Glucagon-secretion inhibition using somatostatin: An old hormone for the treatment of diabetes-associated pancreatectomy

It is now recognized that the metabolic disorders observed in diabetes are not, or not only due to the lack of insulin or insulin resistance, but also to elevated glucagon secretion. Accordingly, selective glucagon receptor antagonists are now proposed as a novel strategy for the treatment of diabetes. However, besides its metabolic actions, glucagon also influences kidney function. The glucagon receptor is expressed in the thick ascending limb, distal tubule, and collecting duct, and glucagon regulates the transepithelial transport of several solutes in these nephron segments. Moreover, it also influences solute transport in the proximal tubule, possibly by an indirect mechanism. This review summarizes the knowledge accumulated over the last 30 years about the influence of glucagon on the renal handling of electrolytes and urea. It also describes a possible novel role of glucagon in the short-term regulation of potassium homeostasis. Several original findings suggest that pancreatic α-cells may express a “potassium sensor” sensitive to changes in plasma K concentration and could respond by adapting glucagon secretion that, in turn, would regulate urinary K excretion. By their combined actions, glucagon and insulin, working in a combinatory mode, could ensure an independent regulation of both plasma glucose and plasma K concentrations. The results and hypotheses reviewed here suggest that the use of glucagon receptor antagonists for the treatment of diabetes should take into account their potential consequences on electrolyte handling by the kidney.

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Co-impairment of autonomic and glucagon responses to insulin-induced hypoglycemia in dogs with naturally occurring insulin-dependent diabetes mellitus

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00379.2020 ◽

2020 ◽

Vol 319 (6) ◽

pp. E1074-E1083

Author(s):

Chen Gilor ◽

Cynthia Duesberg ◽

Denise A. Elliott ◽

Edward C. Feldman ◽

Thomas O. Mundinger ◽

...

Keyword(s):

Diabetes Mellitus ◽

Cell Function ◽

Glucagon Secretion ◽

Insulin Dependent Diabetes Mellitus ◽

Dependent Diabetes Mellitus ◽

Companion Dogs ◽

Naturally Occurring ◽

Function Loss ◽

Insulin Dependent ◽

Treatment Of Diabetes

In dogs with naturally occurring, insulin-dependent (C-peptide negative) diabetes mellitus, impairment of glucagon responses is not due to generalized impairment of α-cell function. Loss of tonic inhibition of glucagon secretion by insulin is not sufficient, by itself, to produce loss of the glucagon response. Rather, impaired activation of the parasympathetic and sympathoadrenal autonomic inputs to the pancreas is also required. Activation of the autonomic inputs to the pancreas is sufficient to mediate an intact glucagon response to insulin-induced hypoglycemia in dogs with naturally occurring diabetes mellitus. These results have important implications that include leading to a greater understanding and insight into the pathophysiology, prevention, and treatment of hypoglycemia during insulin treatment of diabetes in companion dogs and in human patients.

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Glucagon-like peptide 1: evolution of an incretin into a treatment for diabetes

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00014.2004 ◽

2004 ◽

Vol 286 (6) ◽

pp. E882-E890 ◽

Cited By ~ 58

Author(s):

David A. D'Alessio ◽

Torsten P. Vahl

Keyword(s):

Insulin Secretion ◽

Blood Glucose ◽

Cell Mass ◽

Insulin Response ◽

Gastrointestinal Hormones ◽

Glucose Production ◽

Glucagon Secretion ◽

Treatment Of Diabetes ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1

Glucagon-like peptide 1 (GLP-1) is a product of proglucagon that is secreted by specialized intestinal endocrine cells after meals. GLP-1 is insulinotropic and plays a role in the incretin effect, the augmented insulin response observed when glucose is absorbed through the gut. GLP-1 also appears to regulate a number of processes that reduce fluctuations in blood glucose, such as gastric emptying, glucagon secretion, food intake, and possibly glucose production and glucose uptake. These effects, in addition to the stimulation of insulin secretion, suggest a broad role for GLP-1 as a mediator of postprandial glucose homeostasis. Consistent with this role, the most prominent effect of experimental blockade of GLP-1 signaling is an increase in blood glucose. Recent data also suggest that GLP-1 is involved in the regulation of β-cell mass. Whereas other insulinotropic gastrointestinal hormones are relatively ineffective in stimulating insulin secretion in persons with type 2 diabetes, GLP-1 retains this action and is very effective in lowering blood glucose levels in these patients. There are currently a number of products in development that utilize the GLP-1-signaling system as a mechanism for the treatment of diabetes. These compounds, GLP-1 receptor agonists and agents that retard the metabolism of native GLP-1, have shown promising results in clinical trials. The application of GLP-1 to clinical use fulfills a long-standing interest in adapting endogenous insulinotropic hormones to the treatment of diabetes.

