Endogenous Glucose-dependent Insulinotropic Polypeptide Research Articles

GIP receptor antagonism eliminates paradoxical growth hormone secretion in some patients with acromegaly.

About 30% of patients with active acromegaly experience paradoxically increased growth hormone (GH) secretion during the diagnostic oral glucose tolerance test (OGTT). Endogenous glucose-dependent insulinotropic polypeptide (GIP) is implicated in this paradoxical secretion. We used the GIP receptor (GIPR) antagonist GIP(3-30)NH2 to test the hypothesis that GIP mediates this paradoxical response when GIPR is abundantly expressed in somatotropinomas. 25 treatment-naïve patients with acromegaly were enrolled. Each patient underwent one OGTT during simultaneous placebo infusion and one OGTT during a GIP(3-30)NH2 infusion. Blood samples were drawn at baseline and regularly after infusions to measure GH. We assessed pituitary adenoma size by magnetic resonance imaging and GIPR expression by immunohistochemistry on resected somatotropinomas. For mechanistic confirmation, we applied in vitro and ex vivo approaches. The effect of GIP(3-30)NH2 on paradoxical GH secretion during OGTT as a measure of GIP involvement. In four of seven patients with paradoxical GH secretion, GIP(3-30)NH2 infusion completely abolished the paradoxical response (P = 0.0003). Somatotrophs were available from three of four of these patients, all showing abundant GIPR expression. Adenoma size did not differ between patients with and without paradoxical GH secretion. Of 25 patients with acromegaly, seven had paradoxical GH secretion during OGTT, and pharmaceutical GIPR blockade abolished this secretion in four. Corresponding somatotroph adenomas abundantly expressed GIPR, suggesting a therapeutic target in this subpopulation of patients. In vitro and ex vivo analyses confirmed the role of GIP and the effects of the antagonist.

Sitagliptin elevates plasma and CSF incretin levels following oral administration to nonhuman primates: relevance for neurodegenerative disorders

The endogenous incretins glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) possess neurotrophic, neuroprotective, and anti-neuroinflammatory actions. The dipeptidyl peptidase 4 (DPP-4) inhibitor sitagliptin reduces degradation of endogenous GLP-1 and GIP, and, thereby, extends the circulation of these protective peptides. The current nonhuman primate (NHP) study evaluates whether human translational sitagliptin doses can elevate systemic and central nervous system (CNS) levels of GLP-1/GIP in naive, non-lesioned NHPs, in line with our prior rodent studies that demonstrated sitagliptin efficacy in preclinical models of Parkinson’s disease (PD). PD is an age-associated neurodegenerative disorder whose current treatment is inadequate. Repositioning of the well-tolerated and efficacious diabetes drug sitagliptin provides a rapid approach to add to the therapeutic armamentarium for PD. The pharmacokinetics and pharmacodynamics of 3 oral sitagliptin doses (5, 20, and 100 mg/kg), equivalent to the routine clinical dose, a tolerated higher clinical dose and a maximal dose in monkey, were evaluated. Peak plasma sitagliptin levels were aligned both with prior reports in humans administered equivalent doses and with those in rodents demonstrating reduction of PD associated neurodegeneration. Although CNS uptake of sitagliptin was low (cerebrospinal fluid (CSF)/plasma ratio 0.01), both plasma and CSF concentrations of GLP-1/GIP were elevated in line with efficacy in prior rodent PD studies. Additional cellular studies evaluating human SH-SY5Y and primary rat ventral mesencephalic cultures challenged with 6-hydroxydopamine, established cellular models of PD, demonstrated that joint treatment with GLP-1 + GIP mitigated cell death, particularly when combined with DPP-4 inhibition to maintain incretin levels. In conclusion, this study provides a supportive translational step towards the clinical evaluation of sitagliptin in PD and other neurodegenerative disorders for which aging, similarly, is the greatest risk factor.

The Gut-Bone Axis in Diabetes.

To describe recent advances in the understanding of how gut-derived hormones regulate bone homeostasis in humans with emphasis on pathophysiological and therapeutic perspectives in diabetes. The gut-derived incretin hormone glucose-dependent insulinotropic polypeptide (GIP) is important for postprandial suppression of bone resorption. The other incretin hormone, glucagon-like peptide 1 (GLP-1), as well as the intestinotrophic glucagon-like peptide 2 (GLP-2) has been shown to suppress bone resorption in pharmacological concentrations, but the role of the endogenous hormones in bone homeostasis is uncertain. For ambiguous reasons, both patients with type 1 and type 2 diabetes have increased fracture risk. In diabetes, the suppressive effect of endogenous GIP on bone resorption seems preserved, while the effect of GLP-2 remains unexplored both pharmacologically and physiologically. GLP-1 receptor agonists, used for the treatment of type 2 diabetes and obesity, may reduce bone loss, but results are inconsistent. GIP is an important physiological suppressor of postprandial bone resorption, while GLP-1 and GLP-2 may also exert bone-preserving effects when used pharmacologically. A better understanding of the actions of these gut hormones on bone homeostasis in patients with diabetes may lead to new strategies for the prevention and treatment of skeletal frailty related to diabetes.

Endogenous Glucose-Dependent Insulinotropic Polypeptide Contributes to Sitagliptin-Mediated Improvement in β-Cell Function in Patients With Type 2 Diabetes.

