Characterization of genetic variants of GIPR reveals a contribution of ß-arrestin to metabolic phenotypes.

Incretin-based therapies are highly successful in combatting obesity and type 2 diabetes1. Yet both activation and inhibition of the glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR) in combination with glucagon-like peptide-1 (GLP-1) receptor (GLP-1R) activation have resulted in similar clinical outcomes, as demonstrated by the GIPR-GLP-1R co-agonist tirzepatide2 and AMG-133 (ref. 3) combining GIPR antagonism with GLP-1R agonism. This underlines the importance of a better understanding of the GIP system. Here we show the necessity of ß-arrestin recruitment for GIPR function, by combining in vitro pharmacological characterization of 47 GIPR variants with burden testing of clinical phenotypes and in vivo studies. Burden testing of variants with distinct ligand-binding capacity, Gs activation (cyclic adenosine monophosphate production) and ß-arrestin 2 recruitment and internalization shows that unlike variants solely impaired in Gs signalling, variants impaired in both Gs and ß-arrestin 2 recruitment contribute to lower adiposity-related traits. Endosomal Gs-mediated signalling of the variants shows a ß-arrestin dependency and genetic ablation of ß-arrestin 2 impairs cyclic adenosine monophosphate production and decreases GIP efficacy on glucose control in male mice. This study highlights a crucial impact of ß-arrestins in regulating GIPR signalling and overall preservation of biological activity that may facilitate new developments in therapeutic targeting of the GIPR system.

A look at duodenal mucosal resurfacing: Rationale for targeting the duodenum in type 2 diabetes.

Affecting 5%-10% of the world population, type 2 diabetes (T2DM) is firmly established as one of the major health burdens of modern society. People with T2DM require long-term therapies to reduce blood glucose, an approach that can mitigate the vascular complications. However, fewer than half of those living with T2DM reach their glycaemic targets despite the availability of multiple oral and injectable medications. Adherence and access to medications are major barriers contributing to suboptimal diabetes treatment. The gastrointestinal tract has recently emerged as a target for treating T2DM and altering the underlying disease course. Preclinical and clinical analyses have elucidated changes in the mucosal layer of the duodenum potentially caused by dietary excess and obesity, which seem to be prevalent among individuals with metabolic disease. Supporting these findings, gastric bypass, a surgical procedure which removes the duodenum from the intestinal nutrient flow, has remarkable effects that improve, and often cause remission of, diabetes. From this perspective, we explore the rationale for targeting the duodenum with duodenal mucosal resurfacing (DMR). We examine the underlying physiology of the duodenum and its emerging role in T2DM pathogenesis, the rationale for targeting the duodenum by DMR as a potential treatment for T2DM, and current data surrounding DMR. Importantly, DMR has been demonstrated to change mucosal abnormalities common in those with obesity and diabetes. Given the multifactorial aetiology of T2DM, understanding proximate contributors to disease pathogenesis opens the door to rethinking therapeutic approaches to T2DM, from symptom management toward disease modification.

Reduction of prevalence of patients meeting the criteria for metabolic syndrome with tirzepatide: a post hoc analysis from the SURPASS Clinical Trial Program.

