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Chronic treatment with anti-GIPR mAb alone and combined with DPP-4 inhibitor correct obesity, dyslipidemia and nephropathy in rodent animals
Abstract
Objective
Glucose-dependent insulinotropic polypeptide receptor (GIPR) has been identified as a contributor to obesity, and GIPR knockout mice are protected against diet-induced obesity (DIO). Therefore, we developed the anti-GIPR antagonistic monoclonal antibody (mAb) alone and in combination with DPP-4 inhibitor as potential therapeutic strategy for treating obesity and dyslipidemia based on this genetic evidence.
Methods
Fully neutralized GIPR activity of GIPR-monoclonal antibody (mAb) was assessed by regulating the in vitro production of cAMP in the mouse GIPR stably expressing cells. Chronic efficacies of GIPR-mAb alone and in combination with DPP-4 inhibitor Sitagliptin in diabetic or DIO mice were both investigated. Multiple metabolic parameters including body weight, glucose level, fat mass, lipid metabolism-related indicators as well as H&E staining and immunohistochemical analysis were performed. Role of GIPR in pancreatic cells on regulating fat metabolism was explored in GIPR β-cell knockout mouse model.
Results
Chronic treatment of GIPR-mAb improved body weight control, glucose metabolism, and was associated with reduced fat mass, enhanced pancreatic function and exchange ratio of the resting respiratory in diabetic mice. In addition, further study of anti-GIPR mAb combined with Sitagliptin in DIO mice demonstrated significantly improved weight loss compare to the both monomer treatment. Furthermore, we demonstrated important role of GIPR in β-cell in regulating the fat mass and response to antagonistic GIPR-mAb in a conditional GIPR-knockout mouse.
Conclusion
Chronic treatment with anti-GIPR mAb alone and combined with DPP-4 inhibitor provide preclinical therapeutic approaches to treat obesity.
... Thus, the partial GIPR antagonist, (Pro 3 )GIP, has originally been demonstrated to improve obesity-related diabetes, reducing islet hypertrophy and improving insulin sensitivity [122], while also eliciting 8% weight loss following administration alone in obese mice [123]. These observations have been largely confirmed by others employing GIPR monoclonal antibodies [124]. Interestingly, there is a suggestion that the metabolic benefits of chronic GIPR agonism are related to desensitization of the GIPR, thus mimicking GIPR antagonism [125]. ...
Introduction
: Obesity is recognised as a major healthcare challenge. Following years of slow progress in discovery of safe, effective therapies for weight management, recent approval of the glucagon-like peptide 1 receptor (GLP-1R) mimetics, liraglutide and semaglutide, for obesity has generated considerable excitement. It is anticipated these agents will pave the way for application of tirzepatide, a highly effective glucose-dependent insulinotropic polypeptide receptor (GIPR), GLP-1R co-agonist recently approved for management of type 2 diabetes mellitus.
Areas covered
: Following promising weight loss in obese individuals in Phase III clinical trials, liraglutide and semaglutide were approved for weight management without diabetes. Tirzepatide has attained Fast Track designation for obesity management by the US Food and Drug Association. This narrative review summarises experimental, preclinical and clinical data for these agents and related GLP-1R/GIPR co-agonists, prioritising clinical research published within the last 10 years where possible.
Expert Opinion
: GLP-1R mimetics are often discontinued within 24-months, owing to gastrointestinal side-effects, meaning long-term application of these agents in obesity is questioned. Combined GIPR/GLP-1R agonism appears to induce fewer side-effects, indicating GLP-1R/GIPR co-agonists may be more suitable for enduring obesity management. After years of debate, this GIPR-biased GLP-1R/GIPR co-agonist highlights the therapeutic promise of including GIPR modulation for diabetes and obesity therapy.
... Although our results together with several studies of anti-GIPR antibodies (Gault et al., 2005;Killion et al., 2018;Min et al., 2020;Svendsen et al., 2020;Chen et al., 2021) could indicate that GIPR antagonists could protect from diet-induced obesity and improve glycemic and insulinotropic effects, other studies have shown the same for GIPR agonists (Nørregaard et al., 2018;Mroz et al., 2019;Samms et al., 2021). It is therefore still uncertain whether an agonist or an antagonist would be superior for the treatment of obesity. ...
Glucose-dependent insulinotropic polypeptide (GIP) and its receptor (GIPR) are involved in multiple physiological systems related to glucose metabolism, bone homeostasis and fat deposition. Recent research has surprisingly indicated that both agonists and antagonists of GIPR may be useful in the treatment of obesity and type 2 diabetes, as both result in weight loss when combined with GLP-1 receptor activation. To understand the receptor signaling related with weight loss, we examined the pharmacological properties of two rare missense GIPR variants, R190Q (rs139215588) and E288G (rs143430880) linked to lower body mass index (BMI) in carriers. At the molecular and cellular level, both variants displayed reduced G protein coupling, impaired arrestin recruitment and internalization, despite maintained high GIP affinity. The physiological phenotyping revealed an overall impaired bone strength, increased systolic blood pressure, altered lipid profile, altered fat distribution combined with increased body impedance in human carriers, thereby substantiating the role of GIP in these physiological processes.
Aims:
To characterize the pharmacology of MEDI0382, a peptide dual agonist of glucagon-like peptide-1 (GLP-1) and glucagon receptors.
