Genetics and diet shape the relationship between islet function and whole body metabolism

Despite the fact that genes and the environment are known to play a central role in islet function, our knowledge of how these parameters interact to modulate insulin secretory function remains relatively poor. Presently, we performed ex vivo glucose-stimulated insulin secretion and insulin content assays in islets of 213 mice from 13 inbred mouse strains on chow, Western diet (WD), and a high-fat, carbohydrate-free (KETO) diet. Strikingly, among these 13 strains, islets from the commonly used C57BL/6J mouse strain were the least glucose responsive. Using matched metabolic phenotyping data, we performed correlation analyses of isolated islet parameters and found a positive correlation between basal and glucose-stimulated insulin secretion, but no relationship between insulin secretion and insulin content. Using in vivo metabolic measures, we found that glucose tolerance determines the relationship between ex vivo islet insulin secretion and plasma insulin levels. Finally, we showed that islet glucose-stimulated insulin secretion decreased with KETO in almost all strains, concomitant with broader phenotypic changes, such as increased adiposity and glucose intolerance. This is an important finding as it should caution against the application of KETO diet for beta-cell health. Together these data offer key insights into the intersection of diet and genetic background on islet function and whole body glucose metabolism.NEW & NOTEWORTHY Thirteen strains of mice on chow, Western diet, and high-fat, carbohydrate-free (KETO), correlating whole body phenotypes to ex vivo pancreatic islet functional measurements, were used. The study finds a huge spectrum of functional islet responses and insulin phenotypes across all strains and diets, with the ubiquitous C57Bl/6J mouse exhibiting the lowest secretory response of all strains, highlighting the overall importance of considering genetic background when investigating islet function. Ex vivo basal and stimulated insulin secretion are correlated in the islet, and KETO imparts widescale downregulation of islet insulin secretion.