BACKGROUND: Metabolic syndrome is characterized as the co-occurrence of interrelated cardiovascular risk factors, including insulin resistance, hyperinsulinemia, abdominal obesity, dyslipidemia and hypertension. Once weekly tirzepatide is approved in the US and EU for the treatment of type 2 diabetes (T2D) and obesity. In the SURPASS clinical trial program for T2D, tirzepatide demonstrated greater improvements in glycemic control, body weight reduction and other cardiometabolic risk factors versus placebo, subcutaneous semaglutide 1 mg, insulin degludec, and insulin glargine. This post hoc analysis assessed the effect of tirzepatide use on the prevalence of patients meeting the criteria for metabolic syndrome across SURPASS 1-5. METHODS: Metabolic syndrome was defined as having ≥ 3 of 5 criteria according to the US National Cholesterol Education Program: Adult Treatment Panel III. Analyses were based on on-treatment data at the primary endpoint from patients adherent to treatment (taking ≥ 75% study drug). A logistic regression model with metabolic syndrome status as the response variable, metabolic syndrome status at the baseline visit as an adjustment, and randomized treatment as fixed explanatory effect was used. The effect of tirzepatide use on the prevalence of patients meeting the criteria for metabolic syndrome by categorical weight loss, background medication and gender were assessed. RESULTS: In SURPASS, the prevalence of patients meeting the criteria for metabolic syndrome at baseline was 67-88% across treatment groups with reductions at the primary endpoint to 38-64% with tirzepatide versus 64-82% with comparators. Reductions in the prevalence of patients meeting the criteria for metabolic syndrome was significantly greater with all tirzepatide doses versus placebo, semaglutide 1 mg, insulin glargine, and insulin degludec (p < 0.001). Individual components of metabolic syndrome were also reduced to a greater extent with tirzepatide vs comparators. Greater reductions in body weight were associated with greater reductions in the prevalence of patients meeting the criteria for metabolic syndrome and its individual components. Background SGLT2i or sulfonylurea use or gender did not impact the change in prevalence of patients meeting the criteria for metabolic syndrome. CONCLUSIONS: In this post hoc analysis, tirzepatide at all doses studied was associated with a greater reduction in the prevalence of patients meeting the criteria for metabolic syndrome compared to placebo, semaglutide 1 mg, insulin degludec, and insulin glargine. Although more evidence is needed, these data would support greater potential improvement in cardiovascular risk factor profile with tirzepatide treatment in people across the continuum of T2D.

Assessment of the incretin effect in healthy subjects: concordance between clamp and OGTT methods.

The incretin effect describes the insulin response to nutrient ingestion that exceeds the response to glycemia per se. It is mediated by gastrointestinal factors and is necessary to maintain postprandial glucose homeostasis. The incretin effect results in a more than twofold increase of the insulin response to a meal in healthy people and two different techniques have been used in the past to measure its magnitude. Most studies employ an OGTT on 1 day, followed by a matching glucose infusion on a separate day. Another study design employs a hyperglycemic glucose clamp that is maintained after oral ingestion of glucose. Both protocols allow quantification of the incretin effect by comparing the insulin response to an identical glycemic stimulus. Here we performed a within-subject comparison of both techniques to quantify the incretin effect and suggest different calculation methods to interpret the results derived from the clamp experiment in a cohort of healthy young adults (n = 10, age 33 ± 4 yr). All subjects participated on four different study days: 1) OGTT, 2) isoglycemic glucose infusion (Iso-IV), 3) hyperglycemic clamp with oral glucose ingestion (clamp-OGTT), and 4) hyperglycemic clamp (clamp). With the classic OGTT/Iso-IV method, the insulin response to glucose ingestion increased more than twofold and was 60 ± 6% and 49 ± 5% for insulin and c-peptide. Different estimates of the incretin effect based on the clamp method ranged from 58% to 79% for insulin and 38% to 61% for c-peptide, both significantly higher than values derived from the OGTT/isoglycemic infusion method. However, when the effect of continuous hyperglycemia on insulin secretion was accounted for, using extrapolation from early time points of the clamp, good agreement was noted between the two methods. Based on these results, both techniques seem to be equally suited to measure the incretin effect and should be employed according to the scientific questions, experimental contingencies, and investigator experience.NEW & NOTEWORTHY This proof-of-concept study shows that the incretin effect can be reliably assessed by two different methods with similar quantitative results. A single-day hyperglycemic clamp with oral glucose ingestion allows the determination of the incretin effect with fewer study days and less day-to-day variability.

GIPR/GLP-1R dual agonist therapies for diabetes and weight loss-chemistry, physiology, and clinical applications.

The incretin system is an essential metabolic axis that regulates postprandial metabolism. The two incretin peptides that enable this effect are the glucose-dependent insulinotropic polypeptide (GIP) and the glucagon-like peptide 1 (GLP-1), which have cognate receptors (GIPR and GLP-1R) on islet ß cells as well as in other tissues. Pharmacologic engagement of the GLP-1R is a proven strategy for treating hyperglycemia in diabetes and reducing body weight. Tirzepatide is the first monomeric peptide with dual activity at both incretin receptors now available for clinical use, and in clinical trials it has shown unprecedented effects to reduce blood glucose and body weight. Here, we discuss the foundational science that led to the development of monomeric multi-incretin receptor agonists, culminating in the development of tirzepatide. We also look to the future of this field and comment on how the concept of multi-receptor agonists will continue to progress for the treatment of metabolic disease.