Materials and methods:
MEDI0382 was evaluated in vitro for its ability to stimulate cAMP accumulation in cell lines expressing transfected recombinant or endogenous GLP-1 or glucagon receptors, to potentiate glucose-stimulated insulin secretion (GSIS) in pancreatic β-cell lines and stimulate hepatic glucose output (HGO) by primary hepatocytes. The ability of MEDI0382 to reduce body weight and improve energy balance (i.e. food intake and energy expenditure), as well as control blood glucose was evaluated in mouse models of obesity and healthy cynomolgus monkeys following single and repeated daily subcutaneous administration for up to 2 months.
Results:
MEDI0382 potently activated rodent, cynomolgus and human GLP-1 and glucagon receptors and exhibited a 5-fold bias for activation of GLP-1 receptor versus the glucagon receptor. MEDI0382 produced superior weight loss and comparable glucose lowering to the GLP-1 peptide analogue liraglutide when administered daily at comparable doses in DIO mice. The additional fat mass reduction elicited by MEDI0382 likely results from a glucagon receptor-mediated increase in energy expenditure, whereas the food intake suppression results from the activation of the GLP-1 receptor. Notably, the significant weight loss elicited by MEDI0382 in DIO mice was recapitulated in cynomolgus monkeys.
Conclusions:
Repeated administration of MEDI0382 elicits profound weight loss in DIO mice and non-human primates, produces robust glucose control and reduces hepatic fat content and fasting insulin and glucose levels. The balance of activities at the GLP-1 and glucagon receptors is considered to be optimal for achieving weight and glucose control in overweight or obese Type 2 diabetic patients.
Sitagliptin has been reported to improve lipid profiles, but findings from these studies are conflicting. We conducted this meta-analysis to evaluate the effects of sitagliptin on serum lipids in patients with type 2 diabetes mellitus.
We made a comprehensive literature search in PubMed, EMBASE, Cochrane Library, China National Knowledge Infrastructure, Wanfang, and VIP database until June 2015. Eligible studies were randomized clinical trials (RCTs) that investigated the effect of sitagliptin on serum triglycerides (TGs), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), or high-density lipoprotein cholesterol (HDL-C).
Eleven RCTs with 2338 patients were identified. Compared with controls, sitagliptin alone or in combination significantly improved serum TG (weighted mean difference [WMD] −0.24 mmol/L; 95% confidence interval [CI] −0.40 to −0.09; P = 0.002) and HDL-C (WMD 0.05 mmol/L; 95% CI 0.02–0.07; P < 0.001).However, no statistical significances were observed in LDL-C (WMD −0.07 mmol/L; 95% CI −0.22 to 0.08; P = 0.337) and TC (WMD −0.14; 95% CI −0.33 to 0.06; P = 0.177). Subgroup analyses revealed that sitagliptin alone achieved greater improvement in serum TG, TC, and HDL-C levels.
These findings suggested that sitagliptin alone or in combination significantly improved serum TG and HDL-C levels in patients with type 2 diabetes mellitus.
Gastric inhibitory polypeptide (GIP) is an incretin released from enteroendocrine K-cells in response to nutrient intake, especially fat. GIP induces fat accumulation, resulting in obesity. A recent study shows that fatty acid-binding protein 5 (FABP5) is expressed in murine K-cells and is involved in fat-induced GIP secretion. We investigated the mechanism of fat-induced GIP secretion and the impact of FABP5-related GIP response on diet-induced obesity (DIO). Single oral administration of glucose and fat resulted in reduction of GIP response to fat but not to glucose in whole body FABP5 knockout (FABP5(-/-)) mice, with no change in K-cell count or GIP content in K-cells. In gut culture, oleic acid induced only a slight increase in GIP release, which was markedly enhanced by coadministration of bile and oleic acid, together with attenuated GIP response in FABP5(-/-) sample. FABP5(-/-) mice exhibited significant reduction in body weight gain and body fat mass under high-fat diet compared to wild-type (FABP5(+/+)) mice and the difference was abolished between GIP-GFP homozygous knock-in (GIP(gfp/gfp))-FABP5(+/+) mice and GIP(gfp/gfp)-FABP5(-/-) mice in which GIP is genetically deleted. These results demonstrate that bile efficiently amplifies fat-induced GIP secretion and that FABP5 contributes to the development of DIO in a GIP-dependent manner.
Copyright © 2015, American Journal of Physiology - Endocrinology and Metabolism.
Gastric inhibitory polypeptide (GIP) exhibits potent insulinotropic effects on β-cells and anabolic effects on bone formation and fat accumulation. We explored the impact of reduced GIP levels in vivo on glucose homeostasis, bone formation, and fat accumulation in a novel GIP-GFP knock-in (KI) mouse. We generated GIP-GFP KI mice with a truncated prepro-GIP gene. The phenotype was assessed in heterozygous and homozygous state in mice on control fat diet (CFD) and high fat diet (HFD) in vivo and in vitro. Heterozygous GIP-GFP KI mice (GIP-reduced mice: GIP(gfp/+)) exhibited reduced GIP secretion; in homozygous state (GIP-lacking mice: GIP(gfp/gfp)), GIP secretion was undetectable. When fed standard chow, GIP(gfp/+) and GIP(gfp/gfp) showed mild glucose intolerance with decreased insulin levels; bone volume was decreased in GIP(gfp/gfp) and preserved in GIP(gfp/+). Under HFD, glucose levels during OGTT were similar in WT, GIP(gfp/+), and GIP(gfp/gfp), while insulin secretion remained lower. GIP(gfp/+) and GIP(gfp/gfp) showed reduced obesity and reduced insulin resistance, accompanied by higher fat oxidation and energy expenditure. GIP-reduced mice demonstrate that partial reduction of GIP does not alter extensively glucose tolerance, but it alleviates obesity and lessens the degree of insulin resistance under HFD condition, suggesting a potential therapeutic value.
Glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), and glucagon bind to related members
of the same receptor superfamily and exert important effects on glucose homeostasis, insulin secretion, and energy regulation.
The present study assessed the biological actions and therapeutic utility of novel GIP/glucagon/GLP-1 hybrid peptides. Nine
novel peptides were synthesized and exhibited complete DPP-IV resistance and enhanced in vitro insulin secretion. The most promising peptide, [dA2]GLP-1/GcG, stimulated cAMP production in GIP, GLP-1, and glucagon receptor-transfected cells. Acute administration of [dA2]GLP-1/GcG in combination with glucose significantly lowered plasma glucose and increased plasma insulin in normal and obese
diabetic (ob/ob) mice. Furthermore, [dA2]GLP-1/GcG elicited a protracted glucose-lowering and insulinotropic effect in high fat-fed mice. Twice daily administration
of [dA2]GLP-1/GcG for 21 days decreased body weight and nonfasting plasma glucose and increased circulating plasma insulin concentrations
in high fat-fed mice. Furthermore, [dA2]GLP-1/GcG significantly improved glucose tolerance and insulin sensitivity by day 21. Interestingly, locomotor activity was
increased in [dA2]GLP-1/GcG mice, without appreciable changes in aspects of metabolic rate. Studies in knock-out mice confirmed the biological
action of [dA2]GLP-1/GcG via multiple targets including GIP, GLP-1, and glucagon receptors. The data suggest significant promise for novel
triple-acting hybrid peptides as therapeutic options for obesity and diabetes.
Inhibition of dipeptidyl peptidase-4 (DPP-4) activity improves glucose homeostasis through a mode of action related to the stabilization of the active forms of DPP-4-sensitive hormones such as the incretins that enhance glucose-induced insulin secretion. However, the DPP-4 enzyme is highly expressed on the surface of intestinal epithelial cells; hence, the role of intestinal vs. systemic DPP-4 remains unclear. To analyze mechanisms through which the DPP-4 inhibitor sitagliptin regulates glycemia in mice, we administered low oral doses of the DPP-4 inhibitor sitagliptin that selectively reduced DPP-4 activity in the intestine. Glp1r(-/-) and Gipr(-/-) mice were studied and glucagon-like peptide (GLP)-1 receptor (GLP-1R) signaling was blocked by an i.v. infusion of the corresponding receptor antagonist exendin (9-39). The role of the dipeptides His-Ala and Tyr-Ala as DPP-4-generated GLP-1 and glucose-dependent insulinotropic peptide (GIP) degradation products was studied in vivo and in vitro on isolated islets. We demonstrate that very low doses of oral sitagliptin improve glucose tolerance and plasma insulin levels with selective reduction of intestinal but not systemic DPP-4 activity. The glucoregulatory action of sitagliptin was associated with increased vagus nerve activity and was diminished in wild-type mice treated with the GLP-1R antagonist exendin (9-39) and in Glp1r(-/-) and Gipr(-/-) mice. Furthermore, the dipeptides liberated from GLP-1 (His-Ala) and GIP (Tyr-Ala) deteriorated glucose tolerance, reduced insulin, and increased portal glucagon levels. The predominant mechanism through which DPP-4 inhibitors regulate glycemia involves local inhibition of intestinal DPP-4 activity, activation of incretin receptors, reduced liberation of bioactive dipeptides, and activation of the gut-to-pancreas neural axis.
GIP (glucose-dependent insulinotropic polypeptide) is a gastrointestinal hormone that regulates pancreatic islet function. Additionally, emerging evidence suggests an important physiological role for GIP in the regulation of adipocyte metabolism. In previous studies on the lipogenic effects of GIP, it was shown to increase adipocyte lipoprotein lipase (LPL) activity in both differentiated 3T3-L1 cells and human adipocytes through a pathway involving activation of protein kinase B (PKB)/Akt. In the current study, we examined the effects of GIP on LPL gene expression. GIP in the presence of insulin increased LPL gene expression in human adipocytes and LPL promoter activity in GIP receptor-expressing HEK-293 cells, and both effects were greatly reduced by the transcription inhibitor actinomycin D. Subsequent studies established that GIP increased phosphorylation of Serine 133 in cAMP-response element binding protein (CREB) and the nuclear localization of cAMP-responsive CREB coactivator 2 (TORC2) through a pathway involving phosphatidylinositol 3-kinase (PI3-K), PKB, and AMP-activated protein kinase (AMPK). However, in the presence of insulin, GIP failed to activate the cAMP/PKA pathway. Knockdown of CREB and TORC2 using RNA interference reduced LPL expression, supporting a functional regulatory role. GIP-induced phospho-CREB and TORC2 were shown to bind to a cAMP-response element (-II) site in the human LPL promoter and GIP increased protein-protein interactions of these two factors. The lipogenic effects of GIP in the presence of insulin are therefore at least partially mediated by upregulation of adipocyte LPL gene transcription through a pathway involving PI3-K/PKB/AMPK-dependent CREB/TORC2 activation.
