The glucagon-like peptide 1 receptor agonist (GLP-1RA) class of medicines has emerged as transformative for the treatment of diabetes, obesity and other diseases. On the twentieth anniversary of the approval of exenatide (Byetta), three former employees of Amylin Pharmaceuticals acknowledge the contributions of some of the individuals and the innovation responsible for delivering the first approved GLP-1RA — the forerunner to the modern blockbuster drugs.

Body weight loss of ≥ 10% improves the metabolic derangements and liver disease in the majority of non-alcoholic steatohepatitis (NASH) patients, suggesting metabolic modulators may be effective in controlling disease. The pharmacodynamics of ALT-801, a GLP-1/glucagon receptor dual agonist optimized for NASH and weight loss, were compared to semaglutide (GLP-1 receptor agonist) and elafibranor (peroxisome proliferator-activated receptor, PPAR-α/δ, agonist) in a biopsy-confirmed, diet-induced obese (DIO) mouse model of NASH (DIO-NASH). Male C57BL/6J mice were fed Amylin Liver NASH (AMLN) diet for 32 weeks. Animals with biopsy-confirmed steatosis and fibrosis received ALT-801, semaglutide, elafibranor, or vehicle daily for 12 weeks while maintained on the AMLN diet. Study endpoints included body and liver weight, liver and plasma total cholesterol and triglycerides, plasma aminotransferases, histological analysis of liver steatosis, inflammation (galectin-3) and fibrosis (collagen type 1 alpha 1), and evaluation of individual animal changes in composite Non-alcoholic Fatty Liver Disease Activity Score (NAS), and fibrosis stage. ALT-801 demonstrated significant reductions in body weight (approx. 25%), plasma aminotransferases, plasma total cholesterol and liver triglycerides/total cholesterol in conjunction with improved liver steatosis, with greater reductions (p < 0.05) compared to semaglutide and elafibranor. ALT-801 significantly reduced the inflammation marker galectin-3 and the fibrosis marker collagen type 1 alpha 1 vs. vehicle (p < 0.05), with ALT-801 producing greater reductions in galectin-3 vs. elafibranor (p < 0.05). Importantly, all animals treated with ALT-801 significantly improved composite NAS compared to the active controls. This study provides evidence for a potential role for ALT-801 in the therapeutic treatment of NASH.

Combinatorial gut hormone therapy is one of the more promising strategies for identifying improved treatments for metabolic disease. Many approaches combine the established benefits of glucagon-like peptide-1 (GLP-1) agonism with one or more additional molecules with the aim of improving metabolic outcomes. Recent attention has been drawn to the glucose-dependent insulinotropic polypeptide (GIP) system due to compelling pre-clinical evidence describing the metabolic benefits of antagonising the GIP receptor (GIPR). We rationalised that benefit might be accrued from combining GIPR antagonism with GLP-1 agonism. Two GIPR peptide antagonists, GIPA-1 (mouse GIP(3–30)NH2) and GIPA-2 (NαAc-K10[γEγE-C16]-Arg18-hGIP(5–42)), were pharmacologically characterised and both exhibited potent antagonist properties. Acute in vivo administration of GIPA-1 during an oral glucose tolerance test (OGTT) had negligible effects on glucose tolerance and insulin in lean mice. In contrast, GIPA-2 impaired glucose tolerance and attenuated circulating insulin levels. A mouse model of diet-induced obesity (DIO) was used to investigate the potential metabolic benefits of chronic dosing of each antagonist, alone or in combination with liraglutide. Chronic administration studies showed expected effects of liraglutide, lowering food intake, body weight, fasting blood glucose and plasma insulin concentrations while improving glucose sensitivity, whereas delivery of either GIPR antagonist alone had negligible effects on these parameters. Interestingly, chronic dual therapy augmented insulin sensitizing effects and lowered plasma triglycerides and free-fatty acids, with more notable effects observed with GIPA-1 compared to GIPA-2. Thus, the co-administration of both a GIPR antagonist with a GLP1 agonist uncovers interesting beneficial effects on measures of insulin sensitivity, circulating lipids and certain adipose stores that seem influenced by the degree or nature of GIP receptor antagonism.

