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ABSTRACT: The beta cell transcriptional factor musculoaponeurotic fibrosarcoma oncogene family A (MafA) regulates genes important for beta cell function. Loss of nuclear MafA has been implicated in beta cell dysfunction in animal models of type 2 diabetes. We sought to establish if nuclear MafA is less abundant in beta cell nuclei in humans with type 2 diabetes.
Pancreas obtained at surgery from five non-diabetic individuals and six individuals with type 2 diabetes was immunostained for insulin, glucagon and MafA.
Beta cell nuclear MafA was markedly decreased in type 2 diabetes (1.6 ± 1.2% vs 46.3 ± 8.3%, p < 0.001).
Beta cell nuclear MafA is markedly decreased in humans with type 2 diabetes, which may contribute to impaired beta cell dysfunction.
Diabetologia 07/2012; 55(11):2985-8. · 6.81 Impact Factor
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ABSTRACT: In type II diabetes (T2DM), there is a deficit in β-cells, increased β-cell apoptosis and formation of intracellular membrane-permeant oligomers of islet amyloid polypeptide (IAPP). Human-IAPP (h-IAPP) is an amyloidogenic protein co-expressed with insulin by β-cells. IAPP expression is increased with obesity, the major risk factor for T2DM. In this study we report that increased expression of human-IAPP led to impaired autophagy, due at least in part to the disruption of lysosome-dependent degradation. This action of IAPP to alter lysosomal clearance in vivo depends on its propensity to form toxic oligomers and is independent of the confounding effect of hyperglycemia. We report that the scaffold protein p62 that delivers polyubiquitinated proteins to autophagy may have a protective role against human-IAPP-induced apoptosis, apparently by sequestrating protein targets for degradation. Finally, we found that inhibition of lysosomal degradation increases vulnerability of β-cells to h-IAPP-induced toxicity and, conversely, stimulation of autophagy protects β-cells from h-IAPP-induced apoptosis. Collectively, these data imply an important role for the p62/autophagy/lysosomal degradation system in protection against toxic oligomer-induced apoptosis.
Cell death and differentiation 03/2011; 18(3):415-26. · 8.24 Impact Factor
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ABSTRACT: Regulation of blood glucose concentrations requires an adequate number of beta-cells that respond appropriately to blood glucose levels. beta-Cell mass cannot yet be measured in humans in vivo, necessitating autopsy studies, although both pre- and postmorbid changes may confound this approach. Autopsy studies report deficits in beta-cell mass ranging from 0 to 65% in type 2 diabetes (T2DM), and approximately 70-100% in type 1 diabetes (T1DM), and, when evaluated, increased beta-cell apoptosis in both T1DM and T2DM. A deficit of beta-cell mass of approximately 50% in animal studies leads to impaired insulin secretion (when evaluated directly in the portal vein) and induction of insulin resistance. We postulate three phases for diabetes progression. Phase 1: selective beta-cell cytotoxicity (autoimmune in T1DM, unknown in T2DM) leading to impaired beta-cell function and gradual loss of beta-cell mass through apoptosis. Phase 2: decompensation of glucose control when the pattern of portal vein insulin secretion is sufficiently impaired to cause hepatic insulin resistance. Phase 3: adverse consequences of glucose toxicity accelerate beta-cell dysfunction and insulin resistance. The relative contribution of beta-cell loss versus beta-cell dysfunction to diabetes onset remains an area of controversy. However, because cytotoxicity sufficient to induce beta-cell apoptosis predictably disturbs beta-cell function, it is naive to attempt to distinguish the relative contributions of these linked processes to diabetes onset.
Diabetes Obesity and Metabolism 11/2008; 10 Suppl 4:23-31. · 3.38 Impact Factor