Cases of acute pancreatitis have been reported in association with exenatide, sitagliptin, and type 2 diabetes without use of these medications. It remains unknown whether exenatide or sitagliptin increase the risk of acute pancreatitis.
A retrospective cohort study of a large medical and pharmacy claims database was performed. Data for 786,656 patients were analyzed. Cox proportional hazard models were built to compare the risk of acute pancreatitis between diabetic and nondiabetic subjects and between exenatide, sitagliptin, and control diabetes medication use.
Incidence of acute pancreatitis in the nondiabetic control group, diabetic control group, exenatide group, and sitagliptin group was 1.9, 5.6, 5.7, and 5.6 cases per 1,000 patient years, respectively. The risk of acute pancreatitis was significantly higher in the combined diabetic groups than in the nondiabetic control group (adjusted hazard ratio 2.1 [95% CI 1.7-2.5]). Risk of acute pancreatitis was similar in the exenatide versus diabetic control group (0.9 [0.6-1.5]) and sitagliptin versus diabetic control group (1.0 [0.7-1.3]).
Our study demonstrated increased incidence of acute pancreatitis in diabetic versus nondiabetic patients but did not find an association between the use of exenatide or sitagliptin and acute pancreatitis. The limitations of this observational claims-based analysis cannot exclude the possibility of an increased risk.
To characterize the phenotypic changes of adipose tissue macrophages (ATMs) under different conditions of insulin sensitivity.
The number and the expressions of marker genes for M1 and M2 macrophages from mouse epididymal fat tissue were analyzed using flow cytometry after the mice had been subjected to a high-fat diet (HFD) and pioglitazone treatment.
Most of the CD11c-positive M1 macrophages and the CD206-positive M2 macrophages in the epididymal fat tissue were clearly separated using flow cytometry. The M1 and M2 macrophages exhibited completely different gene expression patterns. Not only the numbers of M1 ATMs and the expression of M1 marker genes, such as tumor necrosis factor-alpha and monocyte chemoattractant protein-1, but also the M1-to-M2 ratio were increased by an HFD and decreased by subsequent pioglitazone treatment, suggesting the correlation with whole-body insulin sensitivity. We also found that the increased number of M2 ATMs after an HFD was associated with the upregulated expression of interleukin (IL)-10, an anti-inflammatory Th2 cytokine, in the adipocyte fraction as well as in adipose tissue. The systemic overexpression of IL-10 by an adenovirus vector increased the expression of M2 markers in adipose tissue.
M1 and M2 ATMs constitute different subsets of macrophages. Insulin resistance is associated with both the number of M1 macrophages and the M1-to-M2 ratio. The increased expression of IL-10 after an HFD might be involved in the increased recruitment of M2 macrophages.
Type 2 diabetes mellitus is an increasingly prevalent condition worldwide. The complications of this disease are known to significantly increase the morbidity and mortality of those affected, resulting in substantial direct and indirect costs. Although good glycemic control has been shown to reduce the incidence and progression of diabetes-related microvascular complications, blood glucose levels are not adequately controlled in most individuals with diabetes. The reasons for this are many, and include issues such as poor adherence to complex medication regimes; costs of prescribed therapies; and the failure of traditionally prescribed medications to preserve beta cell function over time. However, our armamentarium of glucose-lowering drugs has expanded recently with the development of medications that act via the incretin pathway. Sitagliptin, the first commercially available dipeptidyl peptidase-4 inhibitor, inhibits the metabolism and inactivation of the incretin hormones GLP-1 and GIP. The subsequent elevation in levels of these hormones and associated prolongation of their actions has been shown to increase insulin secretion and suppress glucagon secretion in a glucose-appropriate fashion. Sitagliptin therapy in individuals with type 2 diabetes has been found to lower significantly hemoglobin A1c (Hb1c) levels with a minimum of adverse side effects such as weight gain or hypoglycemia. Use of sitagliptin in conjunction with the insulin-sensitizing medication metformin has been shown to decrease HbAlc levels more significantly than does either drug alone. This combination of medications is generally well tolerated, with no adverse effects on weight and a very low likelihood of treatment-related hypoglycemia. Use of both drugs will positively affect many of the underlying metabolic abnormalities associated with type 2 diabetes, including the disordered secretion of insulin and glucagon as well as impaired sensitivity to insulin which are known to accompany this disease. Animal studies also suggest that dipeptidyl peptidase-4 inhibitor treatment may help to preserve beta cell mass; however, it is unclear at present whether or not this will prove to be the case in humans.
Objective:
To determine the effect of tirzepatide, a dual agonist of glucose-dependent insulinotropic polypeptide and glucagon-like peptide 1 receptors, on biomarkers of nonalcoholic steatohepatitis (NASH) and fibrosis in patients with type 2 diabetes mellitus (T2DM).
Research design and methods:
Patients with T2DM received either once weekly tirzepatide (1, 5, 10, or 15 mg), dulaglutide (1.5 mg), or placebo for 26 weeks. Changes from baseline in alanine aminotransferase (ALT), aspartate aminotransferase (AST), keratin-18 (K-18), procollagen III (Pro-C3), and adiponectin were analyzed in a modified intention-to-treat population.
