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Clinical Gems

Our clinical gems come from the top selling medical books, and text books because knowledge is everything when it comes to diabetes.

International Textbook of Diabetes Mellitus, 4th Ed., Excerpt #140: The Genetics of Type 2 Diabetes Part 2

Heritability of T2DM: It has long been clear that T2DM clusters in families and it is well established that the risk of developing T2DM depends on both genetic and environmental factors. However, the exact proportion of the two, that is, the heritability, is difficult to determine and heritability estimates therefore vary in the range of 25–80% between studies. Twin-studies have estimated the genetic component by comparing disease concordance in dizygotic twins with concordance in monozygotic twins. In these studies probandwise concordance rates (number of affected twins having a diabetic co-twin) for monozygotic twins vary between 34 and 100%.

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International Textbook of Diabetes Mellitus, 4th Ed., Excerpt #138: Pathogenesis of Type 2 Diabetes Mellitus Part 9

In summary, postbinding defects in insulin action primarily are responsible for the insulin resistance in T2DM. Diminished insulin binding, when present, is modest and secondary to downregulation of the insulin receptor by chronic hyperinsulinemia. In type 2 diabetic patients with overt fasting hyperglycemia, a number of postbinding defects have been demonstrated, including reduced insulin receptor tyrosine kinase activity, insulin signal transduction abnormalities, decreased glucose transport, diminished glucose phosphorylation, and impaired glycogen synthase activity. The glycolytic/glucose oxidative pathway is largely intact and, when defects are observed, they appear to be acquired secondary to enhanced FFA/lipid oxidation. From the quantitative standpoint, impaired glycogen synthesis represents the major pathway responsible for the insulin resistance in T2DM, and is present long before the onset of overt diabetes, that is, in normal glucose-tolerant, insulin-resistant prediabetic subjects and in individuals with IGT. The impairment in glycogen synthase activation appears to result from a defect in the ability of insulin to phosphorylate IRS-1, causing a reduced association of the p85 subunit of PI-3 kinase with IRS-1 and decreased activation of the enzyme PI-3 kinase.

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International Textbook of Diabetes Mellitus, 4th Ed., Excerpt #137: Pathogenesis of Type 2 Diabetes Mellitus Part 8

Glucose transport: Activation of the insulin signal transduction system in insulin target tissues stimulates glucose transport via a mechanism that involves translocation of a large intracellular pool of glucose transporters (associated with low-density microsomes) to the plasma membrane and their subsequent activation after insertion into the cell membrane.

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International Textbook of Diabetes Mellitus, 4th Ed., Excerpt #135: Pathogenesis of Type 2 Diabetes Mellitus Part 6

In utero fetal malnutrition: Low birth weight is associated with the development of IGT and T2DM in a number of populations. Developmental studies in animals and humans have demonstrated that poor nutrition and impaired fetal growth (small babies at birth) are associated with impaired insulin secretion and/or reduced beta-cell mass. Fetal malnutrition can also lead to the development of insulin resistance later in life.

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International Textbook of Diabetes Mellitus, 4th Ed., Excerpt #134: Pathogenesis of Type 2 Diabetes Mellitus Part 5

First-phase insulin secretion: In response to i.v. glucose, insulin is secreted in a biphasic pattern with an early burst of insulin release within the first 10 min followed by a progressively increasing phase of insulin secretion that persists as long as the hyperglycemic stimulus is present. This biphasic insulin response is not observed after oral glucose, because of the more gradual rise in plasma glucose concentration. Loss of first-phase insulin secretion is a characteristic and early abnormality in patients destined to develop T2DM.

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International Textbook of Diabetes Mellitus, 4th Ed., Excerpt #133: Pathogenesis of Type 2 Diabetes Mellitus Part 4

Type 2 diabetes with hypoinsulinemia: A large body of clinical and experimental evidence documents that hyperinsulinemia and insulin resistance precede the onset of T2DM. Nonetheless, a number of studies have shown that absolute insulin deficiency, with or without impaired tissue insulin sensitivity, can lead to the development of T2DM. This scenario is best exemplified by patients with maturity onset diabetes of youth (MODY) [69–71]. This familial subtype of T2DM is characterized by early age of onset, autosomal dominant inheritance with high penetrance, mild-to-moderate fasting hyperglycemia, and impaired insulin secretion.

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International Textbook of Diabetes Mellitus, 4th Ed., Excerpt #132: Pathogenesis of Type 2 Diabetes Mellitus Part 3

Beta-Cell function: Although the plasma insulin response to the development of insulin resistance typically is increased during the natural history of T2DM , this does not mean that the beta cell is functioning normally. To the contrary, studies have demonstrated that the onset of beta-cell failure occurs much earlier and is more severe than previously appreciated.

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International Textbook of Diabetes Mellitus, 4th Ed., Excerpt #131: Pathogenesis of Type 2 Diabetes Mellitus Part 2

The natural history of T2DM has been well described in multiple populations and is reviewed in references [1] and [3]. Individuals destined to develop T2DM inherit a set of genes from their parents that make their tissues resistant to insulin and the insulin resistance is aggravated by weight gain and physical inactivity. Hepatic insulin resistance is manifested by an overproduction of glucose during the basal state despite the presence of fasting hyperinsulinemia [38] and an impaired suppression of hepatic glucose production (HGP)

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International Textbook of Diabetes Mellitus, 4th Ed., Excerpt #130: Pathogenesis of Type 2 Diabetes Mellitus Part 1

Normal glucose homeostasis: Any discussion of the pathogenesis of type 2 diabetes mellitus (T2DM) must start with a review of mechanisms involved in the maintenance of normal glucose homeostasis in the basal o postabsorptive state (10–12-h overnight fast) and following ingestion of a typical mixed meal. In the postabsorptive state the great majority of total body glucose disposal takes place in insulin independent tissues.

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