The incretin co-agonist tirzepatide requires GIPR for hormone secretion from human islets.

The incretins glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) mediate insulin responses that are proportionate to nutrient intake to facilitate glucose tolerance1. The GLP-1 receptor (GLP-1R) is an established drug target for the treatment of diabetes and obesity2, whereas the therapeutic potential of the GIP receptor (GIPR) is a subject of debate. Tirzepatide is an agonist at both the GIPR and GLP-1R and is a highly effective treatment for type 2 diabetes and obesity3,4. However, although tirzepatide activates GIPR in cell lines and mouse models, it is not clear whether or how dual agonism contributes to its therapeutic benefit. Islet beta cells express both the GLP-1R and the GIPR, and insulin secretion is an established mechanism by which incretin agonists improve glycemic control5. Here, we show that in mouse islets, tirzepatide stimulates insulin secretion predominantly through the GLP-1R, owing to reduced potency at the mouse GIPR. However, in human islets, antagonizing GIPR activity consistently decreases the insulin response to tirzepatide. Moreover, tirzepatide enhances glucagon secretion and somatostatin secretion in human islets. These data demonstrate that tirzepatide stimulates islet hormone secretion from human islets through both incretin receptors.

An injectable PEG-like conjugate forms a subcutaneous depot and enables sustained delivery of a peptide drug.

Many biologics have a short plasma half-life, and their conjugation to polyethylene glycol (PEG) is commonly used to solve this problem. However, the improvement in the plasma half-life of PEGylated drugs' is at an asymptote because the development of branched PEG has only had a modest impact on pharmacokinetics and pharmacodynamics. Here, we developed an injectable PEG-like conjugate that forms a subcutaneous depot for the sustained delivery of biologics. The PEG-like conjugate consists of poly[oligo(ethylene glycol) methyl ether methacrylate] (POEGMA) conjugated to exendin, a peptide drug used in the clinic to treat type 2 diabetes. The depot-forming exendin-POEGMA conjugate showed greater efficacy than a PEG conjugate of exendin as well as Bydureon, a clinically approved sustained-release formulation of exendin. The injectable depot-forming exendin-POEGMA conjugate did not elicit an immune response against the polymer, so that it remained effective and safe for long-term management of type 2 diabetes upon chronic administration. In contrast, the PEG conjugate induced an anti-PEG immune response, leading to early clearance and loss of efficacy upon repeat dosing. The exendin-POEGMA depot also showed superior long-term efficacy compared to Bydureon. Collectively, these results suggest that an injectable POEGMA conjugate of biologic drugs that forms a drug depot under the skin, providing favorable pharmacokinetic properties and sustained efficacy while remaining non-immunogenic, offers significant advantages over other commonly used drug delivery technologies.

LY3437943, a novel triple GIP, GLP-1, and glucagon receptor agonist in people with type 2 diabetes: a phase 1b, multicentre, double-blind, placebo-controlled, randomised, multiple-ascending dose trial.

