Incorporation of beta cell redifferentiation therapy into a lipoprivic strategy for reversing type 2 diabetes.
Type 2 diabetes (non-insulin-dependent diabetes mellitus, NIDDM), at least in the majority of patients characterized by insulin resistance and increased visceral fat, appears to be precipitated by the exposure of tissues to excessive levels of free fatty acids; this can contribute to the muscle insulin resistance, excessive hepatic gluconeogenesis, and beta cell dysfunction that collaborate to impair glycemic control. The resultant hyperglycemia, in turn, exacerbates the insulin resistance and beta cells dysfunction. The failure of glucose-stimulated insulin secretion (GSIS) in beta cells helps to sustain the elevations of serum glucose and free fatty acids, which in turn reinforce the failure of GSIS, possibly by inhibiting expression of the transcription factor IDX-1; NIDDM thus represents a vicious cycle that is not easily broken. A new strategy for achieving rapid loss of body fat - hepatothermic therapy (HT), an integrated approach involving exercise training, low-fat, low-glycemic-index food choices, and a supplementation program that promotes hepatic fatty acid oxidation - shows promise for alleviating the excessive fat exposure at the root of the diabetic syndrome, as well as the underlying insulin resistance syndrome responsible for increased macrovascular risk. However, when HT proves incapable of breaking the vicious cycle sustaining beta cell dysfunction, a supplementary strategy, beta cell redifferentiation therapy (BRT), may be required. BRT consists of a protocol in which near-normoglycemia is maintained for several weeks through use of intensive insulin therapy (e.g. artificial pancreas) or other effective measures, during which time beta cell GSIS can be expected to substantially recover owing to relief from glucolipotoxicity. Clinical experience demonstrates that this improved beta cell function, in certain cases, can persist for months or years after temporary BRT. A portion of the improved glycemic control achieved with very low calorie diets in NIDDM is reflective of improved GSIS, presumably consequent to a sustained reduction in diurnal glycemia. Long-lived analogs of glucagon-like peptide-1 (GLP-1) may find a key role in BRT; this incretin hormone not only potentiates GSIS, but also appears to increase the expression and activity of IDX-1 in beta cells, thus promoting beta cell redifferentiation. If HT is instituted prior to and following BRT to alleviate the FFA overexposure that initially precipitated the diabetic syndrome, it seems likely that the benefits of BRT will be conserved in the long term, thus enabling a reversal of NIDDM - in other words, maintenance of normoglycemia without medication. Since NIDDM is inherently preventable, its reversal should be the fundamental goal of diabetes therapy.
D002454:Cell Differentiation; D003924:Diabetes Mellitus, Type 2 / Q000517:prevention & control*; D006801:Humans; D007515:Islets of Langerhans / Q000166:cytology*