scholarly journals Diminished glucagon suppression after β-cell reduction is due to impaired α-cell function rather than an expansion of α-cell mass

2011 ◽  
Vol 300 (4) ◽  
pp. E717-E723 ◽  
Author(s):  
Juris J. Meier ◽  
Sandra Ueberberg ◽  
Simone Korbas ◽  
Stephan Schneider
Keyword(s):  
Insulin Treatment ◽  
Cell Function ◽  
Cell Mass ◽  
Glucagon Secretion ◽  
Pancreatic Tissue ◽  
Oral Glucose ◽  
Inverse Association ◽  
Β Cell ◽  
Glucose Ingestion ◽  
Glucagon Suppression

Impaired suppression of glucagon levels after oral glucose or meal ingestion is a hallmark of type 2 diabetes. Whether hyperglucagonemia after a β-cell loss results from a functional upregulation of glucagon secretion or an increase in α-cell mass is yet unclear. CD-1 mice were treated with streptozotocin (STZ) or saline. Pancreatic tissue was collected after 14, 21, and 28 days and examined for α- and β-cell mass and turnover. Intraperitoneal (ip) glucose tolerance tests were performed at day 28 as well as after 12 days of subcutaneous insulin treatment, and glucose, insulin, and glucagon levels were determined. STZ treatment led to fasting and post-challenge hyperglycemia ( P < 0.001 vs. controls). Insulin levels increased after glucose injection in controls ( P < 0.001) but were unchanged in STZ mice ( P = 0.36). Intraperitoneal glucose elicited a 63.1 ± 4.1% glucagon suppression in control mice ( P < 0.001), whereas the glucagon suppression was absent in STZ mice ( P = 0.47). Insulin treatment failed to normalize glucagon levels. There was a significant inverse association between insulin and glucagon levels after ip glucose ingestion ( r2 = 0.99). β-Cell mass was reduced by ∼75% in STZ mice compared with controls ( P < 0.001), whereas α-cell mass remained unchanged ( P > 0.05). α-Cell apoptosis (TUNEL) and replication (Ki67) were rather infrequently noticed, with no significant differences between the groups. These studies underline the importance of endogenous insulin for the glucose-induced suppression of glucagon secretion and suggest that the insufficient decline in glucagon levels after glucose administration in diabetes is primarily due to a functional loss of intraislet inhibition of α-cell function rather than an expansion of α-cell mass.

scholarly journals Impaired Glucose-Induced Glucagon Suppression after Partial Pancreatectomy

2009 ◽  
Vol 94 (8) ◽  
pp. 2857-2863 ◽  
Author(s):  
Henning Schrader ◽  
Bjoern A. Menge ◽  
Thomas G. K. Breuer ◽  
Peter R. Ritter ◽  
Waldemar Uhl ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Cell Function ◽  
Plasma Concentrations ◽  
Cell Mass ◽  
Oral Glucose ◽  
Partial Pancreatectomy ◽  
C Peptide ◽  
Glucose Ingestion ◽  
Glucagon Suppression

Introduction: The glucose-induced decline in glucagon levels is often lost in patients with type 2 diabetes. It is unclear whether this is due to an independent defect in α-cell function or secondary to the impairment in insulin secretion. We examined whether a partial pancreatectomy in humans would also impair postchallenge glucagon concentrations and, if so, whether this could be attributed to the reduction in insulin levels. Patients and Methods: Thirty-six patients with pancreatic tumours or chronic pancreatitis were studied before and after approximately 50% pancreatectomy with a 240-min oral glucose challenge, and the plasma concentrations of glucose, insulin, C-peptide, and glucagon were determined. Results: Fasting and postchallenge insulin and C-peptide levels were significantly lower after partial pancreatectomy (P &lt; 0.0001). Likewise, fasting glucagon concentrations tended to be lower after the intervention (P = 0.11). Oral glucose ingestion elicited a decline in glucagon concentrations before surgery (P &lt; 0.0001), but this was lost after partial pancreatectomy (P &lt; 0.01 vs. preoperative values). The loss of glucose-induced glucagon suppression was found after both pancreatic head (P &lt; 0.001) and tail (P &lt; 0.05) resection. The glucose-induced changes in glucagon levels were closely correlated to the respective increments in insulin and C-peptide concentrations (P &lt; 0.01). Conclusions: The glucose-induced suppression in glucagon levels is lost after a 50% partial pancreatectomy in humans. This suggests that impaired α-cell function in patients with type 2 diabetes may also be secondary to reduced β-cell mass. Alterations in glucagon regulation should be considered as a potential side effect of partial pancreatectomies.

