Dataset Information

Disrupted and Elevated Circadian Secretion of Glucagon-Like Peptide-1 in a Murine Model of Type 2 Diabetes.

ABSTRACT: Metabolism and circadian rhythms are intimately linked, with circadian glucagon-like peptide-1 (GLP-1) secretion by the intestinal L-cell entraining rhythmic insulin release. GLP-1 secretion has been explored in the context of obesogenic diets, but never in a rodent model of type 2 diabetes (T2D). There is also considerable disagreement regarding GLP-1 levels in human T2D. Furthermore, recent evidence has demonstrated decreased expression of the β-cell exocytotic protein secretagogin (SCGN) in T2D. To extend these findings to the L-cell, we administered oral glucose tolerance tests at 6 time points in 4-hour intervals to the high-fat diet/streptozotocin (HFD-STZ) mouse model of T2D. This revealed a 10-fold increase in peak GLP-1 secretion with a phase shift of the peak from the normal feeding period into the fasting-phase. This was accompanied by impairments in the rhythms of glucose, glucagon, mucosal clock genes (Arntl and Cry2), and Scgn. Immunostaining revealed that L-cell GLP-1 intensity was increased in the HFD-STZ model, as was the proportion of L-cells that expressed SCGN; however, this was not found in L-cells from humans with T2D, which exhibited decreased GLP-1 staining but maintained their SCGN expression. Gcg expression in isolated L-cells was increased along with pathways relating to GLP-1 secretion and electron transport chain activity in the HFD-STZ condition. Further investigation into the mechanisms responsible for this increase in GLP-1 secretion may give insights into therapies directed toward upregulating endogenous GLP-1 secretion.

SUBMITTER: Biancolin AD

PROVIDER: S-EPMC9368029 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature

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Disrupted and Elevated Circadian Secretion of Glucagon-Like Peptide-1 in a Murine Model of Type 2 Diabetes.

Biancolin Andrew D AD Jeong Hyerin H Mak Kimberly W Y KWY Yuan Zixuan Z Brubaker Patricia L PL

Endocrinology 20220901 9

Metabolism and circadian rhythms are intimately linked, with circadian glucagon-like peptide-1 (GLP-1) secretion by the intestinal L-cell entraining rhythmic insulin release. GLP-1 secretion has been explored in the context of obesogenic diets, but never in a rodent model of type 2 diabetes (T2D). There is also considerable disagreement regarding GLP-1 levels in human T2D. Furthermore, recent evidence has demonstrated decreased expression of the β-cell exocytotic protein secretagogin (SCGN) in T ...[more]

PMID: 35876276

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Project description:BackgroundGlucagon-like peptide analogues are a new class of drugs used in the treatment of type 2 diabetes that mimic the endogenous hormone glucagon-like peptide 1 (GLP-1). GLP-1 is an incretin, a gastrointestinal hormone that is released into the circulation in response to ingested nutrients. GLP-1 regulates glucose levels by stimulating glucose-dependent insulin secretion and biosynthesis, and by suppressing glucagon secretion, delayed gastric emptying and promoting satiety.ObjectivesTo assess the effects of glucagon-like peptide analogues in patients with type 2 diabetes mellitus.Search strategyStudies were obtained from electronic searches of The Cochrane Library (last search issue 1, 2011), MEDLINE (last search March 2011), EMBASE (last search March 2011), Web of Science (last search March 2011) and databases of ongoing trials.Selection criteriaStudies were included if they were randomised controlled trials of a minimum duration of eight weeks comparing a GLP-1 analogue with placebo, insulin, an oral anti-diabetic agent, or another GLP-1 analogue in people with type 2 diabetes.Data collection and analysisData extraction and quality assessment of studies were done by one reviewer and checked by a second. Data were analysed by type of GLP-1 agonist and comparison treatment. Where appropriate, data were summarised in a meta-analysis (mean differences and risk ratios summarised using a random-effects model).Main resultsSeventeen randomised controlled trials including relevant analyses for 6899 participants were included in the analysis. Studies were mostly of short duration, usually 26 weeks.In comparison with placebo, all GLP-1 agonists reduced glycosylated haemoglobin A1c (HbA1c) levels by about 1%. Exenatide 2 mg once weekly and liraglutide 1.8 mg reduced it by 0.20% and 0.24% respectively more than insulin glargine. Exenatide 2 mg once weekly reduced HbA1c more than exenatide 10 μg twice daily, sitagliptin and pioglitazone. Liraglutide 1.8 mg reduced HbA1c by 0.33% more than exenatide 10 μg twice daily. Liraglutide led to similar improvements in HbA1c compared to sulphonylureas but reduced it more than sitagliptin and rosiglitazone.Both exenatide and liraglutide led to greater weight loss than most active comparators, including in participants not experiencing nausea. Hypoglycaemia occurred more frequently in participants taking concomitant sulphonylurea. GLP-1 agonists caused gastrointestinal adverse effects, mainly nausea. These adverse events were strongest at the beginning and then subsided. Beta-cell function was improved with GLP-1 agonists but the effect did not persist after cessation of treatment.None of the studies was long enough to assess long-term positive or negative effects.Authors' conclusionsGLP-1 agonists are effective in improving glycaemic control.

Project description:BackgroundGlucagon-like peptide (GLP-1) analogues are a new class of drugs used in the treatment of type 2 diabetes. They are given by injection, and regulate glucose levels by stimulating glucose-dependent insulin secretion and biosynthesis, suppressing glucagon secretion, and delaying gastric emptying and promoting satiety. This systematic review aims to provide evidence on the clinical effectiveness of the GLP-1 agonists in patients not achieving satisfactory glycaemic control with one or more oral glucose lowering drugs.MethodsMEDLINE, EMBASE, the Cochrane Library and Web of Science were searched to find the relevant papers. We identified 28 randomised controlled trials comparing GLP-1 analogues with placebo, other glucose-lowering agents, or another GLP-1 analogue, in patients with type 2 diabetes with inadequate control on a single oral agent, or on dual therapy. Primary outcomes included HbA1c, weight change and adverse events.ResultsStudies were mostly of short duration, usually 26 weeks. All GLP-1 agonists reduced HbA1c by about 1% compared to placebo. Exenatide twice daily and insulin gave similar reductions in HbA1c, but exenatide 2 mg once weekly and liraglutide 1.8 mg daily reduced it by 0.20% and 0.30% respectively more than glargine. Liraglutide 1.2 mg daily reduced HbA1c by 0.34% more than sitagliptin 100 mg daily. Exenatide and liraglutide gave similar improvements in HbA1c to sulphonylureas. Exenatide 2 mg weekly and liraglutide 1.8 mg daily reduced HbA1c by more than exenatide 10 μg twice daily and sitagliptin 100 mg daily. Exenatide 2 mg weekly reduced HbA1c by 0.3% more than pioglitazone 45 mg daily.Exenatide and liraglutide resulted in greater weight loss (from 2.3 to 5.5 kg) than active comparators. This was not due simply to nausea. Hypoglycaemia was uncommon, except when combined with a sulphonylurea. The commonest adverse events with all GLP-1 agonists were initial nausea and vomiting. The GLP-1 agonists have some effect on beta-cell function, but this is not sustained after the drug is stopped.ConclusionsGLP-1 agonists are effective in improving glycaemic control and promoting weight loss.

Dataset Information

Disrupted and Elevated Circadian Secretion of Glucagon-Like Peptide-1 in a Murine Model of Type 2 Diabetes.

Publications

Disrupted and Elevated Circadian Secretion of Glucagon-Like Peptide-1 in a Murine Model of Type 2 Diabetes.

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