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 Pathogenetic substantiation and effectiveness of vildagliptin use inpatients with diabetes mellitus type 2

2009 ◽  
Vol 6 (3) ◽  
pp. 16-26 ◽  
Author(s):  
T I Romantsova
Keyword(s):  
Type 2 Diabetes ◽  
Cell Function ◽  
Glucagon Secretion ◽  
Β Cell ◽  
Dipeptidyl Peptidase 4 ◽  
Glucose Levels ◽  
Β Cell Function ◽  
Control Of Diabetes ◽  
Glucagon Like Peptide 1

Insulin resistance in muscle and liver and β-cell failure represent the core pathophysiologic defects in type 2 diabetes. Now it isrecognized that the β-cell failure occurs much earlier and is more severe than previously thought. As a result, earlier and more aggressive new therapy is needed to achiev e better control of diabetes and to prev ent/slow the progressive B-cell failure that already is w ell established in IGT subjects. One approach is to target the incretin mimetic hormone glucagon-like peptide-1 (GLP-1). When blood glucose levels are elevated, GrP-1 stimulates insulin secretion, decreases glucagon secretion, impro ves β-cell function, and slows gastric emptying. GrP-1 production is reduced in patients with type 2 diabetes. Furthermore, GrP-1 is rapidly degraded by the dipeptidyl peptidase 4 (DPP-4) enzyme. Trials have showed, that new inhibitor DPP-4 vildagliptin (Galvus) hav e been demonstrated to significantly reduce HbA lc, fasting and prandial glucose levels when used as monotherapy and in соmbination with traditional agents. Advantages of vildagliptin include few adverse events, low risk of hypoglycemia, neutral effect on body weight, and a once-daily oral dosing regimen. Inaddition, vildagliptin may preserve the decline in β-cell function. Hence, vildagliptin may modify the natural progressive course of diabetes; this however, must be confirmed with longer-term controlled studies

scholarly journals From Theory to Clinical Practice in the Use of GLP-1 Receptor Agonists and DPP-4 Inhibitors Therapy

2011 ◽  
Vol 2011 ◽  
pp. 1-8 ◽  
Author(s):  
Ilaria Dicembrini ◽  
Laura Pala ◽  
Carlo Maria Rotella
Keyword(s):  
Cell Function ◽  
Lifestyle Modification ◽  
Cell Mass ◽  
Beta Cell Mass ◽  
Minimal Risk ◽  
Dipeptidyl Peptidase 4 ◽  
Receptor Agonists ◽  
Dipeptidyl Peptidase 4 Inhibitors

Promoting long-term adherence to lifestyle modification and choice of antidiabetic agent with low hypoglycemia risk profile and positive weight profile could be the most effective strategy in achieving sustained glycemic control and in reducing comorbidities. From this perspective, vast interest has been generated by glucagon-like peptide-1 (GLP-1) receptor agonists and dipeptidyl peptidase-4 inhibitors (DPP-4i). In this review our ten-year clinical and laboratory experience byin vitroandin vivostudies is reported. Herein, we reviewed available data on the efficacy and safety profile of GLP-1 receptor agonists and DPP-4i. The introduction of incretin hormone-based therapies represents a novel therapeutic strategy, because these drugs not only improve glycemia with minimal risk of hypoglycemia but also have other extraglycemic beneficial effects. In clinical studies, both GLP-1 receptor agonists and DPP-4i, improveβcell function indexes. All these agents showed trophic effects on beta-cell mass in animal studies. The use of these drugs is associated with positive or neucral effect on body weight and improvements in blood pressure, diabetic dyslipidemia, hepatic steazosis markets, and myocardial function. These effects have the potential to reduce the burden of cardiovascular disease, which is a major cause of mortality in patients with diabetes.

