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Autophagy-induced degradation of Notch1, achieved through intermittent fasting, may promote beta cell neogenesis: implications for reversal of type 2 diabetes
  1. James J DiNicolantonio1 and
  2. Mark McCarty2
  1. 1Mid America Heart Insitute, Kansas, Kansas, USA
  2. 2Catalytic Longevity, Encinitas, California, USA
  1. Correspondence to Dr James J DiNicolantonio; jjdinicol{at}gmail.com

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Intermittent fasting boosts neurogenin-3 (Ngn3) expression and beta cell neogenesis

Several recent studies have found that repeated episodes of fasting (or of a low-carb/low-protein diet mimicking the metabolic impact of fasting), of 1–4 days of duration, interspersed with ad libitum food consumption, can induce neogenesis of pancreatic beta cells in several mouse models of diabetes (db/db, high-fat feeding and streptozotocin induced).1–3 This phenomenon is associated with increased expression of Ngn3 in islet cells. Ngn3 is a transcription factor expressed transiently in developing pancreatic islets in utero that is required for the further development of both alpha and beta cells.4 5 The increase in islet beta cells induced by intermittent fasting is accompanied by a corresponding increase in islet insulin content and a marked improvement in glycaemic control. This benefit of intermittent fasting is abrogated if autophagy is concurrently suppressed, suggesting that fasting-induced autophagy is a key mediator of the subsequent beta cell neogenesis.2 It has also been noted that fasting-induced reductions in mTORC1 and protein kinase A (PKA) activity in islet cells are mediators of this phenomenon.1 With respect to autophagy, it is notable that intermittent feeding of a leucine deprived, which would be expected to induce autophagy by episodic inhibition of mTORC1 activity, has likewise been shown to increase Ngn3 expression and beta cell mass in db/db mice.6

These observations are of the greatest interest, inasmuch as type 1 diabetes reflects near-complete inflammatory destruction of islet beta cells, and the later stages of severe type 2 diabetes are characterised by a marked decrease in islet beta cells, reflecting their accelerated loss by apoptosis. If it proves feasible to replicate these observations in human diabetics, this strategy might arguably lend itself the cure of diabetes. In regard to type 2 diabetes, this disorder can sometimes be fully reversed in its early stages if the factors …

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