The separate and combined impact of the intestinal hormones, GIP, GLP-1, and GLP-2, on glucagon secretion in type 2 diabetes

2011 ◽  
Vol 300 (6) ◽  
pp. E1038-E1046 ◽  
Author(s):  
Asger Lund ◽  
Tina Vilsbøll ◽  
Jonatan I. Bagger ◽  
Jens J. Holst ◽  
Filip K. Knop
Keyword(s):  
Type 2 Diabetes ◽  
Glucagon Secretion ◽  
Tolerance Test ◽  
Oral Glucose ◽  
Intestinal Hormones ◽  
Intravenous Glucose ◽  
Glucagon Suppression ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

Type 2 diabetes mellitus (T2DM) is associated with reduced suppression of glucagon during oral glucose tolerance test (OGTT), whereas isoglycemic intravenous glucose infusion (IIGI) results in normal glucagon suppression in these patients. We examined the role of the intestinal hormones glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1), and glucagon-like peptide-2 (GLP-2) in this discrepancy. Glucagon responses were measured during a 3-h 50-g OGTT ( day A) and an IIGI ( day B) in 10 patients with T2DM [age (mean ± SE), 51 ± 3 yr; body mass index, 33 ± 2 kg/m2; HbA1c, 6.5 ± 0.2%]. During four additional IIGIs, GIP ( day C), GLP-1 ( day D), GLP-2 ( day E) and a combination of the three ( day F) were infused intravenously. Isoglycemia during all six study days was obtained. As expected, no suppression of glucagon occurred during the initial phase of the OGTT, whereas significantly ( P < 0.05) lower plasma levels of glucagon during the first 30 min of the IIGI ( day B) were observed. The glucagon response during the IIGI + GIP + GLP-1 + GLP-2 infusion ( day F) equaled the inappropriate glucagon response to OGTT ( P = not significant). The separate GIP infusion ( day C) elicited significant hypersecretion of glucagon, whereas GLP-1 infusion ( day D) resulted in enhancement of glucagon suppression during IIGI. IIGI + GLP-2 infusion ( day E) resulted in a glucagon response in the midrange between the glucagon responses to OGTT and IIGI. Our results indicate that the intestinal hormones, GIP, GLP-1, and GLP-2, may play a role in the inappropriate glucagon response to orally ingested glucose in T2DM with, especially, GIP, acting to increase glucagon secretion.

Regulation of glucagon secretion by incretin-like hormone family in the patients at risk of developing type 2 diabetes mellitus

2014 ◽  
Vol 60 (1) ◽  
pp. 32-35
Author(s):  
E A Shestakova ◽  
A V Ilyin ◽  
A D Deev ◽  
M V Shestakova ◽  
I I Dedov
Keyword(s):  
Type 2 Diabetes ◽  
High Risk ◽  
Glucose Tolerance ◽  
Glucagon Secretion ◽  
Tolerance Test ◽  
Normal Glucose Tolerance ◽  
High Risk Group ◽  
Oral Glucose ◽  
Glucose Load

The study included 127 patients with type 2 diabetes (T2D) risk factors, who underwent oral glucose tolerance test (75 g glucose) with pancreatic and incretin hormones estimated in fasting state, at 30 and 120 minutes after glucose load. According to the test results the population was divided into 3 groups: group with normal glucose tolerance (NGT), group with high risk of diabetes developing (impaired glucose tolerance (IGT) and impaired fasting glycemia (IFG)) and newly-diagnosed T2D. The stimulated glucagon secretion was suppressed in NGT group, whereas in T2D patients there was an increase in glucagon levels at 30 min after the glucose load. Within high risk group the area under curve (AUC) of glucagon secretion was significantly elevated in IFG patients comparing to IGT (0,52 vs 0,07 ng·ml-1·min-1, р=0,0005). AUC of glucagon secretion was positively related only to fasting glucagon-like peptide 2 (GLP-2) level (r=0,61, р=0,0001), that suggests glucagonotropic properties for GLP-2. We conclude that glucagon stimulation by GLP-2 may play a role in decreased glucagon suppression in T2D patients and IFG state development.

scholarly journals Genome-wide association study of circulating levels of glucagon during an oral glucose tolerance test

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Anna Jonsson ◽  
Sara E. Stinson ◽  
Signe S. Torekov ◽  
Tine D. Clausen ◽  
Kristine Færch ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Genome Wide Association Study ◽  
Glucose Tolerance Test ◽  
Tolerance Test ◽  
Oral Glucose ◽  
Plasma Glucagon ◽  
Genome Wide ◽  
Glucagon Suppression ◽  
Circulating Levels

