Exenatide and biotin in conjunction with a protein-sparing fast for normalization of beta cell function in type 2 diabetics

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Summary

The dysdifferentiation of beta cells in type 2 diabetes appears to be caused and maintained by a vicious cycle of glucolipotoxicity: chronic elevations of glucose and free fatty acids induce beta cell dysdifferentiation as well as apoptosis; the resulting failure of glucose-stimulated insulin secretion tends to maintain the elevations of glucose and free fatty acids. Since extended fasts restore normoglycemia in diabetics, the resulting relief from glucotoxicity has been associated with a marked improvement in beta cell function that can be conserved after the fast if the factors precipitating diabetes – obesity, fatty and high-glycemic-index diets, sedentary lifestyle – have been adequately addressed. The new drug exenatide, an analog of the incretin hormone glucagon-like peptide-1, may be a worthwhile adjuvant to such fasting therapy, since it tends to counteract the glucolipotoxicity-induced down-regulation of the crucially important beta cell transcription factor IDX-1. Exenatide also exerts trophic effects on beta cell mass that in the longer term might help to restore diminished beta cell mass. Supraphysiological concentrations of biotin, possibly because they activate the soluble guanylate cyclase, also promote induction of IDX-1 and counteract the adverse impact of glucolipotoxicity in this regard; thus, high-dose biotin, which is well tolerated, may represent an additional adjuvant for therapeutic fasting intended to normalize beta cell function in type 2 diabetics.

Section snippets

Fasting as a strategy for normalizing diabetic beta cell function

The relative failure of glucose-stimulated insulin secretion in type 2 diabetics – especially the loss of the first-phase response – appears to reflect a dysdifferentiation of beta cells that is induced and maintained by chronic glucolipotoxicity [1], [2], [3], [4]. The resulting failure of beta cells to respond properly to elevations in serum glucose tends to perpetuate the chronic elevation of glucose and free fatty acids, thus leading to a vicious cycle that maintains beta cell failure.

A role for exenatide in beta cell redifferentiation therapy

The novel drug exenatide, an analog of glucagon-like peptide-1 (GLP-1) found in the saliva of gila monsters, is now approved as an insulinotropic therapy for type 2 diabetics [23], [24]. By acting as an agonist for GLP-1 receptors on beta cells – which increase cAMP production in these cells – exenatide acts to potentiate insulin secretion in response to a rise in plasma glucose, just like natural incretin hormones do [25]. However, unlike sulphonylureas, GLP-1 and exenatide cannot promote beta

High-dose biotin may complement these benefits

The vitamin biotin, which in modestly supraphysiological concentrations (0.1–1 μM) can directly activate soluble guanylate cyclase [42], [43], [44] – albeit less dramatically than nitric oxide can – has replicated many of the favorable effects of GLP-1 on beta cell function and differentiation in cell culture and rodent studies. Thus, biotin potentiates the insulin secretory response to elevated glucose (without directly provoking insulin secretion), and also boosts expression of IDX-1 and of

A prudent lifestyle required to preserve normalized beta cell function

In diabetic patients who manage to achieve substantial weight loss, and who become dedicated to regular exercise and prudent eating, diabetes is sometimes reversible without ancillary measures [64]. However, in selected patients in whom such efforts nonetheless fail to normalize beta cell function, a protein-sparing fast of moderate duration (for example, a week to 10 days), coupled with concurrent exenatide and biotin therapy, may have the potential to restore normal beta cell differentiation

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