BACKGROUND: Treating hyperglycaemia and obesity in individuals with type 2 diabetes using multi-receptor agonists can improve short-term and long-term outcomes. LY3437943 is a single peptide with agonist activity for glucagon, glucose-dependent insulinotropic polypeptide (GIP), and glucagon-like peptide 1 (GLP-1) receptors that is currently in development for the treatment of type 2 diabetes and for the treatment of obesity and associated comorbidities. We investigated the safety, pharmacokinetics, and pharmacodynamics of multiple weekly doses of LY3437943 in people with type 2 diabetes in a 12-week study. METHODS: In this phase 1b, proof-of-concept, double-blind, placebo-controlled, randomised, multiple-ascending dose trial, adults (aged 20-70 years) with type 2 diabetes for at least 3 months, a glycated haemoglobin A1c (HbA1c) value of 7·0-10·5%, body-mass index of 23-50 kg/m2, and stable bodyweight (<5% change in previous 3 months) were recruited at four centres in the USA. Using an interactive web-response system, participants were randomly assigned to receive once-weekly subcutaneous injections of LY3437943, placebo, or dulaglutide 1·5 mg over a 12-week period. Five ascending dose cohorts were studied, with randomisation in each cohort such that a minimum of nine participants received LY3437943, three received placebo, and one received dulaglutide 1·5 mg within each cohort. The top doses in the two highest dose cohorts were attained via stepwise dose escalations. The primary outcome was to investigate the safety and tolerability of LY3437943, and characterising the pharmacodynamics and pharmacokinetics were secondary outcomes. Safety was analysed in all participants who received at least one dose of study drug, and pharmacodynamics and pharmacokinetics in all participants who received at least one dose of study drug and had evaluable data. This trial is registered at ClinicalTrials.gov, NCT04143802. FINDINGS: Between Dec 18, 2019, and Dec 28, 2020, 210 people were screened, of whom 72 were enrolled, received at least one dose of study drug, and were included in safety analyses. 15 participants had placebo, five had dulaglutide 1·5 mg and, for LY3437943, nine had 0·5 mg, nine had 1·5 mg, 11 had 3 mg, 11 had 3/6 mg, and 12 had 3/6/9/12 mg. 29 participants discontinued the study prematurely. Treatment-emergent adverse events were reported by 33 (63%), three (60%), and eight (54%) participants who received LY3437943, dulaglutide 1·5 mg, and placebo, respectively, with gastrointestinal disorders being the most frequently reported treatment-emergent adverse events. The pharmacokinetics of LY3437943 were dose proportional and its half-life was approximately 6 days. At week 12, placebo-adjusted mean daily plasma glucose significantly decreased from baseline at the three highest dose LY3437943 groups (least-squares mean difference -2·8 mmol/L [90% CI -4·63 to -0·94] for 3 mg; -3·1 mmol/L [-4·91 to -1·22] for 3/6 mg; and -2·9 mmol/L [-4·70 to -1·01] for 3/6/9/12 mg). Placebo-adjusted sHbA1c also decreased significantly in the three highest dose groups (-1·4% [90% CI -2·17 to -0·56] for 3 mg; -1·6% [-2·37 to -0·75] for 3/6 mg; and -1·2% [-2·05 to -0·45] for 3/6/9/12 mg). Placebo-adjusted bodyweight reduction with LY3437943 appeared to be dose dependent (up to -8·96 kg [90% CI -11·16 to -6·75] in the 3/6/9/12 mg group). INTERPRETATION: In this early phase study, LY3437943 showed an acceptable safety profile, and its pharmacokinetics suggest suitability for once-weekly dosing. This finding, together with the pharmacodynamic findings of robust reductions in glucose and bodyweight, provides support for phase 2 development. FUNDING: Eli Lilly and Company.

Tirzepatide, a dual GIP/GLP-1 receptor co-agonist for the treatment of type 2 diabetes with unmatched effectiveness regrading glycaemic control and body weight reduction.

Tirzepatide is the first dual GIP/GLP-1 receptor co-agonist approved for the treatment of type 2 diabetes in the USA, Europe, and the UAE. Tirzepatide is an acylated peptide engineered to activate the GIP and GLP-1 receptors, key mediators of insulin secretion that are also expressed in regions of the brain that regulate food intake. Five clinical trials in type 2-diabetic subjects (SURPASS 1-5) have shown that tirzepatide at 5-15 mg per week reduces both HbA1c (1.24 to 2.58%) and body weight (5.4-11.7 kg) by amounts unprecedented for a single agent. A sizable proportion of patients (23.0 to 62.4%) reached an HbA1c of < 5.7% (which is the upper limit of the normal range indicating normoglycaemia), and 20.7 to 68.4% lost more than 10% of their baseline body weight. Tirzepatide was significantly more effective in reducing HbA1c and body weight than the selective GLP-1 RA semaglutide (1.0 mg per week), and titrated basal insulin. Adverse events related to tirzepatide were similar to what has been reported for selective GLP-1RA, mainly nausea, vomiting, diarrhoea, and constipation, that were more common at higher doses. Cardiovascular events have been adjudicated across the whole study program, and MACE-4 (nonfatal myocardial infarction, non-fatal stroke, cardiovascular death and hospital admission for angina) events tended to be reduced over up to a 2 year-period, albeit with low numbers of events. For none of the cardiovascular events analysed (MACE-4, or its components) was a hazard ratio > 1.0 vs. pooled comparators found in a meta-analysis covering the whole clinical trial program, and the upper bounds of the confidence intervals for MACE were < 1.3, fulfilling conventional definitions of cardiovascular safety. Tirzepatide was found to improve insulin sensitivity and insulin secretory responses to a greater extent than semaglutide, and this was associated with lower prandial insulin and glucagon concentrations. Both drugs caused similar reductions in appetite, although tirzepatide caused greater weight loss. While the clinical effects of tirzepatide have been very encouraging, important questions remain as to the mechanism of action. While GIP reduces food intake and body weight in rodents, these effects have not been demonstrated in humans. Moreover, it remains to be shown that GIPR agonism can improve insulin secretion in type 2 diabetic patients who have been noted in previous studies to be unresponsive to GIP. Certainly, the apparent advantage of tirzepatide, a dual incretin agonist, over GLP-1RA will spark renewed interest in the therapeutic potential of GIP in type 2 diabetes, obesity and related co-morbidities.