Abstract Background In order to explore the pathophysiology underlying type 2 diabetes we examined the impact of gene variants associated with type 2 diabetes on circulating levels of glucagon during an oral glucose tolerance test (OGTT). Furthermore, we performed a genome-wide association study (GWAS) aiming to identify novel genomic loci affecting plasma glucagon levels. Methods Plasma levels of glucagon were examined in samples obtained at three time points during an OGTT; 0, 30 and 120 min, in two separate cohorts with a total of up to 1899 individuals. Cross-sectional analyses were performed separately in the two cohorts and the results were combined in a meta-analysis. Results A known type 2 diabetes variant in EYA2 was significantly associated with higher plasma glucagon level at 30 min during the OGTT (Beta 0.145, SE 0.038, P = 1.2 × 10–4) corresponding to a 7.4% increase in plasma glucagon level per effect allele. In the GWAS, we identified a marker in the MARCH1 locus, which was genome-wide significantly associated with reduced suppression of glucagon during the first 30 min of the OGTT (Beta − 0.210, SE 0.037, P = 1.9 × 10–8), equivalent to 8.2% less suppression per effect allele. Nine additional independent markers, not previously associated with type 2 diabetes, showed suggestive associations with reduced glucagon suppression during the first 30 min of the OGTT (P < 1.0 × 10–5). Conclusions A type 2 diabetes risk variant in the EYA2 locus was associated with higher plasma glucagon levels at 30 min. Ten additional variants were suggestively associated with reduced glucagon suppression without conferring increased type 2 diabetes risk.

Pharmacotherapy for Type 2 Diabetes Mellitus: What’s Up and Coming in the Glucagon-Like Peptide-1 (GLP-1) Pipeline?

2021 ◽  
pp. 089719002110490
Author(s):  
Mary J. Elder ◽  
Emily J. Ashjian
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Glycemic Control ◽  
Glucagon Secretion ◽  
New Drugs ◽  
Beneficial Effects ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

Glucagon-like peptide-1 (GLP-1), an incretin hormone, is known to lower glucose levels, suppress glucagon secretion, and slow gastric emptying. These properties make GLP-1 an ideal target in treating type 2 diabetes mellitus (T2DM). There are many FDA-approved GLP-1 agonists on the market today, several of which have demonstrated benefit beyond improving glycemic control. Given the beneficial effects of GLP-1 agonists in patients with T2DM, new drugs are in development that combine the mechanism of action of GLP-1 receptor agonism with novel mechanisms and with drugs that promote GLP-1 secretion. These agents are designed to improve glycemic control and target greater body weight reduction. This article discusses new GLP-1 drugs in the pipeline for the treatment of T2DM.

Lixisenatide—Once-daily Glucagon-like Peptide-1 Receptor Agonist in the Management of Type 2 Diabetes

2010 ◽  
Vol 8 (1) ◽  
pp. 12 ◽  
Author(s):  
Celeste C L Quianzon ◽  
Mansur E Shomali ◽  
◽  
Keyword(s):  
Type 2 Diabetes ◽  
Weight Loss ◽  
Receptor Agonist ◽  
Potential Role ◽  
Glycosylated Haemoglobin ◽  
Once Daily ◽  
Glucagon Suppression ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

The glucagon-like peptide-1 receptor agonist diabetes medications have become important due to their unique features, such as their potency of glycosylated haemoglobin (HbA1C) lowering, durability of effect, glucose-depending insulin secretion resulting in a low risk of hypoglycaemia, glucagon suppression and weight loss. Lixisenatide is an investigational compound in this class, exhibits all of these features, and has some unique properties, which are highlighted in this review. The pharmacology of lixisenatide, the results of recent clinical trials investigating this agent, and its potential role in the management of type 2 diabetes will be discussed.

