Alterations in β-Cell Calcium Dynamics and Efficacy Outweigh Islet Mass Adaptation in Compensation of Insulin Resistance and Prediabetes Onset

Abstract

Emerging insulin resistance is normally compensated by increased insulin production of pancreatic β-cells, thereby maintaining normoglycemia. However, it is unclear whether this is achieved by adaptation of β-cell function, mass, or both. Most importantly, it is still unknown which of these adaptive mechanisms fail when type 2 diabetes develops. We performed longitudinal in vivo imaging of β-cell calcium dynamics and islet mass of transplanted islets of Langerhans throughout diet-induced progression from normal glucose homeostasis, through compensation of insulin resistance, to prediabetes. The results show that compensation of insulin resistance is predominated by alterations of β-cell function, while islet mass only gradually expands. Hereby, functional adaptation is mediated by increased calcium efficacy, which involves Epac signaling. Prior to prediabetes, β-cell function displays decreased stimulated calcium dynamics, whereas islet mass continues to increase through prediabetes onset. Thus, our data reveal a predominant role of islet function with distinct contributions of triggering and amplifying pathway in the in vivo processes preceding diabetes onset. These findings support protection and recovery of β-cell function as primary goals for prevention and treatment of diabetes and provide insight into potential therapeutic targets.

A post-translational balancing act: the good and the bad of SUMOylation in pancreatic islets

“…So, why not simply maintain a high level of SUMOylation to increase beta cell protection? In models of high metabolic demand and insulin resistance, such as highfat-fed mice or human obesity, beta cells must increase their secretory capacity [22]. In the short term at least, metabolic signalling to the plasma membrane via SENP1 amplifies the secretory capacity of beta cells in response to increasing glucose [18].…”

Islets Transplanted Into the Eye: Do They Improve Our Insight Into Islet Adaptation to Insulin Resistance?

“…In this issue of Diabetes , Chen et al (4) transplanted isolated islets into the anterior chamber of the eye of a recipient mouse. This enabled longitudinal and simultaneous monitoring of β-cell mass and β-cell function.…”

“…Previous work from the group demonstrated the feasibility of the approach for exploring a range of questions related to diabetes (5). In the current study (4), attention was focused on whether β-cell mass or β-cell function preferentially mediates adaptation to insulin resistance and hyperglycemia. This is a major question in the field, and one for which the novel approach used is well suited to provide important answers.…”

“…Chen et al (4) combined high-resolution islet mass measurements based on laser light backscattering (8) with in vivo insulin and glucagon measurements. Transducing the donor islets with a genetically encoded Ca 2+ -sensing probe (GCaMP) permitted the measurement of β-cell Ca 2+ levels and Ca 2+ oscillations in real time.…”

Label-free fast 3D coherent imaging reveals pancreatic islet micro-vascularization and dynamic blood flow

“…These endpoint measurements prevent the assessment of the full blood flow dynamics and alterations in identical islets during diabetes progression. In vivo imaging of the vascularization of islets has been achieved through intravital fluorescence microscopy either in the native pancreas [4,17,18], in grafted islets in the anterior chamber of the eye [19][20][21][22][23][24] or in striated muscle by using a dorsal skin-fold window [25][26][27][28]. However, fluorescent microscopy requires both genetically modified mice expressing fluorescent proteins to detect specific cellular populations and the injection of labelled dextran or labelled red blood cells to image the vascularization and quantify blood flow.…”