Amylin, a 37 amino acid peptide pancreatic hormone co-secreted with insulin, normalizes the altered eating patterns induced by chronic stress in the rat. Because these stress-induced changes are driven, in part, by brain corticotropin-releasing factor and corticosterone, and because alterations in the activity of these molecules and the stress system are commonly associated with neuropsychiatric diseases like anxiety, depression, and schizo-phrenia, we hypothesized that amylin might mitigate behavioral states associated with stress. Therefore, we tested the effects of rat amylin in rodent-based behavioral assays sensitive to neuropsychiatric drugs, including anxiolytic, antidepressant, antipsychotic, and cognitive enhancing drugs: stress-induced hyperthermia (SIH); marble burying; elevated plus maze (EPM)), forced swim test (FST), pre-pulse inhibition, and phencyclidine-induced locomotion. To assess the neural underpinnings of amylin's anxiolytic-like effects, we examined the effect of amylin on SIH after lesioning the area postrema (AP), which mediates amylin's metabolic effects. Amylin injection (IP, 0.1, 1.0, & 10 mg/kg) significantly (P < 0.05) decreased SIH (97% below vehicle) and AP lesions inhibited this effect. Amylin also reduced marble burying (72% below vehicle), but had no effect in the EPM. Together, these effects suggest anxiolytic-like activity or potential. Amylin injection also enhanced cognitive performance in the novel object recognition test. When administered continuously by implanted os-motic pumps, amylin (300 mg/kg/d) blocked SIH when tested at 1 and 4 weeks. Compared to vehicle, amylin infusion (1 and 3 mg/kg/d) reduced the time immobile in the FST (P < 0.05; 30% below vehicle), suggesting antidepressant-like potential. Although further testing is needed, our findings support a potential for peripherally administered amylin to access and benefit pathways that regulate memory, emotion, and mood.

Existing candidates for treating non-alcoholic steatohepatitis (NASH), including glucagon-like peptide-1 (GLP-1) analogs and previous GLP-1/glucagon receptor (GLP-1R/GCGR) dual agonists, do not address the need for substantial weight loss adequately. We sought a more effective, evenly balanced GLP-1/GCGR dual agonist suitable for weekly administration. We studied a new class of covalent modifiers, glycolipid surfactants, to prolong the duration of action of candidate peptides. Variation of the hydrophobic tail of such surfactant modifications resulted in a wide and tunable range of physical properties and t(1/2) values. We selected compound 17, which demonstrated high, evenly balanced potency for activation of human GLP-1R and GCGRs, return of diet induced obese (DIO) rodents to lean body/liver weight and prolonged duration correlated with high serum albumin binding. We observed a prolonged pharmacodynamic (PD) profile in rodents and pharmacokinetics (PK) in mini-pigs (t(1/2) = 52 hours, mean residence time, MRT = 84 hours), suggesting suitability for weekly dosing. Accordingly, 17 (ALT-801) was selected for clinical development.

Inappropriate activation of the renin-angiotensin system increases adipocyte inflammation contributing to the impairment in adipocyte function and increases hepatic PCK1 and G6PC1 mRNA expression in response to a glucose challenge. Ultimately, these effects may contribute to the development of glucose intolerance.