Effects of GLP-1 and GIP on Islet Function in Glucose-Intolerant, Pancreatic-Insufficient Cystic Fibrosis.

Impaired insulin and incretin secretion underlie abnormal glucose tolerance (AGT) in pancreatic insufficient cystic fibrosis (PI-CF). Whether the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) can enhance pancreatic islet function in cystic fibrosis (CF) is not known. We studied 32 adults with PI-CF and AGT randomized to receive either GLP-1 (n = 16) or GIP (n = 16) during glucose-potentiated arginine (GPA) testing of islet function on two occasions, with either incretin or placebo infused, in a randomized, double-blind, cross-over fashion. Another four adults with PI-CF and normal glucose tolerance (NGT) and four matched control participants without CF underwent similar assessment with GIP. In PI-CF with AGT, GLP-1 substantially augmented second-phase insulin secretion but without effect on the acute insulin response to GPA or the proinsulin secretory ratio (PISR), while GIP infusion did not enhance second-phase or GPA-induced insulin secretion but increased the PISR. GIP also did not enhance second-phase insulin in PI-CF with NGT but did so markedly in control participants without CF controls. These data indicate that GLP-1, but not GIP, augments glucose-dependent insulin secretion in PI-CF, supporting the likelihood that GLP-1 agonists could have therapeutic benefit in this population. Understanding loss of GIP's insulinotropic action in PI-CF may lead to novel insights into diabetes pathogenesis.

GLP-1 Receptor Blockade Reduces Stimulated Insulin Secretion in Fasted Subjects With Low Circulating GLP-1.

CONTEXT: Glucagon-like peptide 1 (GLP-1), an insulinotropic peptide released into the circulation from intestinal enteroendocrine cells, is considered a hormonal mediator of insulin secretion. However, the physiological actions of circulating GLP-1 have been questioned because of the short half-life of the active peptide. Moreover, there is mounting evidence for localized, intra-islet mediation of GLP-1 receptor (GLP-1r) signaling including a role for islet dipeptidyl-peptidase 4 (DPP4). OBJECTIVE: To determine whether GLP-1r signaling contributes to insulin secretion in the absence of enteral stimulation and increased plasma levels, and whether this is affected by DPP4. METHODS: Single-site study conducted at an academic medical center of 20 nondiabetic subjects and 13 subjects with type 2 diabetes. This was a crossover study in which subjects received either a DPP4 inhibitor (DPP4i; sitagliptin) or placebo on 2 separate days. On each day they received a bolus of intravenous (IV) arginine during sequential 60-minute infusions of the GLP-1r blocker exendin[9-39] (Ex-9) and saline. The main outcome measures were arginine-stimulated secretion of C-Peptide (C-PArg) and insulin (InsArg). RESULTS: Plasma GLP-1 remained at fasting levels throughout the experiments and IV arginine stimulated both α- and ß-cell secretion in all subjects. Ex-9 infusion reduced C-PArg in both the diabetic and nondiabetic groups by ~14% (P < .03 for both groups). Sitagliptin lowered baseline glycemia but did not affect the primary measures of insulin secretion. However, a significant interaction between sitagliptin and Ex-9 suggested more GLP-1r activation with DPP4i treatment in subjects with diabetes. CONCLUSION: GLP-1r activation contributes to ß-cell secretion in diabetic and nondiabetic people during α-cell activation, but in the absence of increased circulating GLP-1. These results are compatible with regulation of ß-cells by paracrine signals from α-cells. This process may be affected by DPP4 inhibition.

