Somatostatin and insulin mediate glucose-inhibited glucagon secretion in the pancreatic α-cell by lowering cAMP

The dysregulation of glucose-inhibited glucagon secretion from the pancreatic islet α-cell is a critical component of diabetes pathology and metabolic disease. We show a previously uncharacterized [Ca2+]i-independent mechanism of glucagon suppression in human and murine pancreatic islets whereby cAMP and PKA signaling are decreased. This decrease is driven by the combination of somatostatin, which inhibits adenylyl cyclase production of cAMP via the Gαi subunit of the SSTR2, and insulin, which acts via its receptor to activate phosphodiesterase 3B and degrade cytosolic cAMP. Our data indicate that both somatostatin and insulin signaling are required to suppress cAMP/PKA and glucagon secretion from both human and murine α-cells, and the combination of these two signaling mechanisms is sufficient to reduce glucagon secretion from isolated α-cells as well as islets. Thus, we conclude that somatostatin and insulin together are critical paracrine mediators of glucose-inhibited glucagon secretion and function by lowering cAMP/PKA signaling with increasing glucose.

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339-LB: Modulation of Insulin and Glucagon Secretion by Optogenetic Control of Delta-Cell Electrical Activity in Pancreatic Islets

Diabetes ◽

10.2337/db19-339-lb ◽

2019 ◽

Vol 68 (Supplement 1) ◽

pp. 339-LB

Author(s):

HAIQIANG DOU ◽

CAROLINE A. MIRANDA ◽

QUAN ZHANG ◽

PATRIK RORSMAN ◽

JOHAN TOLö

Keyword(s):

Electrical Activity ◽

Pancreatic Islets ◽

Glucagon Secretion ◽

Insulin And Glucagon Secretion ◽

Delta Cell ◽

Optogenetic Control

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The Pleiotropic Intricacies of Hedgehog Signaling: From Craniofacial Patterning to Carcinogenesis

FACE ◽

10.1177/27325016211024326 ◽

2021 ◽

pp. 273250162110243

Author(s):

Mikhail Pakvasa ◽

Andrew B. Tucker ◽

Timothy Shen ◽

Tong-Chuan He ◽

Russell R. Reid

Keyword(s):

Intracellular Signaling ◽

Limb Development ◽

Hedgehog Signaling ◽

Target Genes ◽

Craniofacial Development ◽

Signaling Cascade ◽

Signaling Mechanisms ◽

Intracellular Signaling Cascade ◽

And Function

Hedgehog signaling was discovered more than 40 years ago in experiments demonstrating that it is a fundamental mediator of limb development. Since that time, it has been shown to be important in development, homeostasis, and disease. The hedgehog pathway proceeds through a pathway highly conserved throughout animals beginning with the extracellular diffusion of hedgehog ligands, proceeding through an intracellular signaling cascade, and ending with the activation of specific target genes. A vast amount of research has been done elucidating hedgehog signaling mechanisms and regulation. This research has found a complex system of genetics and signaling that helps determine how organisms develop and function. This review provides an overview of what is known about hedgehog genetics and signaling, followed by an in-depth discussion of the role of hedgehog signaling in craniofacial development and carcinogenesis.

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Presenilin Regulates Insulin Signaling via a γ-Secretase-independent Mechanism

Journal of Biological Chemistry ◽

10.1074/jbc.m111.248922 ◽

2011 ◽

Vol 286 (28) ◽

pp. 25309-25316 ◽

Cited By ~ 10

Author(s):

Masato Maesako ◽

Kengo Uemura ◽

Akira Kuzuya ◽

Kazuki Sasaki ◽

Megumi Asada ◽

...