Despite pharmacological and technical advances, risk of hypoglycemia remains the greatest impediment to optimal glycemia in type 1 diabetes (T1D) and there is increasing interest in how the opposing actions of insulin and glucagon (Gn) may be harnessed to optimize glycemic control. We studied T1D subjects (n=11; age 36±4y, gender M:F 5:6, BMI 25.0±0.7 kg/m2, disease duration 23±3y, A1C 7.0±0.3%, daily insulin dose 43±3u) on two occasions, under meal challenge conditions (liquid mixed meal, 100g carbohydrate) during a phased 6h IV regular insulin infusion with (+Gn) and without (-Gn) IV glucagon. On both occasions, subjects were treated overnight with low dose IV insulin prior to the morning meal to prevent antecedent nocturnal hypoglycemia and to attain near-normal fasting glycemia. Insulin dosing was designed to control the early rise in plasma glucose (PG) but also to elicit hypoglycemia in the later phase. During +Gn, glucagon was co-administered with insulin at a fixed molar ratio. At the two visits, fasting PG was similar (-Gn 121±5, +Gn 119±6 mg/dl) and the initial meal-induced PG elevation (0-3h) was indistinguishable whether glucagon was present or not (peak PG -Gn 224±18, +Gn 228±15 mg/dl; ΔPG 0-180AUC -Gn 10501±3014, +Gn 11537±1778 mg.min/dl). During the latter phase (3-6h), 7/11 -Gn subjects experienced an excessive fall in PG to <80mg/dl with 5/11 dropping to 50mg/dl requiring IV glucose rescue (by protocol). During +Gn, the fall in PG was attenuated in all cases with a significant difference observed in PG nadir (-Gn 51.1±4.0, +Gn100.5±11.0 mg/dl; p=0.007). Appropriate elevations in plasma insulin and glucagon were observed in keeping with study design. To conclude, it is feasible that insulin and glucagon can be co-administered under specific conditions allowing protection against insulin-induced hypoglycemia without impeding hyperglycemic control. This unique observation offers insight into novel approaches to glucose control in diabetes. Disclosure B.W. Bode: Advisory Panel; Self; Medtronic, Novo Nordisk A/S. Consultant; Self; Eli Lilly and Company, Medtronic, Novo Nordisk A/S. Research Support; Self; Abbott, Advance, Boehringer Ingelheim Pharmaceuticals, Inc., Dexcom, Inc., Diasome Pharmaceuticals, Inc., Eli Lilly and Company, Insulet Corporation, Janssen Pharmaceuticals, Inc., MannKind Corporation, Medtronic, National Institutes of Health, Nova Biomedical, Novo Nordisk A/S, Provention Bio, Inc., Sanofi, Senseonics. Speaker’s Bureau; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Janssen Pharmaceuticals, Inc., MannKind Corporation, Medtronic, Novo Nordisk A/S, Sanofi, Senseonics. Stock/Shareholder; Self; Aseko. J. Boyd: None. A. Shah: Consultant; Self; Abvance Therapeutics. Stock/Shareholder; Spouse/Partner; Fractyl Laboratories, Inc. D. Parkes: Consultant; Self; Abvance Therapeutics, Fractyl Laboratories, Inc., Prolynx, ProSciento. S. Ghosh: Consultant; Self; Abvance Therapeutics, Fractyl Laboratories, Inc., Takeda Pharmaceutical Company Limited. A.D. Cherrington: Advisory Panel; Self; Biocon, Fractyl Laboratories, Inc., Metavention, Sekkei Bio, Sensulin, LLC., vTv Therapeutics, Zafgen, Inc. Consultant; Self; Thetis Pharmaceuticals LLC. Research Support; Self; Diasome Pharmaceuticals, Inc. Other Relationship; Self; Abvance Therapeutics, Novo Nordisk Inc.

There is growing evidence that peptidic glucagon-like peptide-1 receptor agonists (GLP-1RA), such as exenatide, may provide useful therapeutic options for treatment of feline diabetes. However, because such drugs are administered subcutaneously, it is desirable that they be long-acting and not require frequent injections. We have developed a chemically controlled delivery system to support half-life extension of peptidic therapeutics. Here, the peptide is covalently attached to hydrogel microspheres by a self-cleaving β-eliminative linker; after subcutaneous injection of the microspheres, the peptide is slowly released from the depot to the systemic circulation. Using this technology, we developed a delivery system that supports once-monthly administration of a stable exenatide analog, [Gln28]exenatide, in rodents (Schneider, et al, ACS Chem Biol 12, 2107 to 2116, 2017). The purposes of the present study were a) to demonstrate pharmacokinetic and pharmacodynamic similarities of the deamidation-sensitive GLP-1RA exenatide and the closely related, more stable [Gln28]exenatide and b) to develop a long-acting GLP-1RA in cats. The results show that exenatide and [Gln28]exenatide injected intravenously or subcutaneously at 10 μg/kg have nearly identical pharmacokinetics in the cat-both having elimination half-lives of ∼40 min-but subcutaneously administered [Gln28]exenatide has superior bioavailability-93% for [Gln28]exenatide vs 52% for exenatide. The results also show that exenatide and [Gln28]exenatide have similar insulinotropic activities in the cat during a high-dose intravenous glucose tolerance test; they increased the area under the curve (AUC) for insulin to a similar extent but had no effect on glucose AUC. Finally, subcutaneous injection of a microsphere-[Gln28]exenatide conjugate containing an appropriate self-cleaving linker in the cat provides plasma [Gln28]exenatide with a half-life of about 40 d vs 40 min with the injected free peptide. Hence, the large body of information available for exenatide can be used to facilitate clinical development of [Gln28]exenatide as a treatment for feline diabetes, and the microsphere-[Gln28]exenatide conjugate is quite suitable for once-monthly subcutaneous administration of the peptide in the cat.