GIPR Is Predominantly Localized to Nonadipocyte Cell Types Within White Adipose Tissue.

The incretin hormone glucose-dependent insulinotropic polypeptide (GIP) augments glucose-dependent insulin secretion through its receptor expressed on islet ß-cells. GIP also acts on adipose tissue; yet paradoxically, both enhanced and reduced GIP receptor (GIPR) signaling reduce adipose tissue mass and attenuate weight gain in response to nutrient excess. Moreover, the precise cellular localization of GIPR expression within white adipose tissue (WAT) remains uncertain. We used mouse genetics to target Gipr expression within adipocytes. Surprisingly, targeting Cre expression to adipocytes using the adiponectin (Adipoq) promoter did not produce meaningful reduction of WAT Gipr expression in Adipoq-Cre:Giprflx/flx mice. In contrast, adenoviral expression of Cre under the control of the cytomegalovirus promoter, or transgenic expression of Cre using nonadipocyte-selective promoters (Ap2/Fabp4 and Ubc) markedly attenuated WAT Gipr expression. Analysis of single-nucleus RNA-sequencing, adipose tissue data sets localized Gipr/GIPR expression predominantly to pericytes and mesothelial cells rather than to adipocytes. Together, these observations reveal that adipocytes are not the major GIPR+ cell type within WAT-findings with mechanistic implications for understanding how GIP and GIP-based co-agonists control adipose tissue biology.

Tirzepatide is an imbalanced and biased dual GIP and GLP-1 receptor agonist.

Tirzepatide (LY3298176) is a dual GIP and GLP-1 receptor agonist under development for the treatment of type 2 diabetes mellitus (T2DM), obesity, and nonalcoholic steatohepatitis. Early phase trials in T2DM indicate that tirzepatide improves clinical outcomes beyond those achieved by a selective GLP-1 receptor agonist. Therefore, we hypothesized that the integrated potency and signaling properties of tirzepatide provide a unique pharmacological profile tailored for improving broad metabolic control. Here, we establish methodology for calculating occupancy of each receptor for clinically efficacious doses of the drug. This analysis reveals a greater degree of engagement of tirzepatide for the GIP receptor than the GLP-1 receptor, corroborating an imbalanced mechanism of action. Pharmacologically, signaling studies demonstrate that tirzepatide mimics the actions of native GIP at the GIP receptor but shows bias at the GLP-1 receptor to favor cAMP generation over ß-arrestin recruitment, coincident with a weaker ability to drive GLP-1 receptor internalization compared with GLP-1. Experiments in primary islets reveal ß-arrestin1 limits the insulin response to GLP-1, but not GIP or tirzepatide, suggesting that the biased agonism of tirzepatide enhances insulin secretion. Imbalance toward GIP receptor, combined with distinct signaling properties at the GLP-1 receptor, together may account for the promising efficacy of this investigational agent.

Discordance between GLP-1R gene and protein expression in mouse pancreatic islet cells.

The insulinotropic actions of glucagon-like peptide 1 receptor (GLP-1R) in ß-cells have made it a useful target to manage type 2 diabetes. Metabolic stress reduces ß-cell sensitivity to GLP-1, yet the underlying mechanisms are unknown. We hypothesized that Glp1r expression is heterogeneous among ß-cells and that metabolic stress decreases the number of GLP-1R-positive ß-cells. Here, analyses of publicly available single-cell RNA-Seq sequencing (scRNASeq) data from mouse and human ß-cells indicated that significant populations of ß-cells do not express the Glp1r gene, supporting heterogeneous GLP-1R expression. To check these results, we used complementary approaches employing FACS coupled with quantitative RT-PCR, a validated GLP-1R antibody, and flow cytometry to quantify GLP-1R promoter activity, gene expression, and protein expression in mouse α-, ß-, and δ-cells. Experiments with Glp1r reporter mice and a validated GLP-1R antibody indicated that >90% of the ß-cells are GLP-1R positive, contradicting the findings with the scRNASeq data. α-cells did not express Glp1r mRNA and δ-cells expressed Glp1r mRNA but not protein. We also examined the expression patterns of GLP-1R in mouse models of metabolic stress. Multiparous female mice had significantly decreased ß-cell Glp1r expression, but no reduction in GLP-1R protein levels or GLP-1R-mediated insulin secretion. These findings suggest caution in interpreting the results of scRNASeq for low-abundance transcripts such as the incretin receptors and indicate that GLP-1R is widely expressed in ß-cells, absent in α-cells, and expressed at the mRNA, but not protein, level in δ-cells.