Results:
Significant (P < 0.05) reductions from baseline in ALT (all groups), AST (all groups except tirzepatide 10 mg), K-18 (tirzepatide 5, 10, 15 mg), and Pro-C3 (tirzepatide 15 mg) were observed at 26 weeks. Decreases with tirzepatide were significant compared with placebo for K-18 (10 mg) and Pro-C3 (15 mg) and with dulaglutide for ALT (10, 15 mg). Adiponectin significantly increased from baseline with tirzepatide compared with placebo (10, 15 mg).
Conclusions:
In post hoc analyses, higher tirzepatide doses significantly decreased NASH-related biomarkers and increased adiponectin in patients with T2DM.
Tirzepatide (TZP), a GIP receptor and GLP-1 receptor (GIPR/GLP-1R) dual agonist, has demonstrated profound effects on glycemic control and bodyweight lowering in T2D subjects. However, the mechanism of action for the dual agonism of TZP is incompletely understood. Adipose expresses GIPR but not GLP-1R and therefore presents a key target tissue to investigate TZP biology. Using differentiated human adipocytes, we explored TZP regulation of lipid and carbohydrate metabolism. TZP demonstrated significant modulation of lipid accumulation, efflux, and oxidation. Similar to insulin, TZP increased expression and secretion of active LPL. While it had no effect on its own, TZP dose dependently suppressed insulin stimulated de novo lipogenesis in [14C]glucose and [14C]acetate incorporation assays. Insulin and TZP counter-regulated lipolysis characterized by insulin suppression and TZP stimulation of glycerol release. Uncoupled oxygen consumption was increased by TZP and subsequently reduced by CPT1 inhibition (etomoxir) demonstrating regulation of fatty acid oxidation. In adipose glycemic control, TZP exhibited both direct and insulin-dependent regulation of glucose transport. TZP at low dose (10pM) provided indirect (insulin sensitizing) effects while higher doses (10 nM) directly stimulated [14C]glucose uptake in adipocytes. While acute GIP infusion in a rat hyperinsulinemic/euglycemic clamp demonstrated no change in total body glucose infusion rate (GIR), chronic treatment (two week) with TZP or GIPR agonist increased GIR and adipose tissue [14C]glucose accumulation. This suggests both tissue-specific and whole-body insulin sensitization through GIPR agonism. Taken together, this data demonstrates GIPR specific activity of TZP in regulating adipose function. These findings and ongoing pathway integration studies will provide clues to the metabolic benefit of TZP GIPR/GLP-1R dual agonism compared with GLP-1R agonism alone.
Disclosure
R.J. Samms: Employee; Self; Eli Lilly and Company. M.E. Christe: Employee; Self; Eli Lilly and Company. X. Ruan: Employee; Self; Eli Lilly and Company. J. Moyers: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company. A. Regmi: Employee; Self; Eli Lilly and Company. W.C. Roell: Employee; Self; Eli Lilly and Company.
Several gastrointestinal (GI) operations originally developed for the treatment of severe obesity (bariatric surgery) promote sustained weight loss as well as dramatic, durable improvements of insulin-resistant states, most notably type 2 diabetes mellitus (T2DM). Experimental evidence shows that some rearrangements of GI anatomy can directly affect glucose homeostasis, insulin sensitivity, and inflammation, supporting the idea that the GI tract is a biologically rational target for interventions aimed at correcting pathophysiologic aspects of cardiometabolic disorders. This article reviews the pathophysiology of metabolic disease and the role of bariatric/metabolic surgery in current clinical guidelines for the treatment of obesity and T2DM.
The glucagon-like peptides include glucagon, GLP-1, and GLP-2, and exert diverse actions on nutrient intake, gastrointestinal motility, islet hormone secretion, cell proliferation and apoptosis, nutrient absorption, and nutrient assimilation. GIP, a related member of the glucagon peptide superfamily, also regulates nutrient disposal via stimulation of insulin secretion. The actions of these peptides are mediated by distinct members of the glucagon receptor superfamily of G protein--coupled receptors. These receptors exhibit unique patterns of tissue-specific expression, exhibit considerable amino acid sequence identity, and share similar structural and functional properties with respect to ligand binding and signal transduction. This article provides an overview of the biology of these receptors with an emphasis on understanding the unique actions of glucagon-related peptides through studies of the biology of their cognate receptors.
Glucagon-like peptide-1 (GLP-1) and GLP-1 receptors (GLP-1Rs) are responsible for glucose homeostasis, and have been shown to reduce inflammation in preclinical studies. The aim of the present study was to determine whether sitagliptin, an inhibitor of the enzyme dipeptidyl peptidase-4 (DPP-4), as a GLP-1 receptor agonist, exerts an anti-inflammatory effect on cardiomyoblasts during lipopolysaccharide (LPS) stimulation. Exposure to LPS increased the expression levels of tumor necrosis factor (TNF)-α, interleukin-6 (IL)-6 and IL-1β in H9c2 cells, and also resulted in elevations in cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) expression and nuclear factor-κB (NF-κB) nuclear translocation. Treatment with the DPP-4 inhibitor sitagliptin dose-dependently downregulated the mRNA levels of IL-6, COX-2 and iNOS in LPS-stimulated H9c2 cells. In addition, sitagliptin inhibited the increased protein expression of IL-6, TNF-α and IL-1β. NF-κB mRNA expression was reduced and its translocation to the nucleus was suppressed by treatment with sitagliptin. The present results demonstrated that sitagliptin exerts a beneficial effect on cardiomyoblasts exposed to LPS by inhibiting expression of inflammatory mediators and suppressing NF-κB activation. These findings indicate that the DPP-4 inhibitor sitagliptin may serve a function in cardiac remodeling attributed to sepsis-induced inflammation.