Insulin resistance increases renal oxidant production by upregulating NADPH oxidase 4 (Nox4) expression contributing to oxidative damage and ultimately albuminuria. Inhibition of the renin‐angiotensin system (RAS) and activation of glucagon‐like peptide‐1 (GLP‐1) receptor signalling may reverse this effect. However, whether angiotensin receptor type 1 (AT1) blockade and GLP‐1 receptor activation improve oxidative damage and albuminuria through different mechanisms is not known. Using insulin‐resistant Otsuka Long‐Evans Tokushima Fatty (OLETF) rats, we tested the hypothesis that simultaneous blockade of AT1 and activation of GLP‐1r additively decrease oxidative damage and urinary albumin excretion (U alb V) in the following groups: (a) untreated, lean LETO (n = 7), (b) untreated, obese OLETF (n = 9), (c) OLETF + angiotensin receptor blocker (ARB; 10 mg olmesartan/kg/d; n = 9), (d) OLETF + GLP‐1 mimetic (EXE; 10 µg exenatide/kg/d; n = 7) and (e) OLETF + ARB +exenatide (Combo; n = 6). Mean kidney Nox4 protein expression and nitrotyrosine (NT) levels were 30% and 46% greater, respectively, in OLETF compared with LETO. Conversely, Nox4 protein expression and NT were reduced to LETO levels in ARB and EXE, and Combo reduced Nox4, NT and 4‐hydroxy‐2‐nonenal levels by 21%, 27% and 27%, respectively. At baseline, U alb V was nearly double in OLETF compared with LETO and increased to nearly 10‐fold greater levels by the end of the study. Whereas ARB (45%) and EXE (55%) individually reduced U alb V, the combination completely ameliorated the albuminuria. Collectively, these data suggest that AT1 blockade and GLP‐1 receptor activation reduce renal oxidative damage similarly during insulin resistance, whereas targeting both signalling pathways provides added benefit in restoring and/or further ameliorating albuminuria in a model of diet‐induced obesity.

SUMMARY The intestine adapts to local nutrient exposure, but little is known about the effect of high-fat diets (HFDs) on topographically distinct segments of the gut. Here, we show obesogenic diets induce different effects on proximal versus distal intestinal mucosa in vivo and mouse and human organoid models. Notably, we demonstrate proximal gut hyperplasia and distal gut hypoplasia in response to HFD in rodents and show that surgical and pharmacologic interventions that circumvent this altered mucosal physiology improve glucose metabolism. In addition, organoids derived from the duodenum of mice or humans demonstrate increased stemness (self-renewal and differentiation) and growth response to increasing amounts of lipid or glucose, while ileal organoids displayed a functionally different and often opposite growth response profile. These results highlight the important role of the small intestinal mucosa in regulating metabolic homeostasis in health and disease and open new avenues and therapeutic approaches to treat metabolic diseases. GRAPHICAL ABSTRACT

