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 disorders characterized by hyperglycemia; altered metabolism of lipids, carbohydrates, and proteins; and an increased risk of complications from vascular disease. Most patients can be classified clinically as having either type 1 or type 2 DM. The American Diabetes Association (ADA) criteria for the diagnosis of DM include symptoms (e.g., polyuria, polydipsia, and unexplained weight loss) and a random plasma glucose concentration of greater than 200 mg/dL (11.1 mM), a fasting plasma glucose concentration of greater than 126 mL/dL (7 mM), or a plasma glucose concentration of greater than 200 mg/dL (11 mM) 2 hours after the ingestion of an oral glucose load.

The incidence of diabetes varies widely throughout the world. In the U.S., 5—10% of all diabetic patients have type 1 DM, with an incidence of 18/100,000 inhabitants/year. The vast majority of diabetic patients (~90% in the U.S.) have type 2 DM. Incidence rates of type 2 DM increase with age, with a mean rate of about 440/100,000/year by the sixth decade in males in the U.S.

Both environmental and genetic components affect the risk of developing DM. These factors are more clearly defined for type 2 DM. Obesity is a major risk factor, and 80—90% of type 2 DM subjects in the U.S. are obese. Studies also support a strong genetic basis for type 2 DM. In a small subset of patients, the genetic basis for type 2 DM is clearly established. Mutations in glucokinase cause the autosomal dominant disorder MODY2; these patients have an increased glycemic threshold for insulin release that results in persistent mild hyperglycemia. Other single-gene mutations cause the other types of MODY, including those affecting pancreatic transcription factors.

For type 1 DM, the concordance rate for identical twins is only 25—50% and environmental influences must have an important role. Type 1 DM involves an autoimmune attack on the pancreatic fi cells. Antibodies to islet cell antigens are detected in up to 80% of patients with type 1 DM shortly after diagnosis or even prior to the onset of clinical disease. Type 1 DM is associated with specific human leukocyte antigen (HLA) alleles, especially at the B and DR loci, and the HLA complex is known to play critical roles in the immune response. However, the trigger for the immune response remains unknown. In about 10% of new cases of type 1 DM, there is no evidence of autoimmune insulitis. The ADA and the World Health Organization (WHO) therefore subdivide this disease into autoimmune (1A) and idiopathic (1B) subtypes.

Whatever the causes, the final result in type 1 DM is an extensive and selective loss of pancreatic fi cells and a state of absolute insulin deficiency. In type 2 DM, fi-cell mass is generally reduced by ~50%. At diagnosis, virtually all persons with type 2 DM have a profound defect in first-phase insulin secretion in response to an intravenous glucose challenge, although some of these fi-cell abnormalities may be secondary to desensitization by chronic hyperglycemia.

Virtually all forms of DM result from a decrease in the circulating concentration of insulin (insulin deficiency) and a decrease in the response of peripheral tissues to insulin (insulin resistance). These abnormalities lead to alterations in the metabolism of carbohydrates, lipids, ketones, and amino acids; the central feature of the syndrome is hyperglycemia.

Insulin lowers the concentration of glucose in blood by inhibiting hepatic glucose production and by stimulating the uptake and metabolism of glucose by muscle and adipose tissue (Table 60-1). These two important effects occur at different concentrations of insulin. Glucose production is inhibited half maximally by an insulin concentration of about 20 ,uunits/mL, whereas glucose utilization is stimulated half maximally at about 50 ,uunits/mL.

Table 60-1

Hypoglycemic Actions of Insulin

Liver

Muscle

Adipose Tissue

Inhibits hepatic glucose production (decreases gluconeogenesis and glycogenolysis) Stimulates hepatic glucose uptake

Stimulates glucose uptake

Inhibits flow of gluconeogenic precursors to the liver (e.g., alanine, lactate, and pyruvate)

Stimulates glucose uptake (amount is small compared to muscle)

Inhibits flow of gluconeogenic precursor to liver (glycerol) and reduces energy substrate for hepatic gluconeogenesis (nonesterfied fatty acids)

In both types of diabetes, glucagon (elevated in untreated patients) opposes the hepatic effects of insulin by stimulating glycogenolysis and gluconeogenesis but has relatively little effect on peripheral glucose utilization. Thus, in the diabetic patient (depressed insulin signaling and hyper-glucagonemia) there is increased hepatic glucose production, decreased peripheral glucose uptake, and decreased conversion of glucose to glycogen in the liver.

Alterations in insulin and glucagon secretion also profoundly affect lipid, ketone, and protein metabolism. At concentrations below those needed to stimulate glucose uptake, insulin inhibits hormone-sensitive lipase in adipocytes and inhibits the hydrolysis of triglyceride stores. This counteracts the lipolytic action of catecholamines, cortisol, and growth hormone and reduces the concentrations of glycerol (a substrate for gluconeogenesis) and free fatty acids (a substrate for production of ketone bodies and a necessary fuel for gluconeogenesis). These actions of insulin are deficient in DM, leading to increased gluconeogenesis and ketogenesis.