Pharmacological antagonism of the incretin system protects against diet-induced obesity.

OBJECTIVE: Glucose-dependent insulinotropic polypeptide is an intestinally derived hormone that is essential for normal metabolic regulation. Loss of the GIP receptor (GIPR) through genetic elimination or pharmacological antagonism reduces body weight and adiposity in the context of nutrient excess. Interrupting GIPR signaling also enhances the sensitivity of the receptor for the other incretin peptide, glucagon-like peptide 1 (GLP-1). The role of GLP-1 compensation in loss of GIPR signaling to protect against obesity has not been directly tested. METHODS: We blocked the GIPR and GLP-1R with specific antibodies, alone and in combination, in healthy and diet-induced obese (DIO) mice. The primary outcome measure of these interventions was the effect on body weight and composition. RESULTS: Antagonism of either the GIPR or GLP-1R system reduced food intake and weight gain during high-fat feeding and enhanced sensitivity to the alternative incretin signaling system. Combined antagonism of both GIPR and GLP-1R produced additive effects to mitigate DIO. Acute pharmacological studies using GIPR and GLP-1R agonists demonstrated both peptides reduced food intake, which was prevented by co-administration of the respective antagonists. CONCLUSIONS: Disruption of either axis of the incretin system protects against diet-induced obesity in mice. However, combined antagonism of both GIPR and GLP-1R produced additional protection against diet-induced obesity, suggesting additional factors beyond compensation by the complementary incretin axis. While antagonizing the GLP-1 system decreases weight gain, GLP-1R agonists are used clinically to target obesity. Hence, the phenotype arising from loss of function of GLP-1R does not implicate GLP-1 as an obesogenic hormone. By extension, caution is warranted in labeling GIP as an obesogenic hormone based on loss-of-function studies.

THE EFFECTS OF PERIOPERATIVE DEXAMETHASONE ON GLYCEMIC CONTROL AND POSTOPERATIVE OUTCOMES.

Objective: Perioperative glucocorticoids are commonly given to reduce pain and nausea in patients undergoing surgery. However, the glycemic effects of steroids and the potential effects on morbidity and mortality have not been systematically evaluated. This study investigated the association between perioperative dexamethasone and postoperative blood glucose, hospital length of stay (LOS), readmission rates, and 90-day survival. Methods: Data from 4,800 consecutive orthopedic surgery patients who underwent surgery between 2000 and 2016 within a single health system were analyzed retrospectively. Results: Patients with and without diabetes mellitus (DM) who were given a single dose of dexamethasone had higher rates of hyperglycemia during the first 24 hours after surgery as compared to those who did not receive dexamethasone (hazard ratio [HR] was 1.81, and 95% confidence interval [CI] was [1.46, 2.24] for the DM cohort; HR 2.34, 95% CI [1.66, 3.29] for the nonDM cohort). LOS was nearly 1 day shorter in patients who received dexamethasone (geometric mean ratio [GMR] 0.79, 95% CI [0.75, 0.83] for patients with DM; GMR 0.75, 95% CI [0.72, 0.79] for patients without DM), and there was no difference in 90-day readmission rates. In patients without DM, dexamethasone was associated with a higher 90-day overall survival (99.07% versus 96.90%; P = .004). Conclusion: In patients with and without DM who undergo orthopedic surgery, perioperative dexamethasone was associated with a transiently higher risk of hyperglycemia. However, dexamethasone treatment was associated with a shorter LOS in patients with and without DM, and a higher overall 90-day survival rate in patients without DM, compared to patients who did not receive dexamethasone. Abbreviations: BMI = body mass index; CAD = coronary artery disease; CI = confidence interval; DM = diabetes mellitus; GMR = geometric mean ratio; HR = hazard ratio; IV = intravenous; LOS = length of stay; POD = postoperative day.

Rapid hepatic metabolism blunts the endocrine action of portally infused GLP-1 in male rats.