Lixisenatide—Once-daily Glucagon-like Peptide-1 Receptor Agonist in the Management of Type 2 Diabetes

2011 ◽  
Vol 07 (02) ◽  
pp. 104
Author(s):  
Celeste C L Quianzon ◽  
Mansur E Shomali ◽  
◽  
Keyword(s):  
Type 2 Diabetes ◽  
Weight Loss ◽  
Receptor Agonist ◽  
Potential Role ◽  
Glycosylated Hemoglobin ◽  
Once Daily ◽  
Glucagon Suppression ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

The glucagon-like peptide-1 receptor agonist diabetes medications have become important due to their unique features, such as their potency of glycosylated hemoglobin (HbA1C) lowering, durability of effect, glucose-depending insulin secretion resulting in a low risk of hypoglycemia, glucagon suppression, and weight loss. Lixisenatide is an investigational compound in this class, exhibits all of these features, and has some unique properties, which are highlighted in this review. The pharmacology of lixisenatide, the results of recent clinical trials investigating this agent, and its potential role in the management of type 2 diabetes will be discussed.

scholarly journals No detectable effect of a type 2 diabetes-associated TCF7L2 genotype on the incretin effect

2020 ◽  
Vol 9 (12) ◽  
pp. 1221-1232
Author(s):  
David S Mathiesen ◽  
Jonatan I Bagger ◽  
Katrine B Hansen ◽  
Anders E Junker ◽  
Astrid Plamboeck ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Beta Cell ◽  
Cell Function ◽  
Tolerance Test ◽  
Detectable Effect ◽  
Oral Glucose ◽  
Incretin Effect ◽  
Intravenous Glucose ◽  
Elevated Glucose

The T allele of TCF7L2 rs7903146 is a common genetic variant associated with type 2 diabetes (T2D), possibly by modulation of incretin action. In this study, we evaluated the effect of the TCF7L2 rs7903146 T allele on the incretin effect and other glucometabolic parameters in normal glucose tolerant individuals (NGT) and participants with T2D. The rs7903146 variant was genotyped in cohorts of 61 NGT individuals (23 were heterozygous (CT) or homozygous (TT) T allele carriers) and 43 participants with T2D (20 with CT/TT). Participants were previously examined by an oral glucose tolerance test (OGTT) and a subsequent isoglycemic intravenous glucose infusion (IIGI). The incretin effect was assessed by quantification of the difference in integrated beta cell secretory responses during the OGTT and IIGI. Glucose and hormonal levels were measured during experimental days, and from these, indices of beta cell function and insulin sensitivity were calculated. No genotype-specific differences in the incretin effect were observed in the NGT group (P = 0.70) or the T2D group (P = 0.68). NGT T allele carriers displayed diminished glucose-dependent insulinotropic polypeptide response during OGTT (P = 0.01) while T allele carriers with T2D were characterized by lower C-peptide AUC after OGTT (P = 0.04) and elevated glucose AUC after OGTT (P = 0.04). In conclusion, our findings do not exclude that this specific TCF7L2 variant increases the risk of developing T2D via diminished incretin effect, but genotype-related defects were not detectable in these cohorts.

scholarly journals An Emerging Role of Glucagon-Like Peptide-1 in Preventing Advanced-Glycation-End-Product-Mediated Damages in Diabetes

2013 ◽  
Vol 2013 ◽  
pp. 1-9 ◽  
Author(s):  
Alessandra Puddu ◽  
François Mach ◽  
Alessio Nencioni ◽  
Giorgio Luciano Viviani ◽  
Fabrizio Montecucco
Keyword(s):  
Type 2 Diabetes ◽  
Cell Function ◽  
Glucagon Secretion ◽  
Advanced Glycation ◽  
Chronic Hyperglycemia ◽  
Gut Hormone ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

Glucagon-like peptide-1 (GLP-1) is a gut hormone produced in the intestinal epithelial endocrine L cells by differential processing of the proglucagon gene. Released in response to the nutrient ingestion, GLP-1 plays an important role in maintaining glucose homeostasis. GLP-1 has been shown to regulate blood glucose levels by stimulating glucose-dependent insulin secretion and inhibiting glucagon secretion, gastric emptying, and food intake. These antidiabetic activities highlight GLP-1 as a potential therapeutic molecule in the clinical management of type 2 diabetes, (a disease characterized by progressive decline of beta-cell function and mass, increased insulin resistance, and final hyperglycemia). Since chronic hyperglycemia contributed to the acceleration of the formation of Advanced Glycation End-Products (AGEs, a heterogeneous group of compounds derived from the nonenzymatic reaction of reducing sugars with free amino groups of proteins implicated in vascular diabetic complications), the administration of GLP-1 might directly counteract diabetes pathophysiological processes (such as pancreaticβ-cell dysfunction). This paper outlines evidence on the protective role of GLP-1 in preventing the deleterious effects mediated by AGEs in type 2 diabetes.

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