Obesity is associated with an inappropriately activated renin–angiotensin–aldosterone system, suppressed glucagon-like peptide-1 (GLP-1), increased renal Na+ reabsorption, and hypertension. To assess the link between GLP-1 and angiotensin receptor type 1 (AT1) signaling on obesity-associated impairment of urinary Na+ excretion (UNaV) and elevated arterial pressure, we measured mean arterial pressure (MAP) and heart rate by radiotelemetry and metabolic parameters for 40 days. We tested the hypothesis that stimulation of GLP-1 signaling provides added benefit to blockade of AT1 by increasing UNaV and further reducing arterial pressure in the following groups: (1) untreated Long–Evans Tokushima Otsuka (LETO) rats (n = 7); (2) untreated Otsuka Long–Evans Tokushima Fatty (OLETF) rats (n = 9); (3) OLETF + ARB (ARB; 10 mg olmesartan/kg/day; n = 9); (4) OLETF + GLP-1 receptor agonist (EXE; 10 µg exenatide/kg/day; n = 7); and (5) OLETF + ARB + EXE (Combo; n = 6). On day 2, UNaV was 60% and 62% reduced in the EXE and Combo groups, respectively, compared with that in the OLETF rats. On day 40, UNaV was increased 69% in the Combo group compared with that in the OLETF group. On day 40, urinary angiotensinogen was 4.5-fold greater in the OLETF than in the LETO group and was 56%, 62%, and 58% lower in the ARB, EXE, and Combo groups, respectively, than in the OLETF group. From day 2 to the end of the study, MAP was lower in the ARB and Combo groups than in the OLETF rats. These results suggest that GLP-1 receptor activation may reduce intrarenal angiotensin II activity, and that simultaneous blockade of AT1 increases UNaV in obesity; however, these beneficial effects do not translate to a further reduction in MAP.

Obesity is associated with the inappropriate activation of the renin-angiotensin system (RAS), which increases arterial pressure, impairs insulin secretion and decreases peripheral tissue insulin sensitivity. RAS blockade reverses these detriments; however, it is not clear whether the disease state of the organism and treatment duration determine the beneficial effects of RAS inhibition on insulin secretion and insulin sensitivity. Therefore, the objective of this study was to compare the benefits of acute vs chronic angiotensin receptor type 1 (AT 1 ) blockade started after the onset of obesity, hyperglycemia and hypertension on pancreatic function and peripheral insulin resistance. We assessed adipocyte morphology, glucose intolerance, pancreatic redox balance and insulin secretion after 2 and 11 weeks of AT 1 blockade in the following groups of rats: (1) untreated Long-Evans Tokushima Otsuka (lean control; n = 10), (2) untreated Otsuka Long-Evans Tokushima Fatty (OLETF; n = 12) and (3) OLETF + ARB (ARB; 10 mg olmesartan/kg/day by oral gavage; n = 12). Regardless of treatment duration, AT 1 blockade decreased systolic blood pressure and fasting plasma triglycerides, whereas chronic AT 1 blockade decreased fasting plasma glucose, glucose intolerance and the relative abundance of large adipocytes by 22, 36 and 70%, respectively. AT 1 blockade, however, did not improve pancreatic oxidative stress or reverse impaired insulin secretion. Collectively, these data show that AT 1 blockade after the onset of obesity, hyperglycemia and hypertension improves peripheral tissue insulin sensitivity, but cannot completely reverse the metabolic derangement characterized by impaired insulin secretion once it has been compromised.

We have developed a chemically controlled very long-acting delivery system to support once-monthly administration of a peptidic GLP-1R agonist. Initially, the prototypical GLP-1R agonist exenatide was covalently attached to hydrogel microspheres by a self-cleaving β-eliminative linker; after subcutaneous injection in rats, the peptide was slowly released into the systemic circulation. However, the short serum exenatide half-life suggested its degradation in the subcutaneous depot. We found that exenatide undergoes deamidation at Asn28 with an in vitro and in vivo half-life of approximately 2 weeks. The [Gln28]exenatide variant and exenatide showed indistinguishable GLP-1R agonist activities as well as pharmacokinetic and pharmacodynamic effects in rodents; however, unlike exenatide, [Gln28]exenatide is stable for long periods. Two different hydrogel-[Gln28]exenatide conjugates were prepared using β-eliminative linkers with different cleavage rates. After subcutaneous injection in rodents, the serum half-lives for the released [Gln28]exenatide from the two conjugates were about 2 weeks and one month. Two monthly injections of the latter in the Zucker diabetic fatty rat showed pharmacodynamic effects indistinguishable from two months of continuously infused exenatide. Pharmacokinetic simulations indicate that the delivery system should serve well as a once-monthly GLP-1R agonist for treatment of type 2 diabetes in humans.

