Metabolic Messengers: glucagon

https://www.tandfonline.com/doi/pdf/10.1586/eog.09.28

Does Kisspeptin signaling offer a new way to treat infertility

Glucagon-like peptide-1 receptor (GLP-1R) agonists are a highly effective therapy class for type 2 diabetes (T2D) and obesity, yet there are variable patient responses. Variation in the human Glp1r gene leading to altered receptor structure, signal transduction, and function might be directly linked to therapeutic responses in patients. A naturally occurring, low-frequency, gain-of-function missense variant, rs10305492 G&gt;A (A316T), protects against T2D and cardiovascular disease. Here we employ CRISPR/Cas9 technology to generate a humanised knock-in mouse model bearing the homozygous Glp1r A316T substitution. Human Glp1r A316T/A316T mice displayed lower fasting blood glucose levels and improved glucose tolerance, as well as increased plasma insulin levels and insulin secretion responses, even under metabolic stress. They also exhibited alterations in islet cytoarchitecture and β-cell identity indicative of compensatory mechanisms under a high-fat, high-sucrose (HFHS) diet challenge. Across all models investigated, the human Glp1r A316T variant exhibited characteristics of constitutive activation but blunted incretin-induced responses. Our results are further supported by cryo-EM analysis and molecular dynamics (MD) simulations of the GLP-1R A316T structure, demonstrating that the A316T Glp1r variant governs basal receptor activity and pharmacological responses to GLP-1R-targeting anti-diabetic therapies, highlighting the importance of the precise molecular characterisation of human Glp1r variants to predict individual therapy responses. 

In vivofunctional profiling and structural characterisation of the humanGlp1rA316T variant

Introduction: Glucagon-like peptide 1 (GLP1) agonists are highly effective agents for the treatment of obesity and type 2 diabetes (T2D). GLP-1 is also implicated in outcomes of bariatric surgery, including appetite changes and T2D remission. Rare, potentially deleterious mutations in the glucagon-like peptide 1 receptor gene (GLP1R) may, therefore, have important implications for pathogenesis of obesity and T2D, and for response to therapeutic interventions. Methods: A custom Axion genotyping array, including 117 rare predicted-deleterious GLP1R mutations (MAF<0.01 in gnomAD, CADD-PHRED >= 15), was used to screen 1714 unrelated adults with BMI >35 kg/m2 from the PMMO study. We also examined the UK Biobank (UKB) exome sequence dataset for rare, predicted-deleterious GLP1R variants and tested their effects on weight and glycaemia-related traits. Results: Thirty-four PMMO participants carried one of the 117 GLP1R variants screened (11 might have been expected using the sum of their gnomAD control MAFs). These 8 variants were associated with T2D in the UKB and subsequent gene-level analysis of the UKB exome sequence dataset (629/39,274 carriers) confirmed that rare GLP1R variants are associated with increased risk of T2D (OR=1.58), as well as with higher HbA1c levels (p= 0.039). Furthermore, our data highlight a potential interaction of these variants with body mass index. Conclusion: Rare, potentially deleterious GLP1R mutations is associated with increased T2D risk, as well as higher HbA1c in UKB participants without diabetes. Future studies should examine the implications of GLP1R mutations for response to GLP1 agonist treatment and explore the observed interactions with obesity in T2D risk, including in larger cohorts with obesity.

/pdf/rare-variants-of-the-glucagon-like-peptide-1-receptor-glp1r-cbb33mxm.pdf

Rare variants of the glucagon-like peptide-1 receptor (GLP1R) gene are overrepresented in a severe obesity cohort and associated with type 2 diabetes in the UK Biobank

Kisspeptin potently increases reproductive hormone release in women with hypothalamic amenorrhoea: a potential novel therapy for infertility