Dipeptidyl peptidase 4 (DPP-4) degrades the incretin hormones glucagon-like peptide 1 and glucose-dependent insulinotropic polypeptide (GIP). DPP-4 inhibitors improve glycemic control in type 2 diabetes, but the importance of protecting GIP from degradation for their clinical effects is unknown. We included 12 patients with type 2 diabetes (mean ± SD BMI 27 ± 2.6 kg/m2, HbA1c 7.1 ± 1.4% [54 ± 15 mmol/mol]) in this double-blind, placebo-controlled, crossover study to investigate the contribution of endogenous GIP to the effects of the DPP-4 inhibitor sitagliptin. Participants underwent two randomized, 13-day treatment courses of sitagliptin (100 mg/day) and placebo, respectively. At the end of each treatment period, we performed two mixed-meal tests with infusion of the GIP receptor antagonist GIP(3-30)NH2 (1,200 pmol/kg/min) or saline placebo. Sitagliptin lowered mean fasting plasma glucose by 1.1 mmol/L compared with placebo treatment. During placebo treatment, postprandial glucose excursions were increased during GIP(3-30)NH2 compared with saline (difference in area under the curve ± SEM 7.3 ± 2.8%) but were unchanged during sitagliptin treatment. Endogenous GIP improved β-cell function by 37 ± 12% during DPP-4 inhibition by sitagliptin. This was determined by the insulin secretion rate/plasma glucose ratio. We calculated an estimate of the absolute sitagliptin-mediated impact of GIP on β-cell function as the insulinogenic index during sitagliptin treatment plus saline infusion minus the insulinogenic index during sitagliptin plus GIP(3-30)NH2. This estimate was expressed relative to the maximal potential contribution of GIP to the effect of sitagliptin (100%), defined as the difference between the full sitagliptin treatment effect, including actions mediated by GIP (sitagliptin + saline), and the physiological response minus any contribution by GIP [placebo treatment + GIP(3-30)NH2]. We demonstrate insulinotropic and glucose-lowering effects of endogenous GIP in patients with type 2 diabetes and that endogenous GIP contributes to the improved β-cell function observed during DPP-4 inhibition.

357-OR: Improved Glycemic Control in Persons with Type 2 Diabetes Improves Beta-Cell Actions of Endogenous Glucose-Dependent Insulinotropic Polypeptide

The insulinotropic effect of exogenous glucose-dependent insulinotropic polypeptide (GIP) is severely reduced or even absent in persons with type 2 diabetes but may be partly regained following improved glycemic control. Here, we examined the beta cell response to endogenous GIP before and after a period of plasma glucose (PG) normalization. In a randomized, double-blind design, 15 metformin-treated persons with dysregulated type 2 diabetes (HbA1c 8.3±0.3% (67±3 mmol/mol) ([mean±SEM]) were subjected to two 75 g-oral glucose tolerance tests (OGTT) with continuous infusions of GIP receptor antagonist (GIP (3-30) NH2) and placebo (saline) , respectively, before and in the end of a 3-4 week period of PG normalization achieved using administration of empagliflozin and individually dosed insulin based on continuous glucose monitoring (CGM) (fasting PG (FPG) target: 72-1mg/mL (4.0-5.9 mmol/L) ; 2-hour postprandial PG target: <162 mg/mL (<9.0 mmol/L)) . At the end of the PG normalization period, FPG was reduced from 195±mg/mL (10.8±0.6 mmol/L) to 114±4 mg/mL (6.3±0.2 mmol/L) (P<0.001) and area under curve (AUC) for PG during OGTT diminished (3,409±95 vs. 2,428±91 mmol/L×min, P<0.001) . Before the period of PG normalization, GIP (3-30) NH2 did not affect oral glucose tolerance. PG normalization amplified GIP (3-30) NH2-induced lowering of beta cell glucose sensitivity (∆baseline-subtracted AUCplasma C-peptide:PG ratio: 1,579±380 vs. 3,296±617 pmol/mmol×min, P=0.021) and resulted in a significant effect of GIP (3-30) NH2 on oral glucose tolerance (baseline-subtracted AUCPG: 1,146±65 vs. 1,225±58 mmol/L×min, P=0.025) . In persons with dysregulated type 2 diabetes, a period of PG normalization increased beta cell sensitivity to GIP, translating into a detectable contribution of endogenous GIP to oral glucose tolerance. Disclosure B.Hoe: None. F.K.Knop: Advisory Panel; Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novo Nordisk, Sanofi, ShouTi, Zucara Therapeutics, Consultant; AstraZeneca, Eli Lilly and Company, Novo Nordisk, Pharmacosmos A/S, Sanofi, ShouTi, Zealand Pharma A/S, Zucara Therapeutics, Research Support; AstraZeneca, Novo Nordisk, Sanofi, Zealand Pharma A/S, Speaker's Bureau; AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk, Sanofi, Stock/Shareholder; Antag Therapeutics. M.B.Lynggaard: None. L.S.Gasbjerg: Speaker's Bureau; Eli Lilly and Company, Stock/Shareholder; Antag Therapeutics. M.M.Helsted: None. S.Stensen: Employee; Novo Nordisk A/S. B.Hartmann: Board Member; Bainan Biotech. J.J.Holst: Advisory Panel; Novo Nordisk, Board Member; Antag Therapeutics, Bainan Biotech. M.B.Christensen: None. T.Vilsbøll: Consultant; AstraZeneca, Bristol-Myers Squibb Company, Eli Lilly and Company, Gilead Sciences, Inc., GlaxoSmithKline plc., Merck Sharp & Dohme Corp., Mundipharma, Novo Nordisk, Sun Pharmaceutical Industries Ltd. Funding The Novo Nordisk Foundation

1362-P: Endogenous Glucose-Dependent Insulinotropic Polypeptide Facilitates Postprandial Intestinal Lipid Uptake in Healthy Men, but Not in Patients with Type 2 Diabetes

