Paracrine signaling by pancreatic δ cells determines the glycemic set point in mice

Abstract

Pancreatic islets contain several endocrine cell types that coordinate to maintain blood glucose homeostasis. While beta and alpha cells are thought to be the main drivers of glucose homeostasis through insulin and glucagon secretion respectively, the contribution of delta cells and somatostatin (SST) secretion to establishing the glycemic set point remains unresolved. Here we remove local SST signaling from delta cells within the pancreatic islet to investigate their contribution to the glycemic set point. Our data demonstrate that ablating delta cells or SST leads to a sustained decrease in the glycemic set point. This coincides with a decreased glucose threshold for insulin response from beta cells, leading to increased insulin secretion to the same glucose challenge. In contrast, alpha cell ablation had no effect on glycemic set point. Collectively, these data establish the physiological role of delta cells in determining the glycemic set point through their interaction with beta cells.

Extracellular electrophysiology on clonal human β-cell spheroids

“…It has indeed been demonstrated that paracrine secretion of ATP from primary b-cells occurs at 3mM glucose and enhances secretion (65), although we do not know whether this ATP release also occurs in EndoC-bH cells. In more general terms, our observation may pinpoint to the crucial role of d-cells in native islets, which are absent in these spheroids, in setting the glucose threshold (66). Notably, in EndoC-bH5 cells a biphasic pattern of electrical activity was apparent upon glucose stimulation, which is a hallmark of primary islets (15) and such a pattern had also been reported in dynamic insulin secretion assays of EndoC-bH5 cells (9).…”

Molecular mechanism responsible for sex differences in electrical activity of mouse pancreatic β-cells

“…We did not quantify the total β cell mass by multiplying the relative insulin-positive area with pancreas weight. But, important for our study is that the islet area and β cell contribution to islets did not show any significant sex-specific differences and therefore we can assume a similar islet cell paracrine modulation (75)(76)(77)(78).…”

The leptin receptor has no role in delta-cell control of beta-cell function in the mouse

“…We, therefore, performed a four-week washout to allow the replenishment of intestinal SST + cells without Lepr ablation before performing any phenotypical examinations. While the regeneration of islet delta cells from an unrecombined progenitor population rarely occurs, intestinal D cells regenerate within two weeks, while gastric D cells demonstrate apparent regrowth within four weeks and completely recover within three months ( 50 ).…”

“…The transgenic Gcg-Cre exhibits silencing, with recombination in only 30-45% of alpha cells, and the inducible gene replacement Gcg-Cre ERT2 line suffers from glucagon haploinsufficiency ( 58 ). Somatostatin, Sst-Cre , and the Sst-rtTA used here are all expressed in gut enteroendocrine D cells, hypothalamic neurons, and the motor cortex ( 50 ).…”