The liver produces ketone bodies by oxidizing free fatty acids to acetyl CoA, which then is converted to acetoacetate and (3-hydroxybutyrate. The initial step in fatty acid oxidation is transport of the fatty acids into the mitochondria. The essential enzyme in this process, acylcarnitine transferase, is inhibited by intramitochondrial malonyl CoA, one of the products of fatty acid synthesis. Normally, insulin inhibits lipolysis, stimulates fatty acid synthesis (thereby increasing the concentration of malonyl CoA), and decreases the hepatic concentration of carnitine; these factors all decrease the production of ketone bodies. Conversely, glucagon stimulates ketone body production by increasing fatty acid oxidation and decreasing concentrations of malonyl CoA. In patients with type 1 DM, insulin deficiency and glucagon in excess provide a hormonal milieu that favors ketogenesis and may lead to ketoacidosis.

Insulin also enhances the transcription of lipoprotein lipase in the capillary endothelium. Thus, hypertriglyceridemia and hypercholesterolemia often occur in untreated or undertreated diabetics. In addition, insulin deficiency may be associated with increased production of VLDL.

The key role of insulin in protein metabolism usually is evident only in diabetic patients with persistently poor glycemic control. Insulin stimulates amino acid uptake and protein synthesis and inhibits protein degradation in muscle and other tissues. The increased conversion of amino acids to glucose also results in increased production and excretion of urea and ammonia. In addition, there are increased circulating concentrations of branched-chain amino acids as a result of increased proteolysis, decreased protein synthesis, and increased release of branched-chain amino acids from the liver.

A nearly pathognomonic feature of diabetes mellitus is thickening of the capillary basement membrane. The progressive narrowing of the vessel lumina causes inadequate perfusion of certain organs, contributing to the major complications of diabetes, including premature atherosclerosis, intercapil-lary glomerulosclerosis, retinopathy, neuropathy, and ulceration and gangrene of the extremities.

It was hypothesized that the factor responsible for the development of most complications of DM is the prolonged exposure of tissues to elevated concentrations of glucose. The results from the Diabetes Control and Complications Trial (DCCT) definitively demonstrated that most diabetic complications arise from prolonged exposure of tissue to elevated glucose concentrations. The DCCT demonstrated unequivocally that improving day-to-day glycemic control in type 1 DM patients can dramatically decrease diabetic complications. A follow-up study showed that intensive therapy reduced cardiovascular adverse events and that the reduction in the risk of progressive retinopathy and nephropathy persists for at least 4 years, even if tight glycemic control is not maintained. Rigorous control of blood glucose provides similar benefits to patients with type 2 diabetes.

The toxic effects of hyperglycemia may relate to the formation and accumulation of products such as glycosylated proteins and lipids. Advanced glycosylation end-products (AGEs) signal through receptors for AGEs (RAGEs) to alter oxidative stress, inflammatory injury, and a variety of other responses that may contribute to the sequelae of diabetes. In the face of elevated blood glucose, hemoglobin (Hb) becomes glycosylated on its amino terminal valine, forming Hb A1c, the concentration of which reflects the severity and duration of the hyperglycemic state and may be assessed clinically.

A serious complication of intensive therapy is an increased incidence of severe hypoglycemia. Therefore, ADA guidelines for treatment include a contraindication for implementing tight metabolic control in infants younger than 2 years old and an extreme caution in children of 2—7 years of age in whom hypoglycemia may impair brain development. Older patients with significant arteriosclerosis also may be vulnerable to permanent injury from hypoglycemia. Current therapies for type 1 and type 2 DM therefore aim for tight metabolic control, always keeping in mind the risks of severe hypoglycemia in individual patients.

Insulin Therapy

Insulin is the mainstay for treatment of virtually all type 1 DM and many type 2 DM patients. When necessary, insulin may be administered intravenously or intramuscularly; however, long-term treatment relies predominantly on subcutaneous injections of the hormone. Subcutaneous administration of insulin differs from physiological secretion of insulin in at least two major ways: The kinetics do not reproduce the normal rapid rise and decline of insulin secretion in response to ingestion of nutrients, and the insulin diffuses into the peripheral circulation instead of being released into the portal circulation; the direct effect of secreted insulin on hepatic metabolic processes thus is eliminated. Nonetheless, when such treatment is performed carefully, considerable success is achieved.

Insulin preparations are classified according to their duration of action into rapid, short, intermediate, and long acting and by their species of origin—human or porcine. Human insulin (humulin, novolin) is widely available, as is porcine insulin, which differs from human insulin by one amino acid (alanine instead of threonine in position B30. Human insulin, produced using recombinant DNA technology, is more water soluble than porcine insulin owing to the presence of an extra hydroxyl group. The vast majority of preparations now are supplied at neutral pH, which improves stability and permits storage for several days at room temperature.

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