Functional beta cell recovery in type 2 diabetes

Some forms of type 2 diabetes (T2D) are viewed as a potentially reversible disorder, rather than a chronic lifelong metabolic disease. Interventions, such as bariatric surgery and hypocaloric diets have been shown to reverse the major pathophysiological hallmarks of the disease, including insulin resistance and beta cell dysfunction. However, the mechanisms associated with this functional plasticity of beta cells are not fully understood. Although the improvements in hepatic insulin sensitivity and beta cell function were associated with a significant reduction of the respective intraorgan fat contents, the decrease in pancreatic fat alone did not guarantee beta cell functional recovery. We hypothesize that metabolic stress-induced beta cell dysfunction is reversible to a certain extent and that the loss of beta cell ability to regain their function during prolonged metabolic stress is linked to specific irreversible alterations in beta cell physiology.

In order to uncover the changes in beta cell (patho)physiology associated with the loss and regain of their function, male INSCre;GCaMP mice are fed with HFD for up to 20 weeks to induce progressing states of impaired glucose tolerance and eventually T2D. We assess the recovery potential after different durations of metabolic stress by switching separate groups of mice to ND for 4 weeks. Our data showed that despite a continuous weight gain in the HFD-fed mice, the non‑fasting and fasting blood glucose levels did not differ until 12 weeks of HFD. Short-term HFD was sufficient to induce impaired glucose tolerance that progressively deteriorated until 8 weeks. Although none of the mice developed T2D until 12 weeks of HFD, an increasing proportion of the mice became prediabetic with increasing HFD durations starting from week 2. Preliminary data revealed that HFD-fed mice for 2 weeks exhibited normal basal and biphasic glucose-stimulated insulin secretory pattern, while 12 weeks of HFD resulted in an increased basal insulin secretion with a reduced beta cell stimulatory capacity, most likely caused by increased stress under basal conditions. Moreover, our data showed that there are no major differences in the beta cell basal and glucose-stimulated calcium dynamics in HFD-fed mice until 12 weeks.

To translate our findings to the human setting, we will assess beta cell dysfunction and recovery in isolated islets from organ donors exposed to glucolipotoxic culture conditions for varying periods of time.

Publication:

Neuroprotective Effects of Filgrastim in Rotenone-Induced Parkinson's Disease in Rats: Insights into its Anti-Inflammatory, Neurotrophic, and Antiapoptotic Effects. M.S. Azmy, E.T. Menze, R.N. El-Naga, M.G. Tadros. Mol Neurobiol. 2018;55:6572-6588.