The following study was conducted by Scientists from University of Geneva; Ecole Polytechnique Fédérale de Lausanne, Switzerland; Uppsala University; University of Göteborg, Sweden. Study is published in Proceedings of the National Academy of Sciences Journal as detailed below.
Proceedings of the National Academy of Sciences (2020); 117(5): 2484-2495
In Pancreatic Islets from Type 2 Diabetes Patients, the Dampened Circadian Oscillators Lead to Reduced Insulin and Glucagon Exocytosis
Significance
Here we report that intact islets and islet cells from type 2 diabetes (T2D) donors exhibit attenuated molecular oscillators bearing lower circadian amplitude and compromised synchronization capacity in vitro. Furthermore, we reveal that secretion profiles of insulin, proinsulin, and glucagon were circadian rhythmic under physiological conditions. The temporal coordination of the islet hormone secretion was perturbed in human T2D islets, concomitant with the islet molecular clock alterations. Strikingly, clock-deficient human islet cells exhibited disrupted insulin and glucagon granule docking and exocytosis. Treating the T2D islets with the clock modulator Nobiletin boosted circadian amplitude and insulin secretion. Our study uncovers a link between human molecular clockwork and T2D, thus considering clock modulators as putative pharmacological intervention to combat this disorder.
Abstract
Circadian clocks operative in pancreatic islets participate in the regulation of insulin secretion in humans and, if compromised, in the development of type 2 diabetes (T2D) in rodents. Here we demonstrate that human islet α- and β-cells that bear attenuated clocks exhibit strongly disrupted insulin and glucagon granule docking and exocytosis. To examine whether compromised clocks play a role in the pathogenesis of T2D in humans, we quantified parameters of molecular clocks operative in human T2D islets at population, single islet, and single islet cell levels. Strikingly, our experiments reveal that islets from T2D patients contain clocks with diminished circadian amplitudes and reduced in vitro synchronization capacity compared to their nondiabetic counterparts. Moreover, our data suggest that islet clocks orchestrate temporal profiles of insulin and glucagon secretion in a physiological context. This regulation was disrupted in T2D subjects, implying a role for the islet cell-autonomous clocks in T2D progression. Finally, Nobiletin, an agonist of the core-clock proteins RORα/γ, boosted both circadian amplitude of T2D islet clocks and insulin secretion by these islets. Our study emphasizes a link between the circadian clockwork and T2D and proposes that clock modulators hold promise as putative therapeutic agents for this frequent disorder.
Source:
Proceedings of the National Academy of Sciences
URL: https://www.pnas.org/content/117/5/2484
Citation:
Petrenko, V., N. R. Gandasi, et al. (2020). “In pancreatic islets from type 2 diabetes patients, the dampened circadian oscillators lead to reduced insulin and glucagon exocytosis.” Proceedings of the National Academy of Sciences 117(5): 2484-2495.
