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Context Glucose-dependent insulinotropic polypeptide (GIP) has been proposed to exert insulin-independent effects on lipid and bone metabolism. Objective We investigated the effects of a 6-day subcutaneous GIP infusion on circulating lipids, white adipose tissue (WAT), brown adipose tissue (BAT), hepatic fat content, inflammatory markers, respiratory exchange ratio (RER), and bone homeostasis in patients with type 1 diabetes. Methods In a randomized, placebo-controlled, double-blind, crossover study, 20 men with type 1 diabetes underwent a 6-day continuous subcutaneous infusion with GIP (6 pmol/kg/min) and placebo (saline), with an interposed 7-day washout period. Results During GIP infusion, participants (26 ± 8 years [mean ± SD]; BMI 23.8 ± 1.8 kg/m2; glycated hemoglobin A1c 51 ± 10 mmol/mol [6.8 ± 3.1%]) experienced transiently increased circulating concentrations of nonesterified fatty acid (NEFA) (P = 0.0005), decreased RER (P = 0.009), indication of increased fatty acid β-oxidation, and decreased levels of the bone resorption marker C-terminal telopeptide (P = 0.000072) compared with placebo. After 6 days of GIP infusion, hepatic fat content was increased by 12.6% (P = 0.007) and supraclavicular skin temperature, a surrogate indicator of BAT activity, was increased by 0.29 °C (P < 0.000001) compared with placebo infusion. WAT transcriptomic profile as well as circulating lipid species, proteome, markers of inflammation, and bone homeostasis were unaffected. Conclusion Six days of subcutaneous GIP infusion in men with type 1 diabetes transiently decreased bone resorption and increased NEFA and β-oxidation. Further, hepatic fat content, and supraclavicular skin temperature were increased without affecting WAT transcriptomics, the circulating proteome, lipids, or inflammatory markers.

We aimed to evaluate the effect of acute hyperglycaemia and hypoglycaemia on cardiac function in patients with type 2 diabetes (T2D) and a control group.In a nonrandomized interventional study, insulin-treated patients with T2D (N = 21, mean ± SD age 62.8 ± 6.5 years, body mass index [BMI] 29.0 ± 4.2 kg/mAcute hyperglycaemia increased left ventricular (LV) ejection fraction from baseline in patients with T2D (mean [95% confidence interval] 4.5 percentage points [1.1; 7.9]) but not in controls (2.0 percentage points [-1.4; 5.4]). Mitral annular peak systolic velocity (s') increased during hyperglycaemia in both patients and controls (0.4 m/s [0.2;0.6] and 0.6 m/s [0.4; 0.8], respectively), whereas global longitudinal strain rate only increased in the controls (-0.05 sAcute hyperglycaemia and hypoglycaemia increase LV systolic function, with no difference between patients with T2D and controls. Standardization of PG may improve reproducibility when evaluating LV systolic function in patients with T2D.

Introduction Glucose-dependent insulinotropic polypeptide (GIP) contributes importantly to glucose and lipid metabolism. We investigated the effects of exogenous GIP on lipid metabolism during stable insulin levels. Methods Ten male patients with type 1 diabetes without endogenous insulin secretion (C-peptide negative) (age [mean ± SD: 26 ± 4 years; BMI: 24 ± 2 kg/m2; HbA1c 7.3 ± 0.856 ± 8 mmol/mol]) were studied in a randomized, double-blind, placebo-controlled, crossover study with continuous intravenous infusions of GIP (4 pmol/kg/min) or placebo (saline), during two separate 90-minute hyperglycemic (12 mmol/L) clamps with basal insulin substitution (0.1–0.2 mU/kg/min). Results Plasma glycerol concentrations increased from baseline during GIP infusion and decreased during placebo infusion (baseline-subtracted area under the curve [bsAUC]: 703 ± 407 vs. −262 ± 240 μmol/L × min, respectively, p textless 0.001). Free fatty acids (FFA) increased during GIP infusions (bsAUC: 5505 ± 2170 μEq/L × min) and remained unchanged during placebo infusion (bsAUC: −74 ± 2363 μEq/L × min) resulting in a significant difference between GIP and placebo infusions (p textless 0.001). Plasma concentrations of glucose, insulin, GLP-1 and glucagon were similar during GIP and placebo infusions. Conclusions GIP increased plasma glycerol and FFA in patients with type 1 diabetes during hyperglycemia and stable basal insulin levels. This supports a direct lipolytic effect of GIP at high glucose and low levels of plasma insulin. Trial registration ClinicalTrials.gov NCT03195257 None.

