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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 #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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International Textbook of Diabetes Mellitus, 4th Ed., Excerpt #129: Beta-Cell Mass and Function in Human Type 2 Diabetes Part 5

Loss of beta-cell functional identity: The dominance of beta-cell functional impairment in T2DM implies that beta-cells have lost, at least in part, their normal insulin secretory phenotype. The associated molecular features have been discussed in a number of insightful reviews and research articles, and the role of genetic, epigenetic, transcriptomic and proteomic changes has been described extensively. At the cellular level, beta-cell insulin degranulation and the recently hypothesized beta-cell dedifferentiation phenomenon could play key roles. Insulin granules can be easily identified by electron microscopy on the basis of their typical morphology, characterized by a dense core and a more or less clearly visible halo. In addition, secretory granules can be subdivided into mature and immature, based on distinct ultrastructural, biochemical, and functional, with a relative ratio of 6 to 10 in normal human beta-cells.

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International Textbook of Diabetes Mellitus, 4th Ed., Excerpt #128: Beta-Cell Mass and Function in Human Type 2 Diabetes Part 4

Incretin defect: Oral glucose elicits a greater insulin response than does intravenous glucose. As first demonstrated by Nauck et al., when tested at matched plasma glucose concentrations (iso- glycemic protocol) the oral route of glucose administration induces a robust increment in insulin secretion as compared with the intravenous route. In nondiabetic subjects, such potentiation — named incretin effect — averages 50 – 70% with a standard (75 g) oral glucose load, and increases with the size of the glucose load. As depicted in Figure 24.10, the incretin effect is characteristically lost in patients with T2DM.

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International Textbook of Diabetes Mellitus, 4th Ed., Excerpt #127: Beta-Cell Mass and Function in Human Type 2 Diabetes Part 3

The dominance of beta-cell functional impairment: As discussed earlier, the available evidence indicates that an average 30% loss of beta-cells is present in the islets of patients with T2DM. However, based on a series of considerations it is unlikely that this beta-cell deficit alone is the cause of most cases of diabetes. First, in vivo assessment of beta-cell function consistently shows a greater than 50% reduction in patients with overt T2DM, a difference that is amplified when using intravenous glucose.

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International Textbook of Diabetes Mellitus, 4th Ed., Excerpt #126: Beta-Cell Mass and Function in Human Type 2 Diabetes Part 2

The role of beta-cell death and regeneration: The loss of beta-cells in T2DM has been mainly attributed to increased beta-cell death due to apoptosis and other forms of cell death, possibly driven by adverse environmental conditions and probably mediated by several intracellular mechanisms. Apoptosis is a type of programmed cell death morphologically characterized by cell rounding up, bleb formation and chromatin condensation. As a matter of fact, in autoptic pancreatic samples apoptosis has been shown to be significantly increased in both obese and lean type 2 diabetic cases as compared to BMI-matched, nondiabetic controls.

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International Textbook of Diabetes Mellitus, 4th Ed., Excerpt #125: Beta-Cell Mass and Function in Human Type 2 Diabetes Part 1

Insulin-producing beta-cells are the predominant endocrine cell type in pancreatic islets, comprising 50 – 80% of islet cells. Studies with autoptic samples, organ donor specimens, and surgical cases have found that beta-cell mass in the human pancreas may vary from 0.6 to 2.1 g, with beta-cell volume and area (relative to the pancreatic tissue) ranging from 1.1 – 2.6% and 0.6 – 1.6%, respectively.

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