Keyword(s):

Insulin Signaling ◽

Independent Mechanism

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Atrial natriuretic peptide (ANP)-induced inhibition of glucagon secretion: Mechanism of action in isolated rat pancreatic islets

Peptides ◽

10.1016/0196-9781(96)00152-0 ◽

1996 ◽

Vol 17 (6) ◽

pp. 1023-1029 ◽

Cited By ~ 18

Author(s):

Eugen J. Verspohl ◽

Irmgard K. Bernemann

Keyword(s):

Atrial Natriuretic Peptide ◽

Pancreatic Islets ◽

Natriuretic Peptide ◽

Mechanism Of Action ◽

Glucagon Secretion ◽

Rat Pancreatic Islets ◽

Isolated Rat ◽

Atrial Natriuretic

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In Vivo Role of Focal Adhesion Kinase in Regulating Pancreatic -Cell Mass and Function Through Insulin Signaling, Actin Dynamics, and Granule Trafficking

Diabetes ◽

10.2337/db11-1344 ◽

2012 ◽

Vol 61 (7) ◽

pp. 1708-1718 ◽

Cited By ~ 42

Author(s):

E. P. Cai ◽

M. Casimir ◽

S. A. Schroer ◽

C. T. Luk ◽

S. Y. Shi ◽

...

Keyword(s):

Focal Adhesion Kinase ◽

Focal Adhesion ◽

Insulin Signaling ◽

Cell Mass ◽

Actin Dynamics ◽

Pancreatic Cell ◽

And Function

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Impact of lack of suppression of glucagon on glucose tolerance in humans

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1999.277.2.e283 ◽

1999 ◽

Vol 277 (2) ◽

pp. E283-E290 ◽

Cited By ~ 23

Author(s):

Pankaj Shah ◽

Ananda Basu ◽

Rita Basu ◽

Robert Rizza

Keyword(s):

Insulin Secretion ◽

Glucose Concentration ◽

Cell Function ◽

Hormone Secretion ◽

Glucose Production ◽

Glucagon Secretion ◽

Β Cell ◽

Β Cell Function ◽

Glucagon Suppression

People with type 2 diabetes have defects in both α- and β-cell function. To determine whether lack of suppression of glucagon causes hyperglycemia when insulin secretion is impaired but not when insulin secretion is intact, twenty nondiabetic subjects were studied on two occasions. On both occasions, a “prandial” glucose infusion was given over 5 h while endogenous hormone secretion was inhibited. Insulin was infused so as to mimic either a nondiabetic ( n = 10) or diabetic ( n = 10) postprandial profile. Glucagon was infused at a rate of 1.25 ng ⋅ kg−1 ⋅ min−1, beginning either at time zero to prevent a fall in glucagon (nonsuppressed study day) or at 2 h to create a transient fall in glucagon (suppressed study day). During the “diabetic” insulin profile, lack of glucagon suppression resulted in a marked increase ( P < 0.002) in both the peak glucose concentration (11.9 ± 0.4 vs. 8.9 ± 0.4 mmol/l) and the area above basal of glucose (927 ± 77 vs. 546 ± 112 mmol ⋅ l−1 ⋅ 6 h) because of impaired ( P < 0.001) suppression of glucose production. In contrast, during the “nondiabetic” insulin profile, lack of suppression of glucagon resulted in only a slight increase ( P< 0.02) in the peak glucose concentration (9.1 ± 0.4 vs. 8.4 ± 0.3 mmol/l) and the area above basal of glucose (654 ± 146 vs. 488 ± 118 mmol ⋅ l−1 ⋅ 6 h). Of interest, when glucagon was suppressed, glucose concentrations differed only minimally during the nondiabetic and diabetic insulin profiles. These data indicate that lack of suppression of glucagon can cause substantial hyperglycemia when insulin availability is limited, therefore implying that inhibitors of glucagon secretion and/or glucagon action are likely to be useful therapeutic agents in such individuals.

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Differential binding of hyaluronan on the surface of tissue-specific endothelial cell lines.