The gut hormone glucose-dependent insulinotropic polypeptide (GIP) stimulates glucose-induced insulin secretion and increases triglyceride deposition in subcutaneous adipose tissue, and these effects are attenuated in both type 2 diabetes (T2D) and obesity. Using the GIP receptor antagonist GIP (3-30) NH2, we investigated the effect of endogenous GIP on circulating lipoproteins (chylomicrons, VLDL, LDL, HDL) during a meal in healthy men and patients with T2D. We measured apolipoprotein B48 (ApoB48) (as a marker of chylomicron count) and plasma lipoprotein triglyceride and cholesterol content during two liquid meal tests (1,894 kJ) with double-blind infusions of GIP (3-30) NH2 or placebo (saline) in randomized order in 12 healthy men (19-65 years, BMI 20.3-25.5 kg/m2) and in patients with T2D (44-72 years, HbA1c 6.2-11% (37-70 mmol/mol) , BMI 27.4-41.2 kg/m2) . Compared to placebo, the GIP (3-30) NH2 infusion lowered postprandial responses of ApoB48 (incremental area under the curve (iAUC0-180 min) (median (95%CI)) : 215 (156-258) vs. 4 (363-541) mg×L-1×min, P=0.0049) , chylomicron-triglyceride content (iAUC0-270 min: 32.7 (-2.32-72.1) vs. 49.5 (1.21-170) mmol× L-1×min P=0.083) and HDL-triglyceride content (iAUC0-270min: -0.90 (-1.95-0.18) vs. 0.95 (-0.72-3.95) mmol× L-1×min, P=0.016) . In patients with T2D, infusion of GIP (3-30) NH2 did not change postprandial responses of ApoB48 or lipoprotein-triglyceride content. In both groups, there were no differences in lipoprotein-cholesterol contents. Disclosure L.S.Gasbjerg: Speaker's Bureau; Eli Lilly and Company, Stock/Shareholder; Antag Therapeutics. C.Christoffersen: None. F.K.Knop: Advisory Panel; Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novo Nordisk, Sanofi, ShouTi, Zucara Therapeutics, Consultant; AstraZeneca, Eli Lilly and Company, Novo Nordisk, Pharmacosmos A/S, Sanofi, ShouTi, Zealand Pharma A/S, Zucara Therapeutics, Research Support; AstraZeneca, Novo Nordisk, Sanofi, Zealand Pharma A/S, Speaker's Bureau; AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk, Sanofi, Stock/Shareholder; Antag Therapeutics. M.M.Rosenkilde: Research Support; Antag Therapeutics, Bainan Biotech, Stock/Shareholder; Antag Therapeutics, Bainan Biotech, Synklino ApS. M.M.Helsted: None. S.Stensen: Employee; Novo Nordisk A/S. L.S.L.Krogh: None. A.H.Sparre-ulrich: Other Relationship; Antag Therapeutics. B.Hartmann: Board Member; Bainan Biotech. T.Vilsbøll: Consultant; AstraZeneca, Bristol-Myers Squibb Company, Eli Lilly and Company, Gilead Sciences, Inc., GlaxoSmithKline plc., Merck Sharp & Dohme Corp., Mundipharma, Novo Nordisk, Sun Pharmaceutical Industries Ltd. M.B.Christensen: None. J.J.Holst: Advisory Panel; Novo Nordisk, Board Member; Antag Therapeutics, Bainan Biotech. Funding EFSD (no. 94815) ; Novo Nordisk Foundation (no. 13777)

The Role of GIP Receptor in the CNS for the Pathogenesis of Obesity.

Glucose-dependent insulinotropic polypeptide (GIP) (also known as gastric inhibitory polypeptide) is a hormone produced in the upper gut and secreted to the circulation in response to the ingestion of foods, especially fatty foods. Growing evidence supports the physiological and pharmacological relevance of GIP in obesity. In an obesity setting, inhibition of endogenous GIP or its receptor leads to decreased energy intake, increased energy expenditure, or both, eventually causing weight loss. Further, supraphysiological dosing of exogenous long-lasting GIP agonists alters energy balance and has a marked antiobesity effect. This remarkable yet paradoxical antiobesity effect is suggested to occur primarily via the brain. The brain is capable of regulating both energy intake and expenditure and plays a critical role in human obesity. In addition, the GIP receptor is widely distributed throughout the brain, including areas responsible for energy homeostasis. Recent studies have uncovered previously underappreciated roles of the GIP receptor in the brain in the context of obesity. This article highlights how the GIP receptor expressed by the brain impacts obesity-related pathogenesis.

85-LB: Glucose-Dependent Insulinotropic Polypeptide (GIP) Contributes Substantially to the Improved Beta-Cell Function during Sitagliptin Treatment in Persons with Type 2 Diabetes

In persons with type 2 diabetes (T2D), dipeptidyl peptidase 4 (DPP-4) inhibitor treatment improves glycemic control by raising the active levels of the insulinotropic gut hormones glucagon-like peptide 1 and glucose-dependent insulinotropic polypeptide (GIP). Using the GIP receptor antagonist GIP(3-30)NH2, we investigated endogenous GIP’s contribution to the insulinotropic effect of DPP-4 inhibition (assessed by insulin secretion rate (ISR) relative to plasma glucose). In a double-blind, placebo-controlled, cross-over study, 12 persons (eight men and four women) with T2D (mean ± SD; BMI 27.4 ± 2.6 kg/m2, HbA1c 7.1 ± 1.4% (54 ± 15 mmol/mol)) underwent two randomized 12-13-day treatment courses with DPP-4 inhibitor (sitagliptin 100 mg once-daily) and placebo, respectively, with an interposed 1-3-week washout period. In the end of each treatment period, two randomized 5-hour liquid mixed-meal tests with infusion of GIP(3-30)NH2 (1,200 pmol/kg/min) or saline (placebo) were performed. During placebo treatment, GIP(3-30)NH2 lowered postprandial serum C-peptide (determined as difference in baseline-subtracted area under curve (ΔbsAUC%) ± SEM: −31 ± 9%, P = 0.005) and increased postprandial plasma glucose excursions (ΔAUC% ± SEM: 7.3 ± 2.8%, P = 0.017) compared to saline. Sitagliptin increased concentrations of active GIP(1-42) (ΔAUC% ± SEM: 153 ± 21%, P < 0.0001) and lowered fasting plasma glucose (mean: 8.7 vs. 7.6 mmol/L, P < 0.0004), whereas postprandial glucose excursions were unchanged compared to placebo treatment. GIP(3-30)NH2 caused a reduction in AUCISR/AUCglucose ratio equivalent to 37 ± 12% of the increments due to sitagliptin. In conclusion, we demonstrate an insulinotropic and glucose-lowering effect of endogenous GIP in persons with T2D and show that endogenous GIP is responsible for more than one third of the improved beta cell function observed during DPP-4 inhibitor treatment. Disclosure S. Stensen: None. L. S. Gasbjerg: Stock/Shareholder; Self; Antag Therapeutics. M. M. Rosenkilde: Board Member; Self; Bainan Biotech, Synklino ApS, Board Member; Spouse/Partner; Antag Therapeutics, Bainan Biotech, Consultant; Self; Antag Therapeutics, Bainan Biotech, Synklino ApS, Stock/Shareholder; Self; Antag Therapeutics, Bainan Biotech, Synklino ApS, Stock/Shareholder; Spouse/Partner; Antag Therapeutics, Bainan Biotech. B. Hartmann: None. T. Vilsbøll: Consultant; Self; Amgen Inc., AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb Company, Gilead Sciences, Inc., Lilly Diabetes, Merck Sharp & Dohme Corp., Mundipharma International, Novo Nordisk, Sanofi, Sun Pharmaceutical Industries Ltd. J. J. Holst: Consultant; Self; Novo Nordisk, Other Relationship; Self; Antag Therapeutics, Bainan Biotech, MSD Corporation, Novo Nordisk, Other Relationship; Spouse/Partner; Antag Therapeutics, Bainan Biotech, Synklino ApS. M. B. Christensen: None. F. K. Knop: Advisory Panel; Self; MSD Corporation, Novo Nordisk A/S, Sanofi, Consultant; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Novo Nordisk A/S, Pharmacosmos, Zealand Pharma A/S, Research Support; Self; Novo Nordisk A/S, Zealand Pharma A/S, Speaker’s Bureau; Self; AstraZeneca, Bayer AG, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, MSD Corporation, Novo Nordisk A/S. Funding European Foundation for the Study of Diabetes/Lilly European Diabetes Research Programme (2018); A.P. Møller Foundation