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

1999 ◽  
Vol 277 (2) ◽  
pp. E283-E290 ◽  
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.

scholarly journals The Role of the α Cell in the Pathogenesis of Diabetes: A World beyond the Mirror

2021 ◽  
Vol 22 (17) ◽  
pp. 9504
Author(s):  
María Sofía Martínez ◽  
Alexander Manzano ◽  
Luis Carlos Olivar ◽  
Manuel Nava ◽  
Juan Salazar ◽  
...  
Keyword(s):  
Cell Function ◽  
Cell Mass ◽  
Glucagon Secretion ◽  
Endocrine Regulation ◽  
Β Cell ◽  
Cell Hyperplasia ◽  
Dipeptidyl Peptidase 4 ◽  
Dipeptidyl Peptidase 4 Inhibitors ◽  
Glucagon Like Peptide 1 ◽  
Chronic Hyperglycaemia

Type 2 Diabetes Mellitus (T2DM) is one of the most prevalent chronic metabolic disorders, and insulin has been placed at the epicentre of its pathophysiological basis. However, the involvement of impaired alpha (α) cell function has been recognized as playing an essential role in several diseases, since hyperglucagonemia has been evidenced in both Type 1 and T2DM. This phenomenon has been attributed to intra-islet defects, like modifications in pancreatic α cell mass or dysfunction in glucagon’s secretion. Emerging evidence has shown that chronic hyperglycaemia provokes changes in the Langerhans’ islets cytoarchitecture, including α cell hyperplasia, pancreatic beta (β) cell dedifferentiation into glucagon-positive producing cells, and loss of paracrine and endocrine regulation due to β cell mass loss. Other abnormalities like α cell insulin resistance, sensor machinery dysfunction, or paradoxical ATP-sensitive potassium channels (KATP) opening have also been linked to glucagon hypersecretion. Recent clinical trials in phases 1 or 2 have shown new molecules with glucagon-antagonist properties with considerable effectiveness and acceptable safety profiles. Glucagon-like peptide-1 (GLP-1) agonists and Dipeptidyl Peptidase-4 inhibitors (DPP-4 inhibitors) have been shown to decrease glucagon secretion in T2DM, and their possible therapeutic role in T1DM means they are attractive as an insulin-adjuvant therapy.

scholarly journals α-Cell Dysfunctions and Molecular Alterations in Male Insulinopenic Diabetic Mice Are Not Completely Corrected by Insulin

Endocrinology ◽  
2015 ◽  
Vol 157 (2) ◽  
pp. 536-547 ◽  
Author(s):  
Rodolphe Dusaulcy ◽  
Sandra Handgraaf ◽  
Mounia Heddad-Masson ◽  
Florian Visentin ◽  
Christian Vesin ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
Insulin Treatment ◽  
Cell Function ◽  
Cell Mass ◽  
Glucagon Secretion ◽  
Diabetic Mice ◽  
Differentiation Markers ◽  
Molecular Alteration ◽  
Cell Dysfunction

Abstract Glucagon and α-cell dysfunction are critical in the development of hyperglycemia during diabetes both in humans and rodents. We hypothesized that α-cell dysfunction leading to dysregulated glucagon secretion in diabetes is due to both a lack of insulin and intrinsic defects. To characterize α-cell dysfunction in diabetes, we used glucagon-Venus transgenic male mice and induced insulinopenic hyperglycemia by streptozotocin administration leading to alterations of glucagon secretion. We investigated the in vivo impact of insulinopenic hyperglycemia on glucagon-producing cells using FACS-sorted α-cells from control and diabetic mice. We demonstrate that increased glucagonemia in diabetic mice is mainly due to increases of glucagon release and biosynthesis per cell compared with controls without changes in α-cell mass. We identified genes coding for proteins involved in glucagon biosynthesis and secretion, α-cell differentiation, and potential stress markers such as the glucagon, Arx, MafB, cMaf, Brain4, Foxa1, Foxa3, HNF4α, TCF7L2, Glut1, Sglt2, Cav2.1, Cav2.2, Nav1.7, Kir6.2/Sur1, Pten, IR, NeuroD1, GPR40, and Sumo1 genes, which were abnormally regulated in diabetic mice. Importantly, insulin treatment partially corrected α-cell function and expression of genes coding for proglucagon, or involved in glucagon secretion, glucose transport and insulin signaling but not those coding for cMAF, FOXA1, and α-cell differentiation markers as well as GPR40, NEUROD1, CAV2.1, and SUMO1. Our results indicate that insulinopenic diabetes induce marked α-cell dysfunction and molecular alteration, which are only partially corrected by in vivo insulin treatment.