SummaryObjectiveCo‐administration of amylin and leptin induces synergistic and clinically meaningful (>10%) weight loss that is attenuated as the degree of obesity increases. We explored whether calorie restriction (CR) could restore amylin/leptin synergy in very obese rats.MethodsSprague Dawley rats on high‐fat diet (696 ± 8 g, n = 72) were randomized to three cohorts (C1–C3). Rats in C1 were administered vehicle, rat amylin (50 µg kg−1 d−1), murine leptin (125 µg kg−1 d−1) or amylin and leptin for 28 days (n = 6 per group) via subcutaneous minipump. Simultaneously, C2 and C3 rats initiated CR. After moderate (12.4 ± 0.3%, 86.7 ± 2.8 g; C2) or severe (24.9 ± 0.3%, 172.7 ± 4.7 g; C3) weight loss, amylin and/or leptin was administered as described.ResultsIn C1, leptin did not alter weight, and amylin induced 40.2 ± 6.1 g weight loss (−6.0 ± 0.9%), which was not enhanced by leptin (44.4 ± 4.9 g, −6.1 ± 0.8%). In C2, vehicle‐treated (75.1 ± 7.8 g weight change from start of treatment, 1.1 ± 0.8% difference from start of pre‐CR phase) and leptin‐treated rats (68.6 ± 9.2 g, −1.3 ± 1.0%) rebounded to pre‐restriction weight that was attenuated by amylin (29.2 ± 11.4 g, −6.2 ± 0.7%). Leptin did not enhance the effect of amylin (22.8 ± 11.7 g, −8.3 ± 1.5%). In C3, vehicle‐treated and leptin‐treated rats regained most of their weight (161.9 ± 11.8, −2.3 ± 0.8% and 144.6 ± 9.5 g, −2.3 ± 0.9%, respectively), which was attenuated by amylin (91.1 ± 16.8 g, −11.2 ± 0.7%), but not enhanced by leptin (83.0 ± 7.6 g, −10.7 ± 0.8%).ConclusionsExtreme obesity associated with leptin resistance perturbs amylin/leptin weight loss synergy in rats, which cannot be restored by pre‐treatment weight loss.

Amylin is a pancreatic β-cell hormone that produces effects in several different organ systems. Here, we review the literature in rodents and in humans on amylin research since its discovery as a hormone about 25 years ago. Amylin is a 37-amino-acid peptide that activates its specific receptors, which are multisubunit G protein–coupled receptors resulting from the coexpression of a core receptor protein with receptor activity–modifying proteins, resulting in multiple receptor subtypes. Amylin’s major role is as a glucoregulatory hormone, and it is an important regulator of energy metabolism in health and disease. Other amylin actions have also been reported, such as on the cardiovascular system or on bone. Amylin acts principally in the circumventricular organs of the central nervous system and functionally interacts with other metabolically active hormones such as cholecystokinin, leptin, and estradiol. The amylin-based peptide, pramlintide, is used clinically to treat type 1 and type 2 diabetes. Clinical studies in obesity have shown that amylin agonists could also be useful for weight loss, especially in combination with other agents.