Type 1 diabetes is characterised by reduced glucagon response to hypoglycaemia, increasing the risk of insulin treatment-associated hypoglycaemia known to hamper glycaemic control. We previously reported a glucagonotropic effect of exogenous glucose-dependent insulinotropic polypeptide (GIP) during insulin-induced hypoglycaemia in individuals with type 1 diabetes. Here we investigate the effect of a 6-day s.c. GIP infusion on time in glycaemic range as assessed by continuous glucose monitoring (CGM) in individuals with type 1 diabetes. In a randomised, placebo-controlled, double-blind crossover study, time in glycaemic range (assessed by double-blinded CGM) was evaluated in 20 men with type 1 diabetes (18–75 years, stable insulin treatment ≥3 months, diabetes duration 2–15 years, fasting plasma C-peptide below 200 pmol/l, BMI 20–27 kg/m2, HbA1c 10 mmol/l, p = 0.32) during night-time or daytime, in mean glucose, or in hypoglycaemic events as assessed by CGM. GIP altered neither self-reported hypoglycaemia nor safety measures. Compared with placebo, GIP significantly increased time in tight range (3.9–7.8 mmol/l) during daytime (06:00–23:59 hours) by [mean ± SEM] 11.2 ± 5.1% [95% CI 0.41, 21.9] (p = 0.02). Six-day s.c. GIP infusion in men with type 1 diabetes did not procure convincing effect on overall time in range, but increased time in tight glycaemic range during daytime by ~2 h per day. ClinicalTrials.gov NCT03734718. The study was funded by grants from The Leona M. and Harry B. Helmsley Charitable Trust and Aase og Ejnar Danielsens Fond.

Objective Hypoglycemia is associated with an increased risk of cardiovascular disease including cardiac arrhythmias. We investigated the effect of hypoglycemia in the setting of acute glycemic fluctuations on cardiac rhythm and cardiac repolarization in insulin-treated patients with type 2 diabetes compared with matched controls without diabetes. Design A non-randomized, mechanistic intervention study. Methods Insulin-treated patients with type 2 diabetes (n = 21, age (mean ± s.d.): 62.8 ± 6.5 years, BMI: 29.0 ± 4.2 kg/m2, HbA1c: 6.8 ± 0.5% (51.0 ± 5.4 mmol/mol)) and matched controls (n = 21, age: 62.2 ± 8.3 years, BMI 29.2 ± 3.5 kg/m2, HbA1c: 5.3 ± 0.3% (34.3 ± 3.3 mmol/mol)) underwent a sequential hyperglycemic and hypoglycemic clamp with three steady-states of plasma glucose: (i) fasting plasma glucose, (ii) hyperglycemia (fasting plasma glucose +10 mmol/L) and (iii) hyperinsulinemic hypoglycemia (plasma glucose < 3.0 mmol/L). Participants underwent continuous ECG monitoring and blood samples for counterregulatory hormones and plasma potassium were obtained. Results Both groups experienced progressively increasing heart rate corrected QT (Fridericia’s formula) interval prolongations during hypoglycemia ((∆mean (95% CI): 31 ms (16, 45) and 39 ms (24, 53) in the group of patients with type 2 diabetes and controls, respectively) with similar increases from baseline at the end of the hypoglycemic phase (P = 0.43). The incidence of ventricular premature beats increased significantly in both groups during hypoglycemia (P = 0.033 and P < 0.0001, respectively). One patient with type 2 diabetes developed atrial fibrillation during recovery from hypoglycemia. Conclusions In insulin-treated patients with type 2 diabetes and controls without diabetes, hypoglycemia causes clinically significant and similar increases in cardiac repolarization that might increase vulnerability for serious cardiac arrhythmias and sudden cardiac death.

