose, thereby causing persistent hyperglycemia. This indicates that a relative excess of glucagon is an essential factor in the development of diabetes.

Insulin Glargine

Litus who require basal (long-acting) insulin for the control of hyperglycemia 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 hyperglycemia.

Neuropathology

Nerve conduction studies showed markedly reduced conduction velocities in the distal nerve segments and prolonged F wave latency and proximal conduction time despite the shorter conduction pathway in diabetic rats. We suggest that the combination of hyperglycemia and ischemia results in oxidative stress and a predominantly sensory neuropathy.