Somatostatin Is Only Partly Required for the Glucagonostatic Effect of Glucose but Is Necessary for the Glucagonostatic Effect of KATP Channel Blockers

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Abstract

The mechanisms of control of glucagon secretion are largely debated. In particular, the paracrine role of somatostatin (SST) is unclear. We studied its role in the control of glucagon secretion by glucose and KATP channel blockers, using perifused islets and the in situ perfused pancreas. The involvement of SST was evaluated by comparing glucagon release of control tissue or tissue without paracrine influence of SST (pertussis toxin–treated islets, or islets or pancreas from Sst−/− mice). We show that removal of the paracrine influence of SST suppresses the ability of KATP channel blockers or KATP channel ablation to inhibit glucagon release, suggesting that in control islets, the glucagonostatic effect of KATP channel blockers/ablation is fully mediated by SST. By contrast, the glucagonostatic effect of glucose in control islets is mainly independent of SST for low glucose concentrations (0–7 mmol/L) but starts to involve SST for high concentrations of the sugar (15–30 mmol/L). This demonstrates that the glucagonostatic effect of glucose only partially depends on SST. Real-time quantitative PCR and pharmacological experiments indicate that the glucagonostatic effect of SST is mediated by two types of SST receptors, SSTR2 and SSTR3. These results suggest that alterations of the paracrine influence of SST will affect glucagon release.

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Alpha-cells of the endocrine pancreas: 35 years of research but the enigma remains.

Jesper Gromada, Isobel Franklin, Claes Wollheim (2007)

Glucagon, a hormone secreted from the alpha-cells of the endocrine pancreas, is critical for blood glucose homeostasis. It is the major counterpart to insulin and is released during hypoglycemia to induce hepatic glucose output. The control of glucagon secretion is multifactorial and involves direct effects of nutrients on alpha-cell stimulus-secretion coupling as well as paracrine regulation by insulin and zinc and other factors secreted from neighboring beta- and delta-cells within the islet of Langerhans. Glucagon secretion is also regulated by circulating hormones and the autonomic nervous system. In this review, we describe the components of the alpha-cell stimulus secretion coupling and how nutrient metabolism in the alpha-cell leads to changes in glucagon secretion. The islet cell composition and organization are described in different species and serve as a basis for understanding how the numerous paracrine, hormonal, and nervous signals fine-tune glucagon secretion under different physiological conditions. We also highlight the pathophysiology of the alpha-cell and how hyperglucagonemia represents an important component of the metabolic abnormalities associated with diabetes mellitus. Therapeutic inhibition of glucagon action in patients with type 2 diabetes remains an exciting prospect.

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Epigenomic plasticity enables human pancreatic α to β cell reprogramming.

Markus Grompe, Klaus Kaestner, Philip R. Streeter … (2013)

Insulin-secreting β cells and glucagon-secreting α cells maintain physiological blood glucose levels, and their malfunction drives diabetes development. Using ChIP sequencing and RNA sequencing analysis, we determined the epigenetic and transcriptional landscape of human pancreatic α, β, and exocrine cells. We found that, compared with exocrine and β cells, differentiated α cells exhibited many more genes bivalently marked by the activating H3K4me3 and repressing H3K27me3 histone modifications. This was particularly true for β cell signature genes involved in transcriptional regulation. Remarkably, thousands of these genes were in a monovalent state in β cells, carrying only the activating or repressing mark. Our epigenomic findings suggested that α to β cell reprogramming could be promoted by manipulating the histone methylation signature of human pancreatic islets. Indeed, we show that treatment of cultured pancreatic islets with a histone methyltransferase inhibitor leads to colocalization of both glucagon and insulin and glucagon and insulin promoter factor 1 (PDX1) in human islets and colocalization of both glucagon and insulin in mouse islets. Thus, mammalian pancreatic islet cells display cell-type-specific epigenomic plasticity, suggesting that epigenomic manipulation could provide a path to cell reprogramming and novel cell replacement-based therapies for diabetes.

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Comprehensive alpha, beta and delta cell transcriptomes reveal that ghrelin selectively activates delta cells and promotes somatostatin release from pancreatic islets

Michael Digruccio, Alex M. Mawla, Cynthia Donaldson … (2016)

Objective Complex local crosstalk amongst endocrine cells within the islet ensures tight coordination of their endocrine output. This is illustrated by the recent demonstration that the negative feedback control by delta cells within pancreatic islets determines the homeostatic set-point for plasma glucose during mouse postnatal development. However, the close association of islet endocrine cells that facilitates paracrine crosstalk also complicates the distinction between effects mediated directly on beta cells from indirect effects mediated via local intermediates, such as somatostatin from delta cells. Methods To resolve this problem, we generated reporter mice that allow collection of pure pancreatic delta cells along with alpha and beta cells from the same islets and generated comprehensive transcriptomes for each islet endocrine cell type. These transcriptomes afford an unparalleled view of the receptors expressed by delta, alpha and beta cells, and allow the prediction of which signal targets which endocrine cell type with great accuracy. Results From these transcriptomes, we discovered that the ghrelin receptor is expressed exclusively by delta cells within the islet, which was confirmed by fluorescent in situ hybridization and qPCR. Indeed, ghrelin increases intracellular calcium in delta cells in intact mouse islets, measured by GCaMP6 and robustly potentiates glucose-stimulated somatostatin secretion on mouse and human islets in both static and perfusion assays. In contrast, des-acyl-ghrelin at the same dose had no effect on somatostatin secretion and did not block the actions of ghrelin. Conclusions These results offer a straightforward explanation for the well-known insulinostatic actions of ghrelin. Rather than engaging beta cells directly, ghrelin engages delta cells to promote local inhibitory feedback that attenuates insulin release. These findings illustrate the power of our approach to resolve some of the long-standing conundrums with regard to the rich feedback that occurs within the islet that is integral to islet physiology and therefore highly relevant to diabetes.