Objective 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. Design A randomized, double-blinded, placebo-controlled, crossover study. Methods 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. Results 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. Conclusions 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.

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)

During the COVID-pandemic, patients diagnosed with diabetes have been overrepresented among patients admitted to hospital with COVID-19. We explored the impact of diabetes on mortality and clinical outcomes in hospitalized patients with COVID-in the Capital Region of Denmark. All patients from the Capital Region of Denmark admitted to hospital with COVID-in the period from February 2020 to March 2021 were included. Patients with a diabetes diagnosis were compared to patients without a diabetes diagnosis in multivariable adjusted analyses. The primary outcome was death within 30 days from hospitalization. Secondary outcomes included time to discharge, use of oxygen treatment, referral to intensive care unit, and use of respirator. Among 3,997 hospital admitted patients, 1,186 had diabetes (1,090 type 2 diabetes; 96 type 1 diabetes) . The patients with diabetes were 59% men, 72±13 years (mean±standard deviation) with BMI 28±6.4 kg/m2, while patients without diabetes were 51% men, 67±years with BMI 26±5.8 kg/m2. Within 30 days, 292 (24.6%) patients with diabetes died compared to 521 (18.5%) without diabetes (adjusted odds ratio (aOR) 1.28 (95% CI 1.02-1.6) for death) . Patients with diabetes were 24% less likely to be discharged alive at any given time compared to patients without diabetes with a hazard ratio of 0.76 (0.70-0.81) . aOR for oxygen treatment was 1. (0.97-1.47) , for referral to intensive care unit 1.37 (1.01-1.85) , and for use of respirator 1. (0.86-1.65) . We found that hospitalized COVID-patients with diabetes had a 28% higher risk of dying within 30 days and were 19% more likely to receive intensive care treatment than hospitalized COVID-patients without diabetes. Disclosure V.Kliim-hansen: None. M.E.Nyeland: None. L.S.Gasbjerg: Speaker's Bureau; Eli Lilly and Company, Stock/Shareholder; Antag Therapeutics. E.Jimenez-solem: None. T.S.Petersen: None. A.Ellegaard: n/a. 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.Christensen: None. Funding Novo Nordisk Foundation (NNF20SA0062873)

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: 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

Obesity is one of the biggest health challenges of the 21st century, already affecting close to 700 million people worldwide, debilitating and shortening lives and costing billions of pounds in healthcare costs and loss of workability. Body weight homeostasis relies on complex biological mechanisms and the development of obesity occurs on a background of genetic susceptibility and an environment promoting increased caloric intake and reduced physical activity. The pathophysiology of common obesity links neuro-endocrine and metabolic disturbances with behavioural changes, genetics, epigenetics and cultural habits. Also, specific causes of obesity exist, including monogenetic diseases and iatrogenic causes. In this review, we provide an overview of obesity mechanisms in humans with a focus on energy homeostasis, endocrine regulation of food intake and eating behavior, as well as the most common specific causes of obesity.

Glucose-dependent insulinotropic polypeptide (GIP) is a gut hormone impacting glucose, lipid and bone metabolism through the GIP receptor (GIPR). The GIP system has key species differences complicating the translation of findings from rodent to human physiology. Furthermore, the effects of endogenous GIP in humans have been difficult to tease out due to the lack of a suitable GIPR antagonist. The naturally occurring GIP(3-30)NH2 has turned out to constitute a safe and efficacious GIPR antagonist for rodent and human use. To study GIP physiology, it is recommended to use the species-specific GIP(3-30)NH2 peptide sequence, and for human intravenous infusions, an antagonist:agonist ratio of a minimum of 600 with a 20min infusion time before the intervention of interest is recommended. Several studies using GIP(3-30)NH2 are coming, hopefully providing new insights into the physiology of GIP, the pathophysiologic involvement of GIP in several diseases and the therapeutic potential of the GIPR.