Effects of endogenous GIP in patients with type 2 diabetes.

The insulinotropic effect of exogenous, intravenously infused glucose-dependent insulinotropic polypeptide (GIP) is impaired in patients with type 2 diabetes. We evaluated the effects of endogenous GIP in relation to glucose and bone metabolism in patients with type 2 diabetes using a selective GIP receptor antagonist and hypothesized that the effects of endogenous GIP were preserved. A randomized, double-blinded, placebo-controlled, crossover study. Ten patients with overweight/obesity and type 2 diabetes (mean±s.d.; HbA1c 52 ± 11 mmol/mol; BMI 32.5 ± 4.8 kg/m2) were included. We infused a selective GIP receptor antagonist, GIP(3-30)NH2 (1200 pmol/kg/min), or placebo (saline) during two separate, 230-min, standardized, liquid mixed meal tests followed by a meal ad libitum. Subcutaneous adipose tissue biopsies were analyzed. Compared with placebo, GIP(3-30)NH2 reduced postprandial insulin secretion (Δbaseline-subtracted area under the curve (bsAUC)C-peptide% ± s.e.m.; -14 ± 6%, P = 0.021) and peak glucagon (Δ% ± s.e.m.; -11 ± 6%, P = 0.046) but had no effect on plasma glucose (P = 0.692). Suppression of bone resorption (assessed by circulating carboxy-terminal collagen crosslinks (CTX)) was impaired during GIP(3-30)NH2 infusion compared with placebo (ΔbsAUCCTX; ±s.e.m.; -4.9 ± 2 ng/mL × min, P = 0.005) corresponding to a ~50% reduction. Compared with placebo, GIP(3-30)NH2 did not affect plasma lipids, meal consumption ad libitum or adipose tissue triglyceride content. Using a selective GIP receptor antagonist during a meal, we show that endogenous GIP increases postprandial insulin secretion with little effect on postprandial glycaemia but is important for postprandial bone homeostasis in patients with type 2 diabetes.

Recent Medicinal Chemistry Approach for the Development of Dipeptidyl Peptidase IV Inhibitors.

Diabetes, a metabolic disease, occurs due to a decreased or no effect of insulin on the blood glucose level. The current oral medications stimulate insulin release, increase glucose absorption and its utilization, and decrease hepatic glucose output. Two major incretin hormones like Glucose-dependent insulinotropic polypeptide (GIP) and glucagonlike peptide - 1 (GLP-1) stimulate insulin release after a meal, but their action is inhibited by enzyme dipeptidyl peptidase- IV. The activity of endogenous GLP-1 and GIP prolongs and extends with DPP IV inhibitors, which are responsible for the stimulation of insulin secretion and regulation of blood glucose level. DPP IV inhibitors have shown effectiveness and endurability with a neutral effect on weight as well as less chances of hypoglycemia in the management of type 2 diabetes. These journeys started from Sitagliptin (marketed in 2006) to Evogliptin (marketed in 2015, Korea). Treatment of type 2 diabetes includes lifestyle changes, oral medications, and insulin. Newer and superior therapies are needed more than currently prescribed drugs. Various heterocyclic derivatives have been tried, but due to masking of DASH proteins, CYP enzymes, and hERG channel, they showed side effects. Based on these, the study has been focused on the development of safe, influential, selective, and long-lasting inhibitors of DPP IV.