Sitagliptin prevents the development of metabolic and hormonal disturbances, increased β-cell apoptosis and liver steatosis induced by a fructose-rich diet in normal rats

2010 ◽  
Vol 120 (2) ◽  
pp. 73-80 ◽  
Author(s):  
Bárbara Maiztegui ◽  
María I. Borelli ◽  
Viviana G. Madrid ◽  
Héctor Del Zotto ◽  
María A. Raschia ◽  
...  
Keyword(s):  
Glucose Tolerance ◽  
Cell Function ◽  
Liver Steatosis ◽  
Cell Mass ◽  
Oral Glucose ◽  
Model Assessment ◽  
Metabolic Disturbances ◽  
Β Cell ◽  
Commercial Diet ◽  
Triacylglycerol Content

The aim of the present study was to test the effect of sitagliptin and exendin-4 upon metabolic alterations, β-cell mass decrease and hepatic steatosis induced by F (fructose) in rats. Normal adult male Wistar rats received a standard commercial diet without (C) or with 10% (w/v) F in the drinking water (F) for 3 weeks; animals from each group were randomly divided into three subgroups: untreated (C and F) and simultaneously receiving either sitagliptin (CS and FS; 115.2 mg/day per rat) or exendin-4 (CE and FE; 0.35 nmol/kg of body weight, intraperitoneally). Water and food intake, oral glucose tolerance, plasma glucose, triacylglycerol (triglyceride), insulin and fructosamine concentration, HOMA-IR [HOMA (homoeostasis model assessment) for insulin resistance], HOMA-β (HOMA for β-cell function) and liver triacylglycerol content were measured. Pancreas immunomorphometric analyses were also performed. IGT (impaired glucose tolerance), plasma triacylglycerol, fructosamine and insulin levels, HOMA-IR and HOMA-β indexes, and liver triacylglycerol content were significantly higher in F rats. Islet β-cell mass was significantly lower in these rats, due to an increase in the percentage of apoptosis. The administration of exendin-4 and sitagliptin to F animals prevented the development of all the metabolic disturbances and the changes in β-cell mass and fatty liver. Thus these compounds, useful in treating Type 2 diabetes, would also prevent/delay the progression of early metabolic and tissue markers of this disease.

scholarly journals Impaired islet turnover in human donor pancreata with aging

2009 ◽  
Vol 160 (2) ◽  
pp. 185-191 ◽  
Author(s):  
Christina Reers ◽  
Saskia Erbel ◽  
Irene Esposito ◽  
Bruno Schmied ◽  
Markus W Büchler ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Cell Volume ◽  
Cell Apoptosis ◽  
Cell Function ◽  
Cell Mass ◽  
Pancreatic Tissue ◽  
Human Pancreas ◽  
Cell Replication ◽  
Β Cell ◽  
Islet Neogenesis

ObjectiveThe prevalence of type 2 diabetes mellitus escalates with aging although β-cell mass, a primary parameter of β-cell function, is subject to compensatory regulation. So far it is unclear whether the proliferative capacity of pancreatic islets is restricted by senescence.Materials and methodsHuman pancreatic tissue from n=20 non-diabetic organ donors with a mean age of 50.2±3.5 years (range 7–66 years) and mean body mass index of 25.7±0.9 kg/m2 (17.2–33.1 kg/m2) was morphometrically analyzed to determine β-cell volume, β-cell replication, β-cell apoptosis, islet neogenesis, and pancreatic duodenal homeobox-1 (PDX-1) expression.ResultsRelative β-cell volume in human pancreata (mean 2.3±0.2%) remains constant with aging (r=0.26, P=ns). β-cell replication (r=0.71, P=0.0004) decreases age-dependently, while β-cell apoptosis does not change significantly (r=0.42, P=0.08). Concomitantly, PDX-1 expression is downregulated with age in human pancreatic tissue (r=0.65, P=0.002). The rate of islet neogenesis is not affected by aging (r=0.13, P=ns).ConclusionsIn non-diabetic humans, aging is linked with impaired islet turnover possibly due to reduced PDX-1 expression. As β-cell replication is considered to be the main mechanism responsible for β-cell regeneration, these changes restrict the flexibility of the aging human pancreas to adapt to changing demands for insulin secretion and increase the risk for the development of diabetes mellitus in older subjects.