The Danish Poison Information Centre (DPIC) regularly receives inquiries about nursing home residents who have been exposed to a medication error. The aim of this prospective cohort study was to describe and discuss the types and consequences of these errors. Data were collected from 1 March 2018 to 31 March 2019. Registered data included characteristics of caller and resident, data related to the suspected medication error, risk assessment and recommendation. Consequences and clinical outcomes were assessed by follow-up telephone calls. Over the study period, the DPIC was consulted about 145 medication errors occurring at Danish nursing homes. The median number of substances administered by error was two (interquartile range 1-5). Hospitalization was recommended in 21% of cases. In one-third of the cases where consultation with the DPIC was done with the resident either on his/her way to or in hospital, hospitalization was found unnecessary, and the resident could have stayed in accustomed surroundings for observation. Follow-up demonstrated that very few medication errors had a severe outcome. This prospective study illustrates that consulting with a poison information centre can qualify risk assessment and potentially reduce hospital admissions following medication errors in a nursing home setting.

Context The mechanisms underlying Roux-en-Y gastric bypass (RYGB) surgery-induced weight loss and the immediate postoperative beneficial metabolic effects associated with the operation remain uncertain. Enteroendocrine cell (EEC) secretory function has been proposed as a key factor in the marked metabolic benefits from RYGB surgery. Objective To identify novel gut-derived peptides with therapeutic potential in obesity and/or diabetes by profiling EEC-specific molecular changes in obese patients following RYGB-induced weight loss. Subjects and Methods Genome-wide expression analysis was performed in isolated human small intestinal EECs obtained from 20 gut-biopsied obese subjects before and after RYGB. Targets of interest were profiled for preclinical and clinical metabolic effects. Results Roux-en-Y gastric bypass consistently increased expression levels of the inverse ghrelin receptor agonist, liver-expressed antimicrobial peptide 2 (LEAP2). A secreted endogenous LEAP2 fragment (LEAP238-47) demonstrated robust insulinotropic properties, stimulating insulin release in human pancreatic islets comparable to the gut hormone glucagon-like peptide-1. LEAP238-47 showed reciprocal effects on growth hormone secretagogue receptor (GHSR) activity, suggesting that the insulinotropic action of the peptide may be directly linked to attenuation of tonic GHSR activity. The fragment was infused in healthy human individuals (n = 10), but no glucoregulatory effect was observed in the chosen dose as compared to placebo. Conclusions Small intestinal LEAP2 expression was upregulated after RYGB. The corresponding circulating LEAP238-47 fragment demonstrated strong insulinotropic action in vitro but failed to elicit glucoregulatory effects in healthy human subjects.

The glucose-dependent insulinotropic polypeptide (GIP) fragment GIP(3-30)NH2 is a selective, competitive GIP receptor antagonist, and doses of 800 to 1200 pmol/kg/min inhibit GIP-induced potentiation of glucose-stimulated insulin secretion by >80% in humans. We evaluated the effects of GIP(3-30)NH2 across a wider dose range in eight healthy men undergoing six separate and randomized 10-mmol/L hyperglycaemic clamps (A-F) with concomitant intravenous infusion of GIP (1.5 pmol/kg/min; A-E) or saline (F). Clamps A to E involved double-blinded, infusions of saline (A) and GIP(3-30)NH2 at four rates: 2 (B), 20 (C), 200 (D) and 2000 pmol/kg/min (E), respectively. Mean plasma concentrations of glucose (A-F) and GIP (A-E) were similar. GIP-induced potentiation of glucose-stimulated insulin secretion was reduced by 44 ± 10% and 84 ± 10% during clamps D and E, respectively. Correspondingly, the amounts of glucose required to maintain the clamp during D and E were not different from F. GIP-induced suppression of bone resorption and increase in heart rate were lowered by clamps D and E. In conclusion, GIP(3-30)NH2 provides extensive, dose-dependent inhibition of the GIP receptor in humans, with most pronounced effects of the doses 200 to 2000 pmol/kg/min within the tested range.