The role of endogenous GIP and GLP-1 in postprandial bone homeostasis

The incretin hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) are well known for their insulinotropic effects and they are thought to affect bone homeostasis as mediators in the so-called entero-osseous axis. We examined the contributions of endogenous GIP and GLP-1, respectively, to postprandial bone homeostasis, in healthy subjects in two randomized and double-blind crossover studies. We included healthy men who received either four oral glucose tolerance tests (OGTTs) (n=18, median age 27 (range 20-70), BMI 27.2 (22.4-37.0) kg/m2) or liquid mixed meal tests (MMTs) (n=12, age 23 (19-65), BMI 23.7 (20.3-25.5) kg/m2) with infusions of 1) the GIP receptor antagonist GIP(3-30)NH2, 2) the GLP-1 receptor antagonist exendin(9-39)NH2, 3) both GIP(3-30)NH2 and exendin(9-39)NH2, or 4) placebo infusions (saline) on four separate visits. Bone resorption was evaluated from levels of circulating carboxy-terminal collagen crosslinks (CTX) and bone formation from levels of procollagen type 1 amino-terminal propeptide (P1NP). During placebo infusions, baseline-subtracted area under the curve values for CTX were -39±5.0 (OGTT) and -57±4.3ng/ml×min (MMT). When GIP(3-30)NH2 was administered, CTX suppression was significantly diminished compared to placebo (-30±4.8 (OGTT) and -45±4.6ng/ml×min (MMT), P=0.0104 and P=0.0288, respectively, compared to placebo. During exendin(9-39)NH2 infusion, CTX suppression after OGTT/MMT was similar to placebo (P=0.28 (OGTT) and P=0.93 (MMT)). The relative contribution of endogenous GIP to postprandial suppression of bone resorption during both OGTT and MMT was similar and reached 22-25%. There were no differences in P1NP concentrations between interventions. In conclusion, endogenous GIP contributes by up to 25% to postprandial suppression of bone resorption in humans whereas an effect of endogenous GLP-1 could not be demonstrated.

89-LB: The Effect of GIP on Plasma Glucose in a Setting of Prandial Insulin Overdose and Physical Activity after Meal Intake in Patients with Type 1 Diabetes

Gluco-regulatory effects of the insulinotropic and glucagonotropic gut hormone glucose-dependent insulinotropic polypeptide (GIP) in type 1 diabetes (T1D) are unclear. We evaluated the effects of exogenous and endogenous GIP on plasma glucose excursions in a setting of prandial insulin over-dose and physical activity after meal ingestion. In a randomized, placebo-controlled, double-blinded, crossover study, 12 men with T1D (age [mean±SD]: 26±6.6 years; BMI: 23±2.3 kg/m2; HbA1c: 6.5±2.7% (48.4±6.3 mmol/mol); diabetes duration: 11.3±5.5 years; plasma C-peptide <200 pmol/L) underwent three separate study days involving a liquid mixed meal test with 125% of regular prandial insulin dose, 30 minutes of intermediate bicycling (60 minutes after mixed-meal), and 270 minute infusions of GIP, the GIP receptor antagonist GIP(3-30)NH2 and placebo, respectively. The GIP infusion attenuated postprandial plasma glucose excursions (Cmax-Cmin) by [mean±SEM] 1.5±0.5 mmol/L and 0.92±0.56 mmol/L compared to GIP(3-30)NH2 and placebo, respectively (P=0.03). Infused glucose needed to avoid plasma glucose <2.5 mmol/L was similar on all 3 study days (P=0.13). In conclusion, GIP infusion seems to attenuate postprandial plasma glucose excursions without significantly increasing the need of glucose to avoid hypoglycemia in patients with T1D. Disclosure B. Hoe: None. S.M. Nguyen Heimbürger: None. L.S. Gasbjerg: Stock/Shareholder; Self; Antag Therapeutics. M.B. Lynggaard: None. B. Hartmann: None. J.J. Holst: Advisory Panel; Self; AstraZeneca, Merck Sharp & Dohme Corp., Novo Nordisk A/S, Zealand Pharma A/S. Other Relationship; Spouse/Partner; Antag Therapeutics. T. Vilsbøll: Advisory Panel; Self; AstraZeneca, Mundipharma International, Novo Nordisk A/S, Sun Pharmaceutical Industries Ltd. Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Lilly Diabetes, Medscape, Merck Sharp & Dohme Corp., Sanofi. A. Lund: Speaker’s Bureau; Self; AstraZeneca, Novo Nordisk A/S, Sanofi. S. Engberg: None. T.F. Dejgaard: Advisory Panel; Self; Novo Nordisk A/S. Consultant; Self; Boehringer Ingelheim International GmbH, Novo Nordisk A/S. Speaker’s Bureau; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Novo Nordisk A/S. M.B. Christensen: None. F.K. Knop: Advisory Panel; Self; AstraZeneca, Merck Sharp & Dohme Corp., Mundipharma International, Novo Nordisk A/S, Sanofi. Consultant; Self; Carmot Therapeutics, Inc., Eli Lilly and Company, Novo Nordisk A/S. Research Support; Self; AstraZeneca, Gubra, Novo Nordisk A/S, Sanofi, Zealand Pharma A/S. Speaker’s Bureau; Self; AstraZeneca, Lupin Pharmaceuticals, Inc., Merck Sharp & Dohme Corp., Norgine B.V., Novo Nordisk A/S. Funding The Leona M. and Harry B. Helmsley Charitable Trust (2018PG-T1D037)

GIP and GLP-1 Receptor Antagonism During a Meal in Healthy Individuals.

The actions of both endogenous incretin hormones during a meal have not previously been characterized. Using specific receptor antagonists, we investigated the individual and combined contributions of endogenous glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) to postprandial glucose metabolism, energy expenditure, and gallbladder motility. Randomized, double-blinded, placebo-controlled, crossover design. On four separate days, four liquid mixed meal tests (1894 kJ) over 270 minutes (min). Twelve healthy male volunteers. Infusions of the GIP receptor antagonist GIP(3-30)NH2 (800 pmol/kg/min), the GLP-1 receptor antagonist exendin(9-39)NH2 (0-20 min: 1000 pmol/kg/min; 20-270 min: 450 pmol/kg/min), GIP(3-30)NH2+exendin(9-39)NH2, or placebo/saline. Baseline-subtracted area under the curve (bsAUC) of C-peptide. Infusion of GIP(3-30)NH2+exendin(9-39)NH2 significantly increased plasma glucose excursions (bsAUC: 261 ± 142 mmol/L × min) during the liquid mixed meals compared with GIP(3-30)NH2 (180 ± 141 mmol/L × min; P = 0.048), exendin(9-39)NH2 (171 ± 114 mmol/L × min; P = 0.046), and placebo (116 ± 154 mmol/L × min; P = 0.015). Correspondingly, C-peptide:glucose ratios during GIP(3-30)NH2+exendin(9-39)NH2 infusion were significantly lower than during GIP(3-30)NH2 (P = 0.0057), exendin(9-39)NH2 (P = 0.0038), and placebo infusion (P = 0.014). GIP(3-30)NH2 resulted in significantly lower AUCs for glucagon than exendin(9-39)NH2 (P = 0.0417). Gallbladder ejection fraction was higher during GIP(3-30)NH2 compared with placebo (P = 0.004). For all interventions, energy expenditure and respiratory quotient were similar. Endogenous GIP and GLP-1 lower postprandial plasma glucose excursions and stimulate insulin secretion but only endogenous GIP affects gallbladder motility. The two incretin hormones potentiate each other's effects in the control of postprandial glycemia in healthy men.