Background Type 2 diabetes (T2D) is characterised by the loss of pulsatile insulin secretion. We studied mice with β-cell specific loss of the glucagon receptor (Gcgr fl/fl X Ins-1Cre), to investigate the role of intra-islet glucagon receptor signalling on pan-islet calcium oscillations and insulin pulsatility. Methods Frequently sampled intravenous glucose tolerance tests were conducted on Gcgr β-cell-/- and littermate controls. Crossing with GCaMP6f (STOP flox) animals further allowed for β-cell specific expression of a fluorescent calcium indicator. These islets were functionally imaged in vitro and in vivo. Wild-type mice were transplanted with islets expressing GCaMP6f in β-cells into the anterior eye chamber and placed on a high fat diet. Part of the cohort received a glucagon analogue (GCG-analogue) for 40 days and the control group were fed to achieve weight matching. Calcium imaging was performed regularly during the development of hyperglycaemia and in response to GCG-analogue treatment. Results Gcgr β-cell-/- mice exhibited impaired glucose tolerance following intraperitoneal glucose challenge (control 12.7mmol/L ±0.6 vs. Gcgr β-cell-/- 15.4mmol/L ±0.0 at 15 min, p=0.002); fasting glycaemia was not different to controls. In vitro, Gcgr β-cell-/- islets showed profound loss of synchronised calcium waves in response to glucose which was only partially rescued in vivo. First-phase insulin pulsatility on peripheral blood sampling (n=5) was significantly disordered in Gcgr β-cell-/- mice (burst mass Gcgr β-cell-/- 0.30 ±0.03 versus 0.84 ±0.23 for controls p=0.04). Diet induced obesity and hyperglycaemia resulted in a loss of co-ordinated [Ca2+]I waves in transplanted islets. This was reversed with GCG-analogue treatment, independently of weight-loss (n=8). Conclusion These data provide novel evidence for the role of intra-islet GCGR signalling in sustaining synchronised calcium oscillations and support a possible therapeutic role for glucagonergic agents to restore the insulin pulsatility lost in T2D.

Intra-islet glucagon signalling regulates pulsatile insulin secretion and glucose homeostasis

Evidence suggests that the ileum is an important player in appetite regulation (1) . The ileum contains a high density of L-cells that secrete appetite suppressing hormones Glucagon Like Peptide-1 and Peptide YY (PYY) in response to luminal nutrients and bacterial fermentation products, short chain fatty acid (SCFAs) (2) . Processing of foods may change their structures and reduce the amount of carbohydrates reaching the ileum, which may reduce appetite hormone release. This can in part explain the association seen between processed food consumption and excess body weight (3) . However owing to access issues, very little is known about the ileum and how different food structures may impact this environment. The aim of this project was to understand the impact of food structures on the ileal environment and appetite hormone release. A randomised crossover trial was conducted with 10 healthy human volunteers who were admitted as inpatients for 4 days and randomly assigned to one of the three intervention diets: High ﬁ bre, intact structures (I-HF); High ﬁ bre, disrupted structures (D-HF) or Low ﬁ bre, disrupted structures (LF). On day one, a nasoenteric tube was inserted into the distal ileum for the collection of ileal samples. On day four, ileal and blood samples were collected in fasted and postprandial states (hourly for 8 hours). Disrupting the food structures of a high ﬁ bre diet (D-HF) reduced the amount of maltose (P = 0.049) in the ileal space compared to a high ﬁ bre intact diet (I-HF). The numbers of bacteria and the concentrations of SCFAs in the ileum dramatically dropped from fasted to postprandial states, and this effect was not different between the groups. Postprandial PYY release was signi ﬁ cantly higher in D-HF (P = 0.008) but not in I-HF (p = 0.068) in comparison to LF group. Metabolomic analysis of ileal contents identi ﬁ ed dynamic changes in several metabolites which were different between groups, including amino acids which were higher in D-HF group. Treatment of ileal organoids with postprandial ileal samples from D-HF group increased PYY release compared to the other diets, con ﬁ rming that ileal metabolites are in part responsible for the observed PYY difference. D-HF group also had higher serum SCFAs compared to I-HF (P = 0.010) and LF (P = 0.017) groups despite a lack of difference in stool SCFAs.

Understanding the effect of food structures on ileal environment and appetite Regulation

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Rare variants of the glucagon-like peptide-1 receptor (GLP1R) gene are overrepresented in a severe obesity cohort and associated with type 2 diabetes in the UK Biobank

Kisspeptin potently increases reproductive hormone release in women with hypothalamic amenorrhoea: a potential novel therapy for infertility

Intra-islet glucagon signalling regulates pulsatile insulin secretion and glucose homeostasis

Understanding the effect of food structures on ileal environment and appetite Regulation