Treatment guidelines for type 2 diabetes (T2D) recommend avoidance of hypoglycemia and less stringent glycemic control in older patients. We examined the relation of glycemic control to glucose-lowering medications use in a cohort of patients aged>80 years with a diagnosis of T2D and a hospital admission in the Capital Region of Denmark in 2012–2016. We extracted data on medication use, diagnoses, and biochemistry from the hospitals’ records. We identified 5,172 T2D patients with high degree of co-morbidity and where 17% had an HbA1c in the range recommended for frail, comorbid, older patients with type 2 diabetes (58–75 mmol/mol (7.5–9%)). Half of the patients (n = 2,575) had an HbA1c 1c-values 1c values 1c within the generally recommended glycemic targets. One third of patients did not meet the diagnostic criteria for T2D, and of the patients who were treated with glucose-lowering medications, one-fifth had HbA1c-values suggesting overtreatment.

Objectives: To map the randomized trial evidence describing the feasibility of discontinuing active medications with potential adverse effects in older patients. Design: Scoping review with systematic search of PubMed, Embase, and Cochrane Library. Setting and Participants: Randomized trials investigating discontinuation of a single medicine or medicine class in patients with mean age ≥65 years. Methods: We extracted trial characteristics including study design and assessed bias. As proxies for the “feasibility of discontinuation,” we extracted the “dropout rate” and “disease recurrence rate.” Results: We identified 40 trials investigating discontinuation of symptomatic (n = 26), preventive (n = 6), or both preventive and symptomatic medicines (n = 8) against psychiatric (n = 10), neurologic (n = 9), musculoskeletal (n = 8), cardiovascular (n = 5), respiratory (n = 4), and urologic diseases (n = 4). Five discontinuation designs were used, 75% (30/40) of trials were placebo-controlled, and 48% (19/40) of trials had bias disfavoring discontinuation. The dropout rate was similar between the discontinuation group and the continuation group in 79% of the trials (30/38), whereas disease recurrence was similar in 72% (23/32) of the trials. In 42% (13/31) of trials reporting both dropout rate and disease recurrence rate, the differences between groups were statistically insignificant and less than 10%; these trials investigated discontinuation of cholinesterase inhibitors for Alzheimer's disease in various settings (n = 3), alendronate for osteoporosis (n = 3), glucosamine for osteoarthritis, lithium as adjunct for unipolar depression, statins for cardiovascular disease in patients with limited life expectancy, droxidopa for neurogenic orthostatic hypotension, tamsulosin for lower urinary tract symptoms, sertraline for major depressive episode, and fentanyl patch for low back or osteoarthritis pain. Conclusions and Implications: We identified 40 randomized trials using a variety of designs investigating discontinuation of both symptomatic and preventive medicines in older patients. Discontinuation of medicines seems feasible for most of the investigated medicines. This scoping review can guide clinical practice and future trials on deprescribing.

Dipeptidyl peptidase 4 (DPP-4) degrades the incretin hormones glucagon-like peptide 1 (GLP-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 to placebo treatment. During placebo treatment, postprandial glucose excursions were increased during GIP(3-30)NH2 compared to saline (ΔAUC%±SEM; +7.3±2.8%) but were unchanged during sitagliptin treatment. Endogenous GIP improved beta 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 beta 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 plus saline) and the physiological response minus any contribution by GIP (placebo treatment plus 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 beta cell function observed during DPP-4 inhibition.