Glucagon-like peptide-1 (GLP-1) is an enteral peptide that contributes to the incretin effect. GLP-1 action is typically described as endocrine, but this mechanism has been questioned because rapid inactivation in the circulation by dipeptidylpeptidase 4 (DPP4) results in a short half-life, limiting the amount of the hormone that can reach the pancreatic islet. An alternative mechanism for GLP-1 to regulate insulin secretion through neuroendocrine signaling originating from sensors in the portal vein has been proposed. We hypothesized that portal infusion of GLP-1 would cause greater glucose-stimulated insulin secretion than equimolar administration into the jugular vein. To test this, hyperglycemic clamps with superimposed graded infusions of GLP-1 into the jugular or portal veins of male rats were performed. These experiments were repeated with pharmacologic DPP4 inhibition to determine the effect of GLP-1 metabolism in the jugular and portal venous beds. Contrary to our hypothesis, we found a higher insulinotropic effect with jugular compared with portal GLP-1, which was associated with higher plasma concentrations of intact GLP-1. The greater insulinotropic effect of jugular venous GLP-1 persisted even with pharmacological DPP4 inhibition. These findings do not support an important role of portal vein GLP-1 signaling for the incretin effect but highlight the hepatoportal bed as a major site of GLP-1 degradation that persists even with pharmacological inhibition. Together, these results support rapid inactivation of enterally released GLP-1 in the liver as limiting endocrine actions on the ß-cell and raise questions about the conventional endocrine model of pharmacologic effects of DPP4 inhibitors.

The Effects of Bariatric Surgery on Islet Function, Insulin Secretion, and Glucose Control.

Although bariatric surgery was developed primarily to treat morbid obesity, evidence from the earliest clinical observations to the most recent clinical trials consistently demonstrates that these procedures have substantial effects on glucose metabolism. A large base of research indicates that bariatric surgeries such as Roux-en-Y gastric bypass (RYGB), vertical sleeve gastrectomy (VSG), and biliopancreatic diversion (BPD) improve diabetes in most patients, with effects frequently evident prior to substantial weight reduction. There is now unequivocal evidence from randomized controlled trials that the efficacy of surgery is superior to intensive life-style/medical management. Despite advances in the clinical understanding and application of bariatric surgery, there remains only limited knowledge of the mechanisms by which these procedures confer such large changes to metabolic physiology. The improvement of insulin sensitivity that occurs with weight loss (e.g., the result of diet, illness, physical training) also accompanies bariatric surgery. However, there is evidence to support specific effects of surgery on insulin clearance, hepatic glucose production, and islet function. Understanding the mechanisms by which surgery affects these parameters of glucose regulation has the potential to identify new targets for therapeutic discovery. Studies to distinguish among bariatric surgeries on key parameters of glucose metabolism are limited but would be of considerable value to assist clinicians in selecting specific procedures and investigators in delineating the resulting physiology. This review is based on literature related to factors governing glucose metabolism and insulin secretion after the commonly used RYGB and VSG, and the less frequently used BPD and adjustable gastric banding.

Role of vagal activation in postprandial glucose metabolism after gastric bypass in individuals with and without hypoglycaemia.

Patients who have undergone gastric bypass surgery (GB) have enhanced postprandial hyperinsulinaemia and a greater incretin effect is apparent. In the present study, we sought to determine the effect of vagal activation, a neural component of the enteroinsular axis, on postprandial glucose metabolism in patients with and without hypoglycaemia after GB. Seven patients with documented post-GB hypoglycaemia, seven asymptomatic patients without hypoglycaemia post-GB, and 10 weight-matched non-surgical controls with normal glucose tolerance were recruited. Blood glucose, and islet hormone and incretin secretion were compared during mixed meal tolerance tests (MMTs) with and without prior sham-feeding on two separate days. Sham feeding preceding the MMT caused a more rapid increase in prandial blood glucose levels but lowered overall glycaemia in all three groups (P < 0.05). Sham feeding had a similar effect to increase early (P < 0.05), but not overall, meal-induced insulin secretion in the three groups. Prandial glucagon concentrations were significantly greater in the GB groups, and sham feeding accentuated this response (P < 0.05). The effect of vagal activation on prandial glucose and islet-cell function is preserved in patients who have undergone GB, in those both with and without hypoglycaemia.