Full The Relationship between Continuous Glucose Monitoring and OGTT in Youth and Young Adults with Cystic Fibrosis

2021 ◽  
Author(s):  
Christine L Chan ◽  
Laura Pyle ◽  
Tim Vigers ◽  
Philip S Zeitler ◽  
Kristen J Nadeau
Keyword(s):  
Cystic Fibrosis ◽  
Continuous Glucose Monitoring ◽  
Cell Function ◽  
Glucose Monitoring ◽  
Oral Glucose ◽  
Β Cell ◽  
Oral Glucose Tolerance Testing ◽  
C Peptide ◽  
Β Cell Function ◽  
The Relationship

Abstract Context Early glucose abnormalities in people with CF (PwCF) are commonly detected by continuous glucose monitoring (CGM). Relationships between these CGM abnormalities and oral glucose tolerance testing (OGTT) in PwCF have not been fully characterized. Objective(s) 1) To determine the relationship between CGM and common OGTT-derived estimates of β-cell function, including C-peptide index and oral disposition index (oDI) and 2) to explore whether CGM can be used to screen for OGTT-defined prediabetes and cystic fibrosis related diabetes (CFRD). Study Design/Methods PwCF not on insulin and healthy controls ages 6-25 yrs were enrolled in a prospective study collecting OGTT and CGM. A subset underwent frequently-sampled OGTTs (fsOGTT) with 7-point glucose, insulin, and C-peptide measurements. Pearson’s correlation coefficient was used to test the association between select CGM and fsOGTT measures. ROC analysis was applied to CGM variables to determine the cutoff optimizing sensitivity and specificity for detecting prediabetes and CFRD. Results A total of 120 participants (controls=35, CF=85), including 69 with fsOGTTs, were included. CGM coefficient of variation correlated inversely with C-peptide index (Cpeptide30-Cpeptide0/Glucose30-Glucose0) (r=-0.45, p&lt;0.001) and oDIcpeptide (C-peptide index)(1/cpep0) (r=-0.48, p&lt;0.0001). In PwCF, CGM variables had ROC-AUCs ranging from 0.43-0.57 for prediabetes and 0.47-0.6 for CFRD. Conclusions Greater glycemic variability on CGM correlated with reduced β-cell function. However, CGM performed poorly at discriminating individuals with and without OGTT-defined CFRD and prediabetes. Prospective studies are now needed to determine how well the different tests predict clinically-relevant non-glycemic outcomes in PwCF.

scholarly journals Follow-up of GK rats during prediabetes highlights increased insulin action and fat deposition despite low insulin secretion

2008 ◽  
Vol 294 (1) ◽  
pp. E168-E175 ◽  
Author(s):  
Jamileh Movassat ◽  
Danièle Bailbé ◽  
Cécile Lubrano-Berthelier ◽  
Françoise Picarel-Blanchot ◽  
Eric Bertin ◽  
...  
Keyword(s):  
Body Composition ◽  
Insulin Secretion ◽  
Insulin Sensitivity ◽  
Cell Function ◽  
Cell Mass ◽  
The Body ◽  
Whole Body ◽  
Β Cell ◽  
Gk Rats

The adult Goto-Kakizaki (GK) rat is characterized by impaired glucose-induced insulin secretion in vivo and in vitro, decreased β-cell mass, decreased insulin sensitivity in the liver, and moderate insulin resistance in muscles and adipose tissue. GK rats do not exhibit basal hyperglycemia during the first 3 wk after birth and therefore could be considered prediabetic during this period. Our aim was to identify the initial pathophysiological changes occurring during the prediabetes period in this model of type 2 diabetes (T2DM). To address this, we investigated β-cell function, insulin sensitivity, and body composition in normoglycemic prediabetic GK rats. Our results revealed that the in vivo secretory response of GK β-cells to glucose is markedly reduced and the whole body insulin sensitivity is increased in the prediabetic GK rats in vivo. Moreover, the body composition of suckling GK rats is altered compared with age-matched Wistar rats, with an increase of the number of adipocytes before weaning despite a decreased body weight and lean mass in the GK rats. None of these changes appeared to be due to the postnatal nutritional environment of GK pups as demonstrated by cross-fostering GK pups with nondiabetic Wistar dams. In conclusion, in the GK model of T2DM, β-cell dysfunction associated with increased insulin sensitivity and the alteration of body composition are proximal events that might contribute to the establishment of overt diabetes in adult GK rats.

Sign in / Sign up

Export Citation Format

Share Document