Age-Dependent Decline in the Coordinated [Ca2+] and Insulin Secretory Dynamics in Human Pancreatic Islets

Abstract

Aging is associated with increased risk for type 2 diabetes, resulting from reduced insulin sensitivity and secretion. Reduced insulin secretion can result from reduced proliferative capacity and reduced islet function. Mechanisms underlying altered β-cell function in aging are poorly understood in mouse and human islets, and the impact of aging on intraislet communication has not been characterized. Here, we examine how β-cell [Ca2+] and electrical communication are impacted during aging in mouse and human islets. Islets from human donors and from mice were studied using [Ca2+] imaging, static and perifusion insulin secretion assays, and gap junction permeability measurements. In human islets, [Ca2+] dynamics were coordinated within distinct subregions of the islet, invariant with islet size. There was a marked decline in the coordination of [Ca2+] dynamics, gap junction coupling, and insulin secretion dynamics with age. These age-dependent declines were reversed by pharmacological gap junction activation. These results show that human islet function declines with aging, which can reduce insulin action and may contribute to increased risk of type 2 diabetes.

Glucose-dependent activation, activity, and deactivation of beta cell networks in acute mouse pancreas tissue slices

“…Advanced network analyses based on thresholded pairwise correlations of Ca 2+ imaging signals have proven to be a valuable tool to quantify the non-trivial intercellular interaction patterns in multicellular systems (Stetter, Battaglia et al 2012, Feldt Muldoon, Soltesz et al 2013, including the pancreatic islets (Hodson, Mitchell et al 2013, Stožer, Gosak et al 2013, Markovic, Stozer et al 2015, Johnston, Mitchell et al 2016, Gosak, Markovic et al 2018). These endeavors have been at least in part motivated by the fact that the arrangement and communication abilities between beta cells is an increasingly popular topic in islet and diabetes research, not only because its critical role in insulin release through the generation of coordinated rhythmic activity (Bavamian, Klee et al 2007, Cigliola, Chellakudam et al 2013, Rutter and Hodson 2014, but also due to the growing evidence that connectivity may plausibly be targeted by both environmental and genetic factors in the pathogenesis of diabetes mellitus (Hodson, Mitchell et al 2013, Farnsworth, Walter et al 2016, Westacott, Farnsworth et al 2017). In the present study we pushed further our understanding of beta cell networks by exploring the glucose dependencies of intercellular behavior and by connecting the network properties with cellular signaling characteristics.…”

Beta-cell hubs maintain Ca2+ oscillations in human and mouse islet simulations

“…GJ coupling between β-cells is essential for islet function. 6,86 The strength of this coupling decreases with age 87,88 and in animal models of diabetes. 89,90 Therefore, our simulations predict that a reduction in GJ coupling would reduce the ability of hubs to generate whole-islet Ca 2+ oscillations, greatly impairing insulin output.…”

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

“…This may explain the decline in beta cell function observed in males ( Figure 5B), and why men suffer a more pronounced deterioration in glucose homeostasis during aging (Basu et al, 2006). Figure 2F) (Arrojo e Drigo et al, 2019; Cnop et al, 2010;Perl et al, 2010;Westacott et al, 2017)). We previously established in rodents that long-lived cells contain long-lived proteins (Arrojo e Drigo et al, 2019;D'Angelo et al, 2009;Toyama et al, 2013).…”

“…These observations led to the hypothesis that aging result in impaired beta cell function, which would contribute to the impaired glucose homeostasis observed in aging humans (Basu et al, 2003). Previous studies have addressed this question and found conflicting results (Almaça et al, 2014;Avrahami et al, 2015;Helman et al, 2016;Westacott et al, 2017). Here, we analyzed data from a glucose-stimulated insulin secretion (GSIS) assay performed on human islets isolated (n=153 isolations) from N.D. donors 18-84 y.o.…”

“…While adult beta cells can secrete more insulin than those of children and adolescents, likely due to their advanced maturation state (Avrahami et al, 2015), it is still unclear whether beta cell function continues to evolve throughout adulthood. For example, using isolated islets, one study found no differences in insulin secretion throughout adulthood (Almaça et al, 2014), whereas others observed a decrease in beta cell calcium dynamics and insulin secretion in humans greater than 40 years of age (Westacott et al, 2017). Furthermore, sex-specific differences in glucose homeostasis and DNA methylation patterns suggest that islet cells from men and women could have different transcriptional and functional profiles (Basu et al, 2006;Hall et al, 2014) and this could underlie sex differences in T2D etiology (Logue et al, 2011).…”