Vildagliptin An Oral Dipeptidyl Peptidase-4 Inhibitor for Type 2 Diabetes

2006 ◽  
Vol 00 (02) ◽  
Author(s):  
Eberhard Standl ◽  
Martin Fuchtenbusch ◽  
Michael Hummel
Keyword(s):  
Type 2 Diabetes ◽  
Large Scale ◽  
Cell Function ◽  
Glucagon Secretion ◽  
Postprandial Glucose ◽  
Dipeptidyl Peptidase ◽  
Β Cell ◽  
Dipeptidyl Peptidase 4 ◽  
Β Cell Function

Vildagliptin is a member of a new class of oral antidiabetogenic agents known as dipeptidyl peptidase-4 (DDP-4) inhibitors.These drugs enhance islet function by improving α- and β-cell responsiveness to glucose. Mechanism of action studies in patients with type 2 diabetes show that vildagliptin increases plasma levels of active glucagon-like peptide-1, improves glucosedependent insulin secretion and β-cell function, improves insulin sensitivity, reduces inappropriate glucagon secretion, reduces fasting and postprandial glucose, and decreases HbA1c. Large-scale treatment trials with vildagliptin 50mg or 100mg per day as monotherapy or in combination in drug-naïve patients or as add-on therapy to on-going anti-diabetic treatment show that it is effective in reducing HbA1c (with greater decreases occurring in patients with higher initial HbA1c levels), maintains efficacy in glycemic control as monotherapy for at least 1 year, is associated with infrequent hypoglycemia, and does not cause weight gain.

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.

Glucagon-like peptide-1: a major regulator of pancreatic beta-cell function

2000 ◽  
pp. 717-725 ◽  
Author(s):  
R Perfetti ◽  
P Merkel
Keyword(s):  
Beta Cell ◽  
Cell Function ◽  
Pancreatic Beta Cell ◽  
Cell Mass ◽  
Beta Cell Mass ◽  
Glucagon Secretion ◽  
Insulin Biosynthesis ◽  
Gut Hormone ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

Glucagon-like peptide-1 (GLP-1) is a gut hormone synthesized by post-translational processing in intestinal L-cells, and it is released in response to food ingestion. GLP-1 stimulates insulin secretion during hyperglycemia, suppresses glucagon secretion, stimulates (pro)-insulin biosynthesis and decreases the rate of gastric emptying and acid secretion. GLP-1 has also been shown to have a pro-satiety effect. In addition, it has been demonstrated that a long-term infusion with GLP-1, or exendin-4, a long-acting analog of human GLP-1, increases beta-cell mass in rats. In conclusion, GLP-1 appears to regulate plasma glucose levels via various and independent mechanisms. GLP-1 is an excellent candidate option for the treatment of patients with type 2 diabetes mellitus.

scholarly journals Incretin System: Recent Advances in Glucagon Like Peptide-1 and Dipeptidyl Peptidase-4 Inhibitors

2015 ◽  
Vol 1 (1) ◽  
pp. 36-42
Author(s):  
Rameshwar Mahaseth
Keyword(s):  
Cell Mass ◽  
Dipeptidyl Peptidase ◽  
Common Adverse Event ◽  
Haemoglobin A1c ◽  
Incretin Mimetics ◽  
Dipeptidyl Peptidase 4 ◽  
Wide Range ◽  
Dipeptidyl Peptidase 4 Inhibitors ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

The endogenous incretins, glucose-dependent insulinotropic polypeptide and Glucagon-like peptide, are peptide hormones secreted from endocrine cells in the small intestine. Glucagon-like peptide-1 stimulates insulin and suppresses glucagon secretion, delays gastric emptying, and reduces appetite and food intake, which explains the positive effect of incretin mimetics on weight. The incretins have also been shown to have a sustained improvement in glycemic control over three years. A wide range of cardiovascular benefits have also been claimed, such as lowering of blood pressure and postprandial lipids. Clinical trials with the incretin mimetic exenatide and liraglutide show reductions in fasting and postprandial glucose concentrations, and haemoglobin A1c (1–2%), associated with weight loss (2–5 kg). The most common adverse event associated with Glucagon-like peptide-1 receptor agonists is nausea, which lessens over time. Orally administered Dipeptidyl Peptidase-4 inhibitors reduce hemoglobin A1c by 0·5–1·0%, with few adverse effects and no weight gain. These new classes of anti-diabetic agents also expand β-cell mass in preclinical studies. However, long-term clinical studies are still needed to determine the benefits of incretin for the treatment of type 2 diabetes. DOI: http://dx.doi.org/10.3126/jpahs.v1i1.13015 Journal of Patan Academy of Health Sciences. 2014 Jun;1(1):36-42 

scholarly journals Upregulated insulin secretion in insulin-resistant mice: evidence of increased islet GLP1 receptor levels and GPR119-activated GLP1 secretion

