Sex differences underlying pancreatic islet biology and its dysfunction

Abstract

BackgroundThe sex of an individual affects glucose homeostasis and the pathophysiology, incidence, and prevalence of diabetes as well as the response to therapy.Scope of the reviewThis review focuses on clinical and experimental sex differences in islet cell biology and dysfunction during development and in adulthood in human and animal models. We discuss sex differences in β-cell and α-cell function, heterogeneity, and dysfunction. We cover sex differences in communication between gonads and islets and islet-cell immune interactions. Finally, we discuss sex differences in β-cell programming by nutrition and other environmental factors during pregnancy.Major conclusionsImportant sex differences exist in islet cell function and susceptibility to failure. These differences represent sex-related biological factors that can be harnessed for gender-based prevention of and therapy for diabetes.

Aging of human endocrine pancreatic cell types is heterogeneous and sex-specific

“…Sex specific differences in alpha and beta cell identity and function. Glucose homeostasis is maintained differently between men and women (Anderwald et al, 2011;Basu et al, 2006;Faerch et al, 2010;Gannon et al, 2018). Although both sexes have similar peripheral insulin sensitivity, women have lower levels of endogenous glucose production, lower fasting plasma glucose concentrations, and higher glucose levels ~2 hours after delivery of an oral bolus of glucose (Anderwald et al, 2011;Basu et al, 2006;Faerch et al, 2010;Gannon et al, 2018).…”

Exposure to maternal obesityper seprograms sex-differences in pancreatic islets of the offspring

“…This is reflected by lower blood glucose and higher serum insulin levels 30 minutes after glucose administration during and IPGTT. Therefore, although these islets are being "overworked" from a young age, they appear to have protective 12 mechanisms in place to cope with the demands of increasing adiposity and insulin resistance.…”

“…Females appear to be protected from β-cell death in most rodent models of T2D [12,20]. In the case of exposure to maternal diet-induced obesity/high fat-feeding and future T2D risk in the offspring, Yokomizo and colleagues showed that islets from female offspring were better to able to compensate and adapt to a high fat diet (HFD) in postnatal life compared to male offspring [9].…”

“…Females are protected from β-cell death and hyperglycemia in most rodent models of T2D [12,20]. This has been attributed, in part, to the actions of 17β-estradiol via estrogen receptor α (ERα) and its role in preventing apoptosis [21][22][23].…”

“…It is, therefore, key that we identify inherent changes, which are programmed by exposure to maternal obesity per se and are distinct from the response of the islets to an existing obesogenic, insulin resistant milieu. This includes investigating the effects on both male and female offspring since sex 4 affects glucose homeostasis, the pathophysiology, incidence and prevalence of T2D as well as response to therapy (reviewed in [12]). For example, using a mouse model of maternal dietinduced obesity, Samuelsson et.…”