To evaluate the protective effect of the DPP IV inhibitor in STZ-induced islet injury and to identify the molecular events that protect islet against apoptosis.
4 diabetic monkeys were treated with streptozotocin (70mg/kg) in the presence or absence of the DPP IV inhibitor (Sitagliptin), continuing administered for 4weeks after STZ. The monkeys were evaluated by plasma DPP IV activity, serum active GLP-1 response, blood glucose, insulin and C-P levels, the insulin resistance index (HOMA-IR), and the expression of insulin, caspase-3, IGF receptor (IGFR), p-Akt and p-mTOR in pancreas islets tissues. To test that DPP IV inhibitors might against islets apoptosis via IGFR/Akt/mTOR signaling pathways, the isolated islets from the normal monkeys were pre-treated with or without 10mM STZ for 1h, followed by GLP-1 (10μM) in the presence or absence of NVP-AEW541 or Wortmannin for 24h, to determined islets function and islet apoptosis.
DPP IV inhibitors treatment showed depressing the degradation of GLP-1 and significantly increased serum GLP-1 levels in DM monkeys. Moreover, treatment of diabetic monkeys with the DPP IV inhibitor or treatment of isolated islets with GLP-1 can decrease islet apoptosis, and enhanced islet function and survival, and the expression of IGF receptor, p-Akt and p-mTOR in islets. When the IGFR/Akt/mTOR signaling pathways was blocked by NVP-AEW541 or Wortmannin, the protective effects of GLP1 on STZ-induced islets injury were inhibited in vitro.
Our data provides evidence that DPP IV inhibitors confer resistance to STZ-induced islet injury. The protective effects of DPP IV inhibitor on STZ-induced islets injury were dependent on activation of the IGFR/Akt/mTOR signaling pathways by GLP-1 in islets of monkeys.
Copyright © 2014. Published by Elsevier Inc.
Context:
Glucose-dependent insulinotropic peptide (GIP) has a central role in glucose homeostasis through its amplification of insulin secretion; however, its physiological role in adipose tissue is unclear.
Objective:
Our objective was to define the function of GIP in human adipose tissue in relation to obesity and insulin resistance.
Design:
GIP receptor (GIPR) expression was analyzed in human sc adipose tissue (SAT) and visceral adipose (VAT) from lean and obese subjects in 3 independent cohorts. GIPR expression was associated with anthropometric and biochemical variables. GIP responsiveness on insulin sensitivity was analyzed in human adipocyte cell lines in normoxic and hypoxic environments as well as in adipose-derived stem cells obtained from lean and obese patients.
Results:
GIPR expression was downregulated in SAT from obese patients and correlated negatively with body mass index, waist circumference, systolic blood pressure, and glucose and triglyceride levels. Furthermore, homeostasis model assessment of insulin resistance, glucose, and G protein-coupled receptor kinase 2 (GRK2) emerged as variables strongly associated with GIPR expression in SAT. Glucose uptake studies and insulin signaling in human adipocytes revealed GIP as an insulin-sensitizer incretin. Immunoprecipitation experiments suggested that GIP promotes the interaction of GRK2 with GIPR and decreases the association of GRK2 to insulin receptor substrate 1. These effects of GIP observed under normoxia were lost in human fat cells cultured in hypoxia. In support of this, GIP increased insulin sensitivity in human adipose-derived stem cells from lean patients. GIP also induced GIPR expression, which was concomitant with a downregulation of the incretin-degrading enzyme dipeptidyl peptidase 4. None of the physiological effects of GIP were detected in human fat cells obtained from an obese environment with reduced levels of GIPR.
Conclusions:
GIP/GIPR signaling is disrupted in insulin-resistant states, such as obesity, and normalizing this function might represent a potential therapy in the treatment of obesity-associated metabolic disorders.
Most patients with type 2 diabetes (T2DM) struggle with excess body weight. Many management strategies for achievement of euglycemia in T2DM are associated with weight gain, which worsens insulin resistance over time, increases health risk associated with obesity, and is associated with poor compliance with treatment. This review will discuss a host of new medications for management of hyperglycemia that have emerged and are emerging which are weight neutral, or facilitate weight loss. Incretin therapies are reviewed, including DPP-4 inhibitors which are weight neutral, and GLP-1 receptor agonists which can facilitate weight loss. SGLT-2 inhibitors, anticipated to become available soon, facilitate modest weight loss. Pramlintide can improve glycemic control and facilitate weight loss in T2DM patients on concomitant insulin therapy. The bile acid sequestering agent colesevelam, more recently approved for management of T2DM, modestly improves glycemic control and is weight neutral. The advent of these newer therapies makes it increasingly possible to optimize concomitant management of type 2 diabetes and obesity.
Aims/hypothesis:
Glucagon-like peptide-1 (GLP-1) exerts beneficial effects on the cardiovascular system. Here, we examined the effect of sitagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, on systemic inflammation and pro-inflammatory (M1)/anti-inflammatory (M2)-like phenotypes of peripheral blood monocytes in diabetic patients.
Methods:
Forty-eight type 2 diabetic patients were divided into the following two groups: sitagliptin-treatment (50mg daily for 3months) (n=24) and untreated control (n=24) groups. Measurements were undertaken to assess changes in glucose-lipid metabolism, serum levels of inflammatory cytokines such as serum amyloid A-LDL (SAA-LDL), C-reactive protein (CRP), interleukin-6 (IL-6), IL-10 and tumor necrosis factor-α (TNF-α). Furthermore, the effects of sitagliptin treatment on M1/M2-like phenotypes in peripheral blood monocytes were examined.