Acta Biochimica Polonica ◽

10.18388/abp.2008_3198 ◽

2008 ◽

Vol 55 (1) ◽

pp. 35-42 ◽

Cited By ~ 13

Author(s):

Karol Szczepanek ◽

Claudine Kieda ◽

Joanna Cichy

Keyword(s):

Endothelial Cells ◽

Endothelial Cell ◽

Tumor Cells ◽

Cell Lines ◽

Tissue Specific ◽

Independent Mechanism ◽

Differential Binding ◽

And Function ◽

Pathologic Processes ◽

Tissue Origin

Tissue-specific heterogeneity of endothelial cells, both structural and functional, plays a crucial role in physiologic as well as pathologic processes, including inflammation, autoimmune diseases and tumor metastasis. This heterogeneity primarily results from the differential expression of adhesion molecules that are involved in the interactions between endothelium and circulating immune cells or disseminating tumor cells. Among these molecules present on endothelial cells is hyaluronan (HA), a glycosaminoglycan that contributes to primary (rolling) interactions through binding to its main receptor CD44 expressed on leukocytes and tumor cells. While the regulation of CD44 expression and function on either leukocytes or tumor cells has been well characterized, much less is known about the ability of endothelial cells to express HA on their surface. Therefore, in these studies we analyzed HA levels on tissue-specific endothelium. We used endothelial cell lines of different origin, including lung, skin, gut and lymph nodes that had been established previously as model lines to study interactions between the endothelium and leukocytes/tumor cells. Our results indicate that HA is accumulated on the surface of all endothelial cells examined. Moreover, retention of endogenous HA differs between the lines and may depend on their tissue origin. Analysis of binding of exogenous HA reveals the presence of specific HA binding sites on all endothelial cell lines tested. However, the retention of endogenous HA and the binding of exogenous HA is mediated through a CD44-independent mechanism.

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A novel GPR40 agonist, CNX-011-67, suppresses glucagon secretion in pancreatic islets under chronic glucolipotoxic conditions in vitro

BMC Research Notes ◽

10.1186/1756-0500-7-595 ◽

2014 ◽

Vol 7 (1) ◽

pp. 595 ◽

Cited By ~ 4

Author(s):

Mahesh Verma ◽

Sanghamitra Biswas ◽

Bhawna Chandravanshi ◽

Korrapati Neelima ◽

Anup M Oommen ◽

...

Keyword(s):

Pancreatic Islets ◽

Glucagon Secretion

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Selective Insulin Resistance in the Kidney

BioMed Research International ◽

10.1155/2016/5825170 ◽

2016 ◽

Vol 2016 ◽

pp. 1-8 ◽

Cited By ~ 20

Author(s):

Shoko Horita ◽

Motonobu Nakamura ◽

Masashi Suzuki ◽

Nobuhiko Satoh ◽

Atsushi Suzuki ◽

...

Keyword(s):

Insulin Resistance ◽

Proximal Tubule ◽

Insulin Signaling ◽

Glucose Production ◽

Signaling Cascades ◽

Sodium Reabsorption ◽

Insulin Receptor Substrate ◽

Target Organs ◽

And Function ◽

Selective Impairment

Insulin resistance has been characterized as attenuation of insulin sensitivity at target organs and tissues, such as muscle and fat tissues and the liver. The insulin signaling cascade is divided into major pathways such as the PI3K/Akt pathway and the MAPK/MEK pathway. In insulin resistance, however, these pathways are not equally impaired. For example, in the liver, inhibition of gluconeogenesis by the insulin receptor substrate (IRS) 2 pathway is impaired, while lipogenesis by the IRS1 pathway is preserved, thus causing hyperglycemia and hyperlipidemia. It has been recently suggested that selective impairment of insulin signaling cascades in insulin resistance also occurs in the kidney. In the renal proximal tubule, insulin signaling via IRS1 is inhibited, while insulin signaling via IRS2 is preserved. Insulin signaling via IRS2 continues to stimulate sodium reabsorption in the proximal tubule and causes sodium retention, edema, and hypertension. IRS1 signaling deficiency in the proximal tubule may impair IRS1-mediated inhibition of gluconeogenesis, which could induce hyperglycemia by preserving glucose production. In the glomerulus, the impairment of IRS1 signaling deteriorates the structure and function of podocyte and endothelial cells, possibly causing diabetic nephropathy. This paper mainly describes selective insulin resistance in the kidney, focusing on the proximal tubule.

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