2013 ◽  
Vol 2 (2) ◽  
pp. 69-78 ◽  
Author(s):  
L Ahlkvist ◽  
K Brown ◽  
B Ahrén
Keyword(s):  
Cell Function ◽  
Hormone Secretion ◽  
Glucagon Secretion ◽  
Β Cell ◽  
Insulin Resistant ◽  
Protein Levels ◽  
Islet Hormone ◽  
Β Cell Function ◽  
Glucagon Like Peptide 1 ◽  
Insulin Responses

We previously demonstrated that the overall incretin effect and the β-cell responsiveness to glucagon-like peptide-1 (GLP1) are increased in insulin-resistant mice and may contribute to the upregulated β-cell function. Now we examined whether this could, first, be explained by increased islet GLP1 receptor (GLP1R) protein levels and, secondly, be leveraged by G-protein-coupled receptor 119 (GPR119) activation, which stimulates GLP1 secretion. Female C57BL/6J mice, fed a control (CD, 10% fat) or high-fat (HFD, 60% fat) diet for 8 weeks, were anesthetized and orally given a GPR119 receptor agonist (GSK706A; 10 mg/kg) or vehicle, followed after 10 min with gavage with a liquid mixed meal (0.285 kcal). Blood was sampled for determination of glucose, insulin, intact GLP1, and glucagon, and islets were isolated for studies on insulin and glucagon secretion and GLP1R protein levels. In HFD vs CD mice, GPR119 activation augmented the meal-induced increase in the release of both GLP1 (AUCGLP1 81±9.6 vs 37±6.9 pM×min, P=0.002) and insulin (AUCINS 253±29 vs 112±19 nM×min, P<0.001). GPR119 activation also significantly increased glucagon levels in both groups (P<0.01) with, however, no difference between the groups. By contrast, GPR119 activation did not affect islet hormone secretion from isolated islets. Glucose elimination after meal ingestion was significantly increased by GPR119 activation in HFD mice (0.57±0.04 vs 0.43±0.03% per min, P=0.014) but not in control mice. Islet GLP1R protein levels was higher in HFD vs CD mice (0.8±0.1 vs 0.5±0.1, P=0.035). In conclusion, insulin-resistant mice display increased islet GLP1R protein levels and augmented meal-induced GLP1 and insulin responses to GPR119 activation, which results in increased glucose elimination. We suggest that the increased islet GLP1R protein levels together with the increased GLP1 release may contribute to the upregulated β-cell function in insulin resistance.

scholarly journals Hope and fear for new classes of type 2 diabetes drugs: is there preclinical evidence that incretin-based therapies alter pancreatic morphology?

2014 ◽  
Vol 221 (1) ◽  
pp. T43-T61 ◽  
Author(s):  
Benjamin J Lamont ◽  
Sofianos Andrikopoulos
Keyword(s):  
Type 2 Diabetes ◽  
Cell Mass ◽  
Preclinical Studies ◽  
Β Cells ◽  
Β Cell ◽  
Dipeptidyl Peptidase 4 ◽  
Dpp4 Inhibitors ◽  
Natural Progression ◽  
Glucagon Like Peptide 1

Incretin-based therapies appear to offer many advantages over other approaches for treating type 2 diabetes. Some preclinical studies have suggested that chronic activation of glucagon-like peptide 1 receptor (GLP1R) signalling in the pancreas may result in the proliferation of islet β-cells and an increase in β-cell mass. This provided hope that enhancing GLP1 action could potentially alter the natural progression of type 2 diabetes. However, to date, there has been no evidence from clinical trials suggesting that GLP1R agonists or dipeptidyl peptidase-4 (DPP4) inhibitors can increase β-cell mass. Nevertheless, while the proliferative capacity of these agents remains controversial, some studies have raised concerns that they could potentially contribute to the development of pancreatitis and hence increase the risk of pancreatic cancer. Currently, there are very limited clinical data to directly assess these potential benefits and risks of incretin-based therapies. However, a review of the preclinical studies indicates that incretin-based therapies probably have only a limited capacity to regenerate pancreatic β-cells, but may be useful for preserving any remaining β-cells in type 2 diabetes. In addition, the majority of preclinical evidence does not support the notion that GLP1R agonists or DPP4 inhibitors cause pancreatitis.

Sign in / Sign up

Export Citation Format

Share Document