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Abstract

Abstract 

  1. Diabetes mellitus is a syndrome characterized by elevated levels of glucose in the plasma. The American Diabetes Association has recently proposed revised criteria for the diagnosis of diabetes: (a) a fasting plasma glucose level >126 mg/dl, or (b) a plasma glucose level >200 mg/dl at 2 h after the ingestion of oral glucose (75 g), or (c) random plasma glucose >200 mg/dl.

  2. Diabetes is a heterogeneous clinical syndrome with multiple etiologies. Type 1 diabetes is caused by destruction of pancreatic beta cells, most often by autoimmune mechanisms. Type 2 diabetes (the most common form of diabetes, accounting for >90 percent of patients) is caused by a combination of two physiological defects: resistance to the action of insulin combined with a deficiency in insulin secretion. Although the molecular basis of the common form of type 2 diabetes has not been elucidated, it is thought to result from genetic defects that cause both insulin resistance and insulin deficiency. Type 2 diabetes generally has onset after the age of 40. Unlike type 1 diabetes, type 2 diabetes is usually associated with relatively mild hyperglycemia, and ketoacidosis seldom develops. Gestational diabetes mellitus is a form of diabetes that has its initial onset during pregnancy, and resolves after the end of the pregnancy.

  3. Insulin exerts multiple effects upon target cells—especially skeletal muscle, liver, and adipose tissue. In general, insulin promotes storage of fuels (e.g., glycogen and triglyceride), and inhibits the breakdown of stored fuel. To accomplish these general physiological functions, insulin exerts multiple specific actions upon target cells. For example, insulin promotes recruitment of glucose transporters from intracellular vesicles to the plasma membrane, thereby stimulating glucose transport into skeletal muscle and adipocytes. Insulin also regulates many metabolic enzymes, either by increasing or decreasing the level of protein phosphorylation. In addition, insulin regulates the level of intracellular metabolites that regulate enzyme activity by allosteric mechanisms. Finally, insulin regulates the level of gene expression—inducing the expression of some genes (e.g., hepatic glucokinase) and inhibiting expression of other genes (e.g., phosphoenolpyruvate carboxykinase).

  4. The biologic actions of insulin are mediated by a cell surface receptor. The receptor possesses an extracellular domain that binds insulin, and an intracellular domain that possesses tyrosine-specific protein kinase activity. Insulin binding activates the receptor tyrosine kinase, leading to autophosphorylation of the receptor as well as phosphorylation of several intracellular proteins (e.g., insulin receptor substrates -1, -2, -3, and -4). Insulin-stimulated tyrosine phosphorylation ultimately leads to the activation of multiple downstream signaling pathways. Among these, activation of phosphatidylinositol 3-kinase is the most important in mediating the metabolic actions of insulin. Increasing the cellular content of phosphatidylinositol 3,4,5-trisphosphate activates phosphoinositide-dependent protein kinases (e.g., PDK-1). PDK-1 phosphorylates and activates multiple downstream protein kinases, including protein kinase B, atypical protein kinase C, and p70 S6 kinase. Activation of these protein kinases is responsible for mediating many of the ultimate metabolic actions of insulin, including translocation of GLUT4, activation of glycogen synthesis, and suppressing gluconeogenesis by inhibiting transcription of the gene encoding phosphoenolpyruvate carboxykinase.

  5. Although the primary causes of insulin resistance have not yet been elucidated in most patients with type 2 diabetes, mutations in the insulin receptor gene have been demonstrated to cause several rare syndromes associated with insulin resistance (e.g., type A insulin resistance, leprechaunism, and the Rabson-Mendenhall syndrome). In general, patients with two mutant alleles are more severely insulin resistant than are patients with one mutant allele. In some cases, the mutation decreases the number of insulin receptors expressed on the cell surface; in other cases, the mutations impair the functions of the insulin receptor (i.e., insulin binding or insulin-stimulated tyrosine kinase activity).

  6. Recent studies with knockout mice provide animal models for polygenically inherited type 2 diabetes. For example, knockout of the IRS-1 gene leads to insulin resistance, but not diabetes. If this genetic defect in the insulin action pathway is combined with a genetic defect that impairs insulin secretion (e.g., heterozygosity for a null allele of the glucokinase gene), this causes the mice to become diabetic. Furthermore, it is also possible to cause diabetes by heterozygous knockout of two distinct genes in the insulin action pathway (e.g., the genes encoding the insulin receptor and IRS-1). Although knockout mice lacking IRS-1 did not develop diabetes, homozygous knockout of IRS-2 actually caused diabetes. The reason these mice developed diabetes was that knockout of the IRS-2 gene led to two physiological defects: the expected defect in the insulin action pathway plus an unexpected defect in insulin secretion that impaired the ability of the β-cell to compensate for insulin resistance.

  7. Type 2 diabetes is associated with two physiological defects: insulin resistance and impaired insulin secretion. However, the disease evolves over many years, and progresses through multiple stages. Although there is some controversy about the precise sequence of events in the natural history of type 2 diabetes, the following is one formulation of the progressive evolution of type 2 diabetes in a typical patient. Peripheral insulin resistance develops relatively early in the course of the disease. So long as the pancreatic beta cell retains sufficient functional reserve, plasma insulin levels will rise to compensate for the insulin resistance. Nevertheless, the compensation may not be complete, and the patient may develop impaired glucose tolerance and/or impaired fasting glucose. As the disease continues to evolve, there is a progressive impairment in the ability of the beta cell to secrete insulin. This is the time of onset of overt diabetes—that is, at the time when impaired beta cell function prevents the beta cell from compensating for the preexisting insulin resistance. Ultimately, it is hepatic glucose production that determines the magnitude of the elevation in fasting plasma glucose. Thus, in the final stage in the evolution of type 2 diabetes, the liver becomes insulin resistant, and this (combined with impaired insulin secretion plus peripheral insulin resistance) results in severe hyperglycemia and decompensated diabetes.

  8. Although the primary (genetic) causes of insulin resistance are not known, much is known about some factors that contribute to the pathogenesis of insulin resistance. Most patients with type 2 diabetes are obese, and the increase in adiposity is believed to be an important causal factor in the development of insulin resistance. The increase in adipose tissue is associated with an increase in plasma free fatty acid levels, which promotes hepatic glucose production and inhibits peripheral glucose utilization. In addition, the diabetic state leads to a vicious cycle in which insulin deficiency and hyperglycemia both exacerbate insulin resistance and further impair insulin secretion. There is evidence that “glucose toxicity” is not directly caused by hyperglycemia, but rather that the effects are mediated by glucosamine, the levels of which are elevated in response to hyperglycemia.

  9. Among the therapies for type 2 diabetes, at least two drugs (troglitazone and metformin) are said to function as insulin sensitizers. Troglitazone, a ligand for the peroxisome proliferator-activated receptor-γ, is thought to act directly upon adipose tissue, thereby exerting indirect effects to increase insulin sensitivity in skeletal muscle. Metformin exerts its principal action to suppress hepatic glucose production. In addition, by reducing the mass of adipose tissue, weight loss also increases insulin sensitivity. However, even therapies that work by other mechanisms (e.g., insulin and sulfonylureas) exert indirect effects to increase insulin sensitivity—for example, by alleviating the adverse effects of glucose toxicity.

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