The study of metabolic improvement by nutritional intervention controlling endogenous GIP (Mini Egg study): a randomized, cross-over study

BackgroundGiven the major role of glucose-dependent insulinotropic polypeptide (GIP) in the regulation of adiposity, this study examined the effects induced by a diet based on the Japanese tradition (SMART WASHOKU) on the visceral fat area (VFA) and GIP secretions.MethodsOverweight/obese men (n = 21; mean age, 41.0 ± 9.0 years; mean BMI, 25.2 ± 2.0 kg/m2) without diabetes were placed on either a SMART WASHOKU or control meal for 2 weeks, in a randomized, cross-over setup with a four-week washout period.ResultsFor the meal tolerance test, blood samples were collected at 0, 30, 60, 120, 180, and 240 min post-meal, followed by measuring blood glucose, insulin, GIP, and glucagon-like peptide-1 (GLP-1) levels. Relative to a control meal, SMART WASHOKU meal yielded significantly lower plasma postprandial GIP concentrations (AUC: 700.0 ± 208.0 vs. 1117.0 ± 351.4 pmol/L・4 h, P < 0.05); however, between meals, there was no significant difference in the levels of GLP-1, peptide YY, and ghrelin. Compared to the control meal, SMART WASHOKU intervention significantly reduced VFA and the levels of LDL-cholesterol, triglyceride, and HbA1c after the chronic meal intervention.ConclusionsIn conclusion, a SMART WASHOKU meal may decrease VFA and improve metabolic parameters in overweight/obese men, possibly via suppressing GIP secretion.

64-OR: Postprandial Effects of Endogenous Glucose-Dependent Insulinotropic Polypeptide in Type 2 Diabetes

The incretin hormone glucose-dependent insulinotropic polypeptide (GIP) is released from the small intestine following meal ingestion and potentiates glucose-stimulated insulin secretion. Exogenous GIP has a poor insulinotropic effect in patients with type 2 diabetes (T2D). We investigated postprandial effects of endogenous GIP in patients with T2D using the GIP receptor antagonist, GIP(3-30)NH2. In a randomized, double-blinded, placebo-controlled, cross-over study, 10 patients with T2D (mean±SD; HbA1c 6.9±3.2%; BMI 32.5±4.8 kg/m2) received 250-minute infusions of GIP(3-30)NH2 (1,200 pmol/kg/min) or placebo (saline) during two separate standardized liquid meal tests. Compared with placebo, GIP(3-30)NH2 infusion caused lower postprandial insulin (Δ%±SD; -19±15%, P=0.010) and C-peptide (-14±21%, P=0.021) responses (area under the curve) but had no effect on plasma glucagon (P=0.580) or glucose excursions (P=0.692). Postprandial inhibition of bone resorption (assessed by carboxy-terminal collagen crosslinks) was ∼50% lower during GIP(3-30)NH2 infusion compared with placebo (P=0.005; Figure 1). In conclusion, endogenous GIP slightly reduced postprandial insulin secretion with no effect on postprandial glucagon or glucose concentrations in patients with T2D. In contrast, endogenous GIP was a major determinant of postprandial suppression of bone resorption in these patients. Disclosure S. Stensen: None. L.S. Gasbjerg: Stock/Shareholder; Self; Antag Therapeutics. L.S. Krogh: None. A.H. Sparre-Ulrich: Other Relationship; Self; Antag Therapeutics. K. Skov-Jeppesen: None. M. Jensen: Employee; Self; Antag Therapeutics. B. Hartmann: None. T. Vilsbøll: None. J.J. Holst: Advisory Panel; Self; Novo Nordisk A/S. M.M. Rosenkilde: Consultant; Self; Antag Therapeutics. M.B. Christensen: None. F.K. Knop: Advisory Panel; Self; AstraZeneca, MedImmune, Merck Sharp &amp; Dohme Corp., Mundipharma, Novo Nordisk A/S, Sanofi. Consultant; Self; Amgen Inc., Carmot Therapeutics, Novo Nordisk A/S. Research Support; Self; AstraZeneca, Novo Nordisk A/S. Speaker's Bureau; Self; AstraZeneca, MedImmune, Merck Sharp &amp; Dohme Corp., Mundipharma, Norgine, Novo Nordisk A/S. Funding Novo Nordisk Foundation; European Foundation for the Study of Diabetes

773-P: The Study of Metabolic Improvement by Nutritional Intervention Controlling Endogenous GIP (Mini Egg Study): A Randomized, Double-Blinded, Crossover Study