Results:
Treatment with sitagliptin significantly decreased fasting plasma glucose, hemoglobin A1c (HbA1c), serum levels of inflammatory markers, such as SAA-LDL, CRP, and TNF-α. In contrast, sitagliptin increased serum IL-10, an anti-inflammatory cytokine, as well as plasma GLP-1. In addition, sitagliptin increased monocyte IL-10 expression and decreased monocyte TNF-α expression. Multivariate regression analysis revealed that the sitagliptin treatment was the only factor independently associated with an increase in monocyte IL-10 (β=0.499; R(2)=0.293, P<0.05). However, other factors including the improvement of glucose metabolism were not associated with the increase.
Conclusions/interpretation:
This study is the first to show that a DPP-4 inhibitor, sitagliptin, reduces inflammatory cytokines and improves the unfavorable M1/M2-like phenotypes of peripheral blood monocytes in Japanese type 2 diabetic patients.
Obesity is rapidly becoming a major health concern and could be considered equal to smoking as a preventable cause of premature death. The National Institute for Health and Clinical Excellence (NICE 2006) estimated that 1.1 billion people are overweight, a number rivalling those who are underweight globally. Recent statistics for England from the National Health Service (NHS 2011) report that in 2009/10 there were 7,214 bariatric surgical procedures performed on people of varying ages.
The delivery of nutrients from the stomach into the duodenum and their subsequent interaction with the small intestine to stimulate incretin hormone release are central determinants of the glycemic response. The incretin effect has hitherto been attributed to the secretion of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) from enteroendocrine cells in the intestinal epithelium. A number of recent studies have yielded fundamental insights into the influence of individual nutrients on incretin release and the mechanisms involved in the detection of carbohydrates, fats, and proteins by enteroendocrine cells, including the K(ATP) channel, sodium-glucose cotransporter 1 (SGLT1), sweet taste receptors, G-protein-coupled receptors (GPRs), and oligopeptide transporter 1 (PepT1). Dietary modification, including modifying macronutrient composition or the consumption of "preloads" in advance of a meal, represents a novel approach to manipulate the incretin response and thereby regulate glucose homeostasis in patients with type 2 diabetes. This review focuses on the effects of individual nutrients on incretin hormone secretion, our current understanding of the signaling mechanisms that trigger secretion by enteroendocrine cells, and the therapeutic implications of these observations.
Incretin hormones often display inhibitory actions on gut motility. The aim of this study was to investigate if altered responsiveness to glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide-1 (GLP-1) as regards insulin release and small bowel motility could bring further clarity to the pathophysiology of diabetes in the Goto-Kakizaki (GK) rat. The isolated perfused pancreas was studied in male GK and Wistar rats (controls) under euglycemic and hyperglycemic conditions. Glucose-dependent insulinotropic peptide (10 nmol L(-1)) or GLP-1 (10 nmol L(-1)) were added to the medium and perfusate was collected and analysed for insulin. Moreover, GK and Wistar rats were supplied with bipolar electrodes in the small bowel and myoelectric activity was recorded during intravenous administration of GIP (1-400 pmol kg(-1) min(-1)) or GLP-1 (0.1-20 pmol kg(-1) min(-1)). Finally, tissue was collected from GK and Wistar rats for RNA extraction. Under euglycemia, GIP and GLP-1 stimulated the initial insulin response by 10-fold in GK rats (P < 0.05). At later hyperglycemia, the insulin response to GIP and GLP-1 was blunted to about one-third compared with controls (P < 0.05). In the bowel GLP-1 was about 2.6-16.7 times more potent than GIP in abolishing the migrating myoelectric complex in the GK and control rats. Polymerase chain reaction (PCR) showed GIP and GLP-1 receptor gene expression in pancreatic islets and in small bowel. The initially high, but later low insulin responsiveness to stimulation with GIP and GLP-1 along with inhibition of small bowel motility in the GK rat indicates a preserved incretin response on motility in diabetes type 2.
A very large number of weight-reducing surgical techniques have been developed over the last 25 years. Today only a handful of these techniques can be recommended. Gastric bypass, vertical banded gastroplasty, and variable banding can all be recommended although gastric bypass should be reserved for heavier patients. For the heaviest, biliopancreatic diversion or biliopancreatic diversion with duodenal switch might be considered. The controlled intervention study Swedish Obese Subjects has shown that most but not all cardiovascular risk factors are improved over 10 years by surgically induced weight loss. Quality of life as well as cardiac structure and function are dramatically improved. The average weight loss for gastric bypass and vertical banded gastroplasty was 16% after 10 years. No non-surgical treatment available today can achieve such results, not even over 2 years. Surgical treatment for obesity needs to become much more common, particularly in obese patients with metabolic disturbances.
Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are gut-derived incretins secreted in response to nutrient ingestion. Both incretins potentiate glucose-dependent insulin secretion and enhance beta-cell mass through regulation of beta-cell proliferation, neogenesis and apoptosis. In contrast, GLP-1, but not GIP, inhibits gastric emptying, glucagon secretion, and food intake. Furthermore, human subjects with Type 2 diabetes exhibit relative resistance to the actions of GIP, but not GLP-1R agonists. The physiological importance of both incretins has been investigated through generation and analysis of incretin receptor knockout mice. Elimination of incretin receptor action in GIPR-/- or GLP-1R-/- mice produces only modest impairment in glucose homeostasis. Similarly, double incretin receptor knockout (DIRKO) mice exhibit normal body weight and normal levels of plasma glucagon and hypoglycemic responses to exogenous insulin. However, glucose-stimulated insulin secretion is significantly decreased following oral but not intraperitoneal glucose challenge in DIRKO mice and the glucose lowering actions of dipeptidyl peptidase-IV (DPP-IV) inhibitors are extinguished in DIRKO mice. Hence, incretin receptor signaling exerts physiologically relevant actions critical for glucose homeostasis, and represents a pharmacologically attractive target for development of agents for the treatment of Type 2 diabetes.
Glucagon-like peptide 1 (GLP-1) is a gut-derived incretin hormone that stimulates insulin and suppresses glucagon secretion, inhibits gastric emptying, and reduces appetite and food intake. Therapeutic approaches for enhancing incretin action include degradation-resistant GLP-1 receptor agonists (incretin mimetics), and inhibitors of dipeptidyl peptidase-4 (DPP-4) activity (incretin enhancers). Clinical trials with the incretin mimetic exenatide (two injections per day or long-acting release form once weekly) and liraglutide (one injection per day) show reductions in fasting and postprandial glucose concentrations, and haemoglobin A1c (HbA1c) (1-2%), associated with weight loss (2-5 kg). The most common adverse event associated with GLP-1 receptor agonists is mild nausea, which lessens over time. Orally administered DPP-4 inhibitors, such as sitagliptin and vildagliptin, reduce HbA1c by 0.5-1.0%, with few adverse events and no weight gain. These new classes of antidiabetic agents, and incretin mimetics and enhancers, also expand beta-cell mass in preclinical studies. However, long-term clinical studies are needed to determine the benefits of targeting the incretin axis for the treatment of type 2 diabetes.
This review focuses on the mechanisms regulating the synthesis, secretion, biological actions, and therapeutic relevance of the incretin peptides glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1). The published literature was reviewed, with emphasis on recent advances in our understanding of the biology of GIP and GLP-1. GIP and GLP-1 are both secreted within minutes of nutrient ingestion and facilitate the rapid disposal of ingested nutrients. Both peptides share common actions on islet beta-cells acting through structurally distinct yet related receptors. Incretin-receptor activation leads to glucose-dependent insulin secretion, induction of beta-cell proliferation, and enhanced resistance to apoptosis. GIP also promotes energy storage via direct actions on adipose tissue, and enhances bone formation via stimulation of osteoblast proliferation and inhibition of apoptosis. In contrast, GLP-1 exerts glucoregulatory actions via slowing of gastric emptying and glucose-dependent inhibition of glucagon secretion. GLP-1 also promotes satiety and sustained GLP-1-receptor activation is associated with weight loss in both preclinical and clinical studies. The rapid degradation of both GIP and GLP-1 by the enzyme dipeptidyl peptidase-4 has led to the development of degradation-resistant GLP-1-receptor agonists and dipeptidyl peptidase-4 inhibitors for the treatment of type 2 diabetes. These agents decrease hemoglobin A1c (HbA1c) safely without weight gain in subjects with type 2 diabetes. GLP-1 and GIP integrate nutrient-derived signals to control food intake, energy absorption, and assimilation. Recently approved therapeutic agents based on potentiation of incretin action provide new physiologically based approaches for the treatment of type 2 diabetes.
Increased physical activity is an integral part of weight loss programs in adolescents. We prospectively investigated the effects of exercise on glucagon-like peptide-1 (GLP-1) concentrations and on appetite markers.
Normal weight (NW) and at risk of overweight/overweight (OW) male adolescents (n = 17/gr) underwent five consecutive days of aerobic exercise (1 h/day). A test meal was administered prior to the first exercise session and 36 hours following the last exercise session. GLP-1 and markers of appetite were assessed.
GLP-1 concentrations over the course of the test meal were lower in OW compared to NW boys (P < 0.05), while fasting GLP-1 concentrations tended to be lower in OW boys (0.05 < P < 0.1). Exercise caused an increase in the acute GLP-1 response to the liquid meal (from 52 to 78%, P = 0.02) that was similar in NW and OW adolescents. OW adolescents expressed greater restraint compared to NW adolescents (three-factor eating questionnaire, TFEQ) and there was a significant correlation between TFEQ for restraint score and BMI s.d. both before and after exercise intervention (P < 0.015). There was no significant correlation between markers of appetite and GLP-1 concentrations.
Lower concentrations of GLP-1, a satiety hormone, in OW compared to NW male adolescents support the theory that GLP-1 plays a role in the etiology of overweight. Whether the greater meal-induced, 0-30 min GLP-1 response following exercise is associated with increased satiety, a potentially beneficial effect of exercise, needs to be evaluated in larger studies. Obesity (2008) 16, 202-204. doi:10.1038/oby.2007.39.
Obesity, type 2 diabetes, and the metabolic syndrome: pathophysiologic relationships and guidelines for surgical intervention
- L Genser
- Jrc Mariolo
- L Castagneto-Gissey
- S Panagiotopoulos
- F Rubino
Recent advances in the relationship between obesity, inflammation, and insulin resistance
- P G Mcternan
- C M Kusminski
- S Kumar