Intercellular communication mediated by connexin 36 gap junction channels coordinate and regulate the dynamics of islet calcium oscillations and insulin secretion. Impaired gap junction coupling occurs in prediabetic mice under a high fat diet. Dietary interventions, such as calorie restriction, can regain weight and modulate insulin secretion. However, it is unknown whether caloric restriction can recover impaired gap junctions coupling and calcium regulation in islets of mice fed a high fat diet. Here, we tested if caloric restriction can protect against obesity-induced decreases in connexin36 coupling and altered islet function. We used C57BL6 mice under a normal diet (Envigo 2020X), or a high fat diet (HFD) (Envigo TD.03584) which causes prediabetes after three months. HFD mice were also submitted to 40% caloric restriction (2g/day) for one month. We performed intraperitoneal glucose tolerance tests, insulin tolerance tests, in vivo insulin level measurements. In isolated islets we measured glucose-stimulated insulin secretion, islet Ca2+ dynamics, metabolic activity, along with gap junction permeability. We observed that caloric restriction improved glucose tolerance (p=0.002), insulin sensitivity (p=0.001), and islet function. This included normalization glucose-induced insulin secretion (p=0.01), enhanced Ca2+ oscillation amplitude (p=0.002) and greater coordination (p=0.04). These improvements correlated with restoration in gap junction permeability (p=0.02). Caloric restriction also promoted a slight increase in NAD(P)H increase by elevated glucose (p=0.04) indicating improved metabolic activity and viability of these cells. We conclude that the decline in gap junction coupling. mediated by connexin 36 in islets that occurs in diet-induced obesity, is improved by short term caloric restriction. This improvement contributes to improved islet function.
M.C. Amaral: None. V. Kravets: None. J.M. Dwulet: None. N.L. Farnsworth: None. R.A. Piscopio: None. W. Schleicher: None. J. Miranda: None. R.K. Benninger: None.
JDRF (5-CDA-2014-198-A-N); National Institutes of Health (R01DK102950, R01DK106412 to R.K.B.); Fundação de Amparo à Pesquisa do Estado de São Paulo (2018/04536-6)