Objective: Given the major role of glucose-dependent insulinotropic polypeptide (GIP) in the regulation of adiposity, this study examined the effects induced by a diet based on the Japanese tradition (SMART WASHOKU) on the visceral fat area (VFA) and GIP secretions. Research Design and Methods: Overweight/obese men (n=21; mean age: 41 ± 9 y; mean BMI: 25.2 ± 2.0 kg/m2) without diabetes were placed on either a SMART WASHOKU (protein/fat=1.0, fiber/carb ratio≥0.063, and omega-3 PUFA/fat ratio ≥0.054) or isocaloric control meal for two weeks, in a randomized, double-blind, cross-over setup with a four-week washout period. For the meal tolerance test, blood samples were collected at 0, 30, 60, 120, 180, and 240 minutes post-meal, followed by measuring blood glucose, insulin, GIP, and glucagon-like peptide-1 (GLP-1) levels. Results: Relative to a control meal, SMART WASHOKU meal yielded significantly lower plasma postprandial GIP concentrations (AUC: 700.0 ± 208.0 vs. 1117.0 ± 351.4, P &amp;lt; 0.05); however, between meals, there was no significant difference in the levels of GLP-1, PYY, and ghrelin. Relative to control meal, a SMART WASHOKU intervention produced a modest but significant reduction of VFA in our participants (-3.4 ± 12.3 vs. -13.0 ± 9.3 cm2, P &amp;lt; 0.05). Compared with the control meal, SMART WASHOKU meal did not modify the concentrations of AST, ALT, GGT, and hs-CRP; however, we did observe a significantly reduced in the levels of LDL-cholesterol, triglyceride, and HbA1c. Conclusions: Based on our findings, we conclude that in overweight/obese men, a SMART WASHOKU meal would be helpful in decreasing VFA and improving metabolic parameters, possibly via suppressing GIP secretion. Disclosure N. Sakane: Board Member; Spouse/Partner; Kao Corporation. H. Takase: Employee; Self; Kao Corporation. J. Suzuki: Employee; Self; Kao Corporation. C. Suzukamo: Employee; Self; Kao Corporation. S. Nirengi: None. A. Suganuma: None. N. Osaki: Employee; Self; Kao Corporation. Funding Kao Corporation; Japan Society for the Promotion of Science (18K01988); Strategic Innovation Project of Japan (14533567); Bio-oriented Technology Research Advancement Institution, NARO

GIP and GLP-1: Stepsiblings Rather Than Monozygotic Twins Within the Incretin Family.

The importance of the incretin effect for the postprandial augmentation of insulin released has long been recognized (1). However, there has been a long-standing controversy as to the relative importance of the various gastrointestinal hormones in mediating this effect. While earlier studies suggested a contribution of gastrin, secretin, and cholecystokinin (2), it later became obvious that in humans, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) are the predominant incretin hormones (1). Which of the two incretins is the most relevant one is still a matter of debate. Gasbjerg et al. (3) performed studies in healthy human subjects receiving oral glucose loads of 75 g in the fasting state on four different days. The known incretin hormones, GIP and GLP-1, which are secreted in response to glucose administration/absorption, were antagonized with the established peptide receptor antagonist exendin(9-39), blocking the stimulation of GLP-1 receptors, or with the novel GIP receptor antagonist, GIP(3-30)amide, a naturally occurring fragment of intact GIP (full sequence 1–42), which has recently been characterized as a specific GIP receptor antagonist for use in human studies (4). A similar GIP receptor antagonist, GIP(7-30)amide, had previously been used in animal studies but had not been validated for human experiments (5). These incretin receptor antagonists were compared with placebo and used alone and in combination. The result was a slight rise in postload glucose concentrations and a minor reduction in insulin secretory responses, when the GLP-1 receptor was blocked, and a substantial rise in glycemic excursions after the glucose load and a more pronounced reduction in insulin secretory responses, when the recently validated GIP antagonist GIP(3-30)amide was administered at an approximately 1,000-fold excess (∼60 nmol/L) over endogenous peak GIP concentrations (∼60 pmol/L). The combination of exendin(9-39) and GIP(3-30)amide further raised plasma glucose and reduced insulin secretory responses over and above …

Separate and Combined Glucometabolic Effects of Endogenous Glucose-Dependent Insulinotropic Polypeptide and Glucagon-like Peptide 1 in Healthy Individuals.

The incretin hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) are secreted postprandially and contribute importantly to postprandial glucose tolerance. In this study, we assessed the individual and combined contributions of endogenous GIP and GLP-1 to the postprandial changes in glucose and glucoregulatory hormones using the novel GIP receptor antagonist GIP(3-30)NH2 and the well-established GLP-1 receptor antagonist exendin(9-39)NH2 During 4-h oral glucose tolerance tests (75 g) combined with an ad libitum meal test, 18 healthy men received on four separate days in randomized, double-blinded order intravenous infusions of A) GIP(3-30)NH2 (800 pmol/kg/min) plus exendin(9-39)NH2 (0-20 min: 1,000 pmol/kg/min; 20-240 min: 450 pmol/kg/min), B) GIP(3-30)NH2, C) exendin(9-39)NH2, and D) saline, respectively. Glucose excursions were significantly higher during A than during B, C, and D, while glucose excursions during B were higher than during C and D. Insulin secretion (assessed by C-peptide/glucose ratio) was reduced by 37 ± 16% (A), 30 ± 17% (B), and 8.6 ± 16% (C) compared with D (mean ± SD). A and C resulted in higher glucagon levels and faster gastric emptying. In conclusion, endogenous GIP affects postprandial plasma glucose excursions and insulin secretion more than endogenous GLP-1, but the hormones contribute additively to postprandial glucose regulation in healthy individuals.

Postprandial Effects of Individual and Combined GIP and GLP-1 Receptor Antagonization in Healthy Subjects