Introduction Due to reports of severely reduced insulinotropic effect of the incretin hormone glucose-dependent insulinotropic polypeptide (GIP) in type 2 diabetes (T2D), GIP has not been considered therapeutically viable. Recently, however, tirzepatide, a novel dual incretin receptor agonist (activating the GIP receptor and the glucagon-like peptide 1 (GLP-1) receptor) has demonstrated greater glucose and body weight-lowering properties as compared to GLP-1 receptor agonist therapy. The contribution of GIP receptor activation to effects of tirzepatide remains unknown. We will evaluate the glucose-lowering effect of exogenous GIP in the context of pharmacological GLP-1 receptor activation in patients with T2D. Methods and analysis In this randomised, double-blind, four-arm parallel, placebo-controlled trial, 60 patients with T2D will be included (18–74 of age; on diet and exercise and/or metformin therapy only; glycated haemoglobin 6.5–10.5% (48–91 mmol/mol)). Participants will be randomised to an 8-week run-in period with subcutaneous (s.c.) placebo or semaglutide injections once-weekly (0.5 mg). Participants will then be randomised to 6 weeks’ add-on treatment with continuous s.c. placebo or GIP infusion (16 pmol/kg/min). The primary endpoint is change in mean glucose levels (assessed by 14-day continuous glucose monitoring) from the end of the run-in period to end of trial. Ethics and dissemination The present study was approved by the Regional Committee on Health Research Ethics in the Capitol Region of Denmark (identification no. H-20070184) and by the Danish Medicines Agency (EudraCT no. 2020-004774-22). All results, positive, negative and inconclusive, will be disseminated at national and/or international scientific meetings and in peer-reviewed scientific journals. Trial registration numbers NCT05078255 and U1111-1259-1491.

The gastric hormone ghrelin stimulates food intake and increases plasma glucose through activation of the growth hormone secretagogue receptor (GHSR). Liver-expressed antimicrobial peptide 2 (LEAP2) has been proposed to inhibit actions of ghrelin through inverse effects on GHSR activity. Here, we investigate the effects of exogenous LEAP2 on postprandial glucose metabolism and

Hyperglucagonemia is a common observation in both obesity and type 2 diabetes, and the etiology is primarily thought to be hypersecretion of glucagon. We investigated whether altered elimination kinetics of glucagon could contribute to the hyperglucagonemia in type 2 diabetes and obesity. Individuals with type 2 diabetes and preserved kidney function (8 with and 8 without obesity) and matched control individuals (8 with and 8 without obesity) were recruited. Each participant underwent a 1-hour glucagon infusion (4 ng/kg/min), achieving steady-state plasma glucagon concentrations, followed by a 1-hour wash-out period. Plasma levels, the metabolic clearance rate (MCR), half-life (T½) and volume of distribution of glucagon were evaluated and a pharmacokinetic model was constructed. Glucagon MCR and volume of distribution were significantly higher in the type 2 diabetes group compared to the control group, while no significant differences between the groups were found in glucagon T½. Individuals with obesity had neither a significantly decreased MCR, T½, nor volume of distribution of glucagon. In our pharmacokinetic model, glucagon MCR associated positively with fasting plasma glucose and negatively with body weight. In conclusion, our results suggest that impaired glucagon clearance is not a fundamental part of the hyperglucagonemia observed in obesity and type 2 diabetes.

Hyperglucagonemia is a common observation in both obesity and type 2 diabetes, and the etiology is primarily thought to be hypersecretion of glucagon. We investigated whether altered elimination kinetics of glucagon could contribute to hyperglucagonemia in type 2 diabetes and obesity. Individuals with type 2 diabetes and preserved kidney function (eight with and eight without obesity) and matched control individuals (eight with and eight without obesity) were recruited. Each participant underwent a 1-h glucagon infusion (4 ng/kg/min), achieving steady-state plasma glucagon concentrations, followed by a 1-h washout period. Plasma levels, metabolic clearance rate (MCR), half-life (T1/2), and volume of distribution of glucagon were evaluated, and a pharmacokinetic model was constructed. Glucagon MCR and volume of distribution were significantly higher in the type 2 diabetes group compared with the control group, while no significant differences between the groups were found in glucagon T1/2. Individuals with obesity had neither a significantly decreased MCR, T1/2, nor volume of distribution of glucagon. In our pharmacokinetic model