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Stathmin-2 Mediates Glucagon Secretion from Pancreatic α-Cells

10.1101/832493 ◽

2019 ◽

Author(s):

Farzad Asadi ◽

Savita Dhanvantari

Keyword(s):

Secretory Granule ◽

Secretory Granules ◽

Glucagon Secretion ◽

Alpha Cell ◽

Cell Protein ◽

Mrna Levels ◽

Neuronal Protein ◽

Mouse Pancreatic Islets ◽

Treatment Of Diabetes ◽

Lysosomal System

AbstractInhibition of glucagon hypersecretion from pancreatic α-cells is an appealing strategy for the treatment of diabetes. Our hypothesis is that proteins that associate with glucagon within alpha cell secretory granules will regulate glucagon secretion, and may provide druggable targets for controlling abnormal glucagon secretion in diabetes. Recently, we identified a dynamic glucagon interactome within the secretory granules of the α cell line, αTC1-6, and showed that select proteins within the interactome could modulate glucagon secretion. In the present study, we show that one of these interactome proteins, the neuronal protein stathmin-2, is expressed in aTC1-6 cells and in mouse pancreatic alpha cells, and is a novel regulator of glucagon secretion. Stathmin-2 was co-secreted with glucagon in response to 55 mM K+, and immunofluorescence confocal microscopy showed co-localization of stathmin-2 with glucagon and the secretory granule markers chromogranin A and VAMP-2 in αTC1-6 cells. In mouse pancreatic islets, Stathmin-2 co-localized with glucagon, but not with insulin, indicating that it is an alpha cell protein. To show a function for stathmin-2 in regulating glucagon secretion, we showed that siRNA - mediated depletion of stathmin-2 in aTC1-6 cells caused glucagon secretion to become constitutive without any effect on proglucagon mRNA levels, while overexpression of stathmin-2 completely abolished both basal and K+-stimulated glucagon secretion. Overexpression of stathmin-2 increased the localization of glucagon into the endosomal-lysosomal compartment, while depletion of stathmin-2 reduced the endosomal localization of glucagon. Therefore, we describe stathmin-2 as having a novel role as an alpha cell secretory granule protein that modulates glucagon secretion via trafficking through the endosomal-lysosomal system. These findings describe a potential new pathway for the regulation of glucagon secretion, and may have implications for controlling glucagon hypersecretion in diabetes.

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CARDIOVASCULAR SAFETY OF GLIPTINS. FOCUS ON ALOGLIPTIN

Medical Council ◽

10.21518/2079-701x-2017-3-32-37 ◽

2017 ◽

pp. 32-37

Author(s):

N. A. Petunina ◽

E. V. Goncharova ◽

S. A. Potapova

Keyword(s):

Progressive Disease ◽

Glucagon Secretion ◽

Β Cells ◽

Dipeptidyl Peptidase 4 ◽

Dipeptidyl Peptidase 4 Inhibitors ◽

Chronic Progressive Disease ◽

Treatment Of Diabetes ◽

New Strategies ◽

Neutral Effect

Type 2 diabetes is a chronic progressive disease the prevalence of which is increasing. The development of new strategies for the treatment of diabetes, among which drugs that modulate the “incretin effect” are worth noting, continues. Dipeptidyl peptidase-4 inhibitors (DPP-4, gliptins) are a group of oral antidiabetic incretin drugs that enhance the glucose-induced activity of β-cells and suppress excessive glucagon secretion by pancreatic α-cells. This group of antidiabetic drugs is widespread due to a number of relevant benefits, such as neutral effect on body weight, low risk of hypoglycaemia, convenient administration scheme and good adherence to treatment. Efficacy and safety of treatment demonstrated by global multicenter trials allow for a wide use of gliptins in clinical practice.

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Temporal Patterns of Glucagon and Its Relationships with Glucose and Insulin following Ingestion of Different Classes of Macronutrients

Nutrients ◽

10.3390/nu14020376 ◽

2022 ◽

Vol 14 (2) ◽

pp. 376

Author(s):

Christian Göbl ◽

Micaela Morettini ◽

Benedetta Salvatori ◽

Wathik Alsalim ◽

Hana Kahleova ◽

...

Keyword(s):

Insulin Secretion ◽

Area Under The Curve ◽

Glucagon Secretion ◽

Plasma Glucagon ◽

Food Ingestion ◽

Mixed Meal ◽

C Peptide ◽

Significant Relationships ◽

Basal Insulin Secretion ◽

Secretion Inhibition

Background: glucagon secretion and inhibition should be mainly determined by glucose and insulin levels, but the relative relevance of each factor is not clarified, especially following ingestion of different macronutrients. We aimed to investigate the associations between plasma glucagon, glucose, and insulin after ingestion of single macronutrients or mixed-meal. Methods: thirty-six participants underwent four metabolic tests, based on administration of glucose, protein, fat, or mixed-meal. Glucagon, glucose, insulin, and C-peptide were measured at fasting and for 300 min following food ingestion. We analyzed relationships between time samples of glucagon, glucose, and insulin in each individual, as well as between suprabasal area-under-the-curve of the same variables (ΔAUCGLUCA, ΔAUCGLU, ΔAUCINS) over the whole participants’ cohort. Results: in individuals, time samples of glucagon and glucose were related in only 26 cases (18 direct, 8 inverse relationships), whereas relationship with insulin was more frequent (60 and 5, p < 0.0001). The frequency of significant relationships was different among tests, especially for direct relationships (p ≤ 0.006). In the whole cohort, ΔAUCGLUCA was weakly related to ΔAUCGLU (p ≤ 0.02), but not to ΔAUCINS, though basal insulin secretion emerged as possible covariate. Conclusions: glucose and insulin are not general and exclusive determinants of glucagon secretion/inhibition after mixed-meal or macronutrients ingestion.

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