The gut-derived incretin hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) are known for insulinotropic and glucose-lowering effects. However, their individual roles in postprandial glucose homeostasis are unknown. We infused the GIP receptor antagonist GIP(3-30)NH2 and the GLP-1 receptor antagonist exendin(9-39) during a meal to determine the roles of endogenous GIP and GLP-1 on postprandial glucose metabolism. On four separate days, 12 healthy men (age 19-65 years, BMI 20-25 kg/m2) received a liquid mixed meal test with randomized and double-blinded infusions of GIP(3-30)NH2 (800 pmol/kg/min) + Ex(9-39) (450 pmol/kg/min) (A), GIP(3-30)NH2 (B), Ex(9-39) (C), and saline (D). On Day A, B and C, glucose excursions were significantly increased by 85%, 55% and 15%, respectively, compared to D. Day A and B excursions were significantly higher than C (Figure). Glucagon levels at 60 min differed between Day A and B (11.5±1.2 vs. 7.5±0.6 pmol/l, P=0.01), and Day B and C (11.5±1.2 vs. 12.9±1.5 pmol/l, P=0.008). GLP-1 was higher on Day A (P=0.01) and C (P=0.02) than D. No significant effects on insulin, C-peptide, gastric emptying, or GIP were observed. We conclude that endogenous GIP affects postprandial plasma glucose excursions more pronouncedly than GLP-1, and that both hormones additively contribute to control postprandial glycemia in healthy subjects. Disclosure L.S. Gasbjerg: Stock/Shareholder; Self; Antag Therapeutics. M.M. Helsted: None. A.H. Sparre-Ulrich: Employee; Self; Antag Therapeutics ApS. A.R. Lanng: None. S. Stensen: None. M. Jakobsen: None. B. Hartmann: None. M.B. Christensen: None. J.J. Holst: Advisory Panel; Self; Novo Nordisk A/S. Board Member; Self; Zealand Pharma A/S. Speaker's Bureau; Self; Merck Sharp &amp; Dohme Corp., AstraZeneca. Research Support; Self; Danish Diabetes Academy, Novo Nordisk Foundation. Other Relationship; Self; Antag Therapeutics. Other Relationship; Spouse/Partner; Antag Therapeutics. T. Vilsbøll: Advisory Panel; Self; Amgen Inc., Boehringer Ingelheim GmbH, Eli Lilly and Company, AstraZeneca, MSD K.K., Sanofi, Novo Nordisk A/S. Consultant; Self; Amgen Inc., Boehringer Ingelheim GmbH, Eli Lilly and Company, AstraZeneca, MSD K.K., Sanofi, Novo Nordisk A/S. Speaker's Bureau; Self; Amgen Inc., Boehringer Ingelheim GmbH, Eli Lilly and Company, AstraZeneca, MSD K.K., Sanofi, Novo Nordisk A/S. Research Support; Self; Eli Lilly and Company, Novo Nordisk A/S. M.M. Rosenkilde: Other Relationship; Self; Antag Therapeutics. Advisory Panel; Spouse/Partner; Novo Nordisk A/S. Board Member; Spouse/Partner; Zealand Pharma A/S. Speaker's Bureau; Spouse/Partner; Merck Sharp &amp; Dohme Corp., AstraZeneca. Research Support; Spouse/Partner; Danish Diabetes Academy, Novo Nordisk Foundation. Other Relationship; Spouse/Partner; Antag Therapeutics. F.K. Knop: Advisory Panel; Self; AstraZeneca. Consultant; Self; AstraZeneca. Research Support; Self; AstraZeneca. Speaker's Bureau; Self; AstraZeneca. Advisory Panel; Self; Eli Lilly and Company. Speaker's Bureau; Self; Eli Lilly and Company. Advisory Panel; Self; Amgen Inc.. Speaker's Bureau; Self; Merck Sharp &amp; Dohme Corp.. Advisory Panel; Self; Novo Nordisk A/S. Consultant; Self; Novo Nordisk A/S. Speaker's Bureau; Self; Novo Nordisk A/S. Consultant; Self; Amgen Inc.. Advisory Panel; Self; MedImmune, Sanofi. Consultant; Self; Sanofi. Research Support; Self; Sanofi. Speaker's Bureau; Self; Sanofi.

Effects of MEDI0382 on Pancreatic and Incretin Hormones

MEDI0382, a GLP-1/glucagon dual receptor agonist, is being developed for the treatment of T2DM. GLP-1 receptor agonists promote glucose-dependent insulin release, suppress glucagon, and increase or have minimal effect on glucose-dependent insulinotropic polypeptide (GIP); knowledge of the effect on GLP-1 is limited. We characterized fasting and postprandial hormone profiles associated with MEDI0382 therapy. In a phase 2a study (NCT02548585), 51 subjects with T2DM and BMI 27-40 kg/m2 received MEDI0382 (uptitrated to 200 µg) or placebo (PBO) daily for 41 days. Glucose, insulin, glucagon, GIP, and GLP-1 were measured at baseline (day -1) and day 41 during a liquid mixed-meal tolerance test. MEDI0382 significantly reduced fasting glucose (-49.9 vs. -19.2 mg/dL for PBO; P &amp;lt; 0.0001) and glucose AUC0-4h (-32.8 vs. -10.2% for PBO; P &amp;lt; 0.0001) in association with increased fasting insulin (2.2 mU/L vs. -3.9 mU/L for PBO; P = 0.016), but postprandial insulin AUC was unchanged. In contrast, fasting and postprandial endogenous glucagon, GIP (Figure), and active and inactive GLP-1 were suppressed, and a delay in their kinetics was observed after MEDI0382 therapy. The results suggest that MEDI0382 is insulinotropic and might also cause delayed gastric emptying. The effects of MEDI0382 on GIP have not been observed with GLP-1 receptor mono-agonists and may represent a footprint of dual GLP-1/glucagon receptor agonism in this complex hormone signaling network. Disclosure V.E.R. Parker: Employee; Self; MedImmune. Stock/Shareholder; Self; Accenture. Employee; Self; AstraZeneca. L. Tsai: Employee; Self; MedImmune. D. Robertson: Employee; Self; MedImmune. Employee; Spouse/Partner; GlaxoSmithKline plc. M. Petrone: Employee; Self; MedImmune. Stock/Shareholder; Self; MedImmune. C. Rondinone: Employee; Self; MedImmune. Stock/Shareholder; Self; AstraZeneca, F. Hoffmann-La Roche Ltd., Abbott, AbbVie Inc. B. Hirshberg: Employee; Self; AstraZeneca, MedImmune. L. Jermutus: Employee; Self; AstraZeneca. Stock/Shareholder; Self; AstraZeneca. P. Ambery: Employee; Self; MedImmune. Stock/Shareholder; Self; AstraZeneca.