Aim To test the impact of cholecystokinin ( CCK ) plus either amylin or a glucagon‐like peptide‐1 receptor ( GLP‐1R ) agonist on metabolic variables in diet‐induced obese ( DIO ) rodents. Methods A stabilized acetylated version of CCK ‐8 (Ac‐Y*‐ CCK ‐8), selective CCK1 receptor ( CCK1R ) or CCK2 receptor ( CCK2R ) agonists, amylin or the GLP‐1R agonist and exenatide analogue AC3174 were administered in select combinations via continuous subcutaneous infusion to DIO rats for 14 days, or Lep ob /Lep ob mice for 28 days, and metabolic variables were assessed. Results Combined administration of Ac‐Y*‐ CCK ‐8 with either amylin or AC3174 induced greater than additive weight loss in DIO rats, with the overall magnitude of effect being greater with AC3174 + Ac‐Y*‐ CCK ‐8 treatment. Co‐infusion of AC3174 with a specific CCK1R agonist, but not a CCK2R agonist, recapitulated the weight loss mediated by AC3174 + Ac‐Y*‐ CCK ‐8 in DIO rats, suggesting that synergy is mediated by CCK1R activation. In a 4 × 4 full‐factorial response surface methodology study in DIO rats, a synergistic interaction between AC3174 and the CCK1R ‐selective agonist on body weight and food intake was noted. Co‐administration of AC3174 and the CCK1R ‐selective agonist to obese diabetic Lep ob /Lep ob mice elicited a significantly greater reduction in percentage of glycated haemoglobin and food intake relative to the sum effects of monotherapy groups. Conclusions The anti‐obesity and antidiabetic potential of combined GLP‐1R and CCK1R agonism is an approach that warrants further investigation.

The combined glucose-lowering effect of exenatide and dapagliflozin has not yet been studied. We investigated this combination (single-dose or 4-week dosing) in diabetic ob/ob mice. Vehicle-corrected basal glucose showed greater reduction 1 h following exenatide + dapagliflozin than with exenatide or dapagliflozin alone, and stayed significantly lower for all groups versus vehicle over 3 h. During an oral glucose tolerance test, glucose excursion (30 min post-dose) was significantly lower for exenatide + dapagliflozin versus exenatide or dapagliflozin, or vehicle. Exenatide + dapagliflozin and exenatide, but not dapagliflozin alone, reduced glucose excretion over 24 h versus vehicle. After dosing for 4 weeks, exenatide, dapagliflozin and exenatide + dapagliflozin similarly decreased haemoglobin A1c (HbA1c). Body weight was reduced only with exenatide or exenatide + dapagliflozin. The glomerular filtration rate was similar with exenatide, dapagliflozin and vehicle, and increased with exenatide + dapagliflozin. Optimized combinatorial dosing of these antidiabetic agents may provide additive glucose lowering in type 2 diabetes mellitus.

AimGlucose-dependent insulinotropic peptide (GIP) is an incretin hormone that is released from intestinal K cells in response to nutrient ingestion. We aimed to investigate the therapeutic potential of the novel N- and C-terminally modified GIP analogue AC163794.MethodsAC163794 was synthesized by solid-phase peptide synthesis. Design involved the substitution of the C-terminus tail region of the dipeptidyl peptidase IV (DPP-IV)-resistant GIP analogue [d-Ala(2)]GIP(1-42) with the unique nine amino acid tail region of exenatide. The functional activity and binding of AC163794 to the GIP receptor were evaluated in RIN-m5F -cells. In vitro metabolic stability was tested in human plasma and kidney membrane preparations. Acute insulinotropic effects were investigated in isolated mouse islets and during an intravenous glucose tolerance test in normal and diabetic Zucker fatty diabetic (ZDF) rats. The biological actions of AC163794 were comprehensively assessed in normal, ob/ob and high-fat-fed streptozotocin (STZ)-induced diabetic mice. Acute glucoregulatory effects of AC163794 were tested in diet-induced obese mice treated subchronically with AC3174, the exendatide analogue [Leu(14)] exenatide. Human GIP or [d-Ala(2)]GIP(1-42) were used for comparison.ResultsAC163794 exhibited nanomolar functional GIP receptor potency in vitro similar to GIP and [d-Ala(2)]GIP(1-42). AC163794 was metabolically more stable in vitro and displayed longer duration of insulinotropic action in vivo versus GIP and [d-Ala(2)]GIP(1-42). In diabetic mice, AC163794 improved HbA1c through enhanced insulinotropic action, partial restoration of pancreatic insulin content and improved insulin sensitivity with no adverse effects on fat storage and metabolism. AC163794 provided additional baseline glucose-lowering when injected to mice treated with AC3174.ConclusionsThese studies support the potential use of a novel GIP analogue AC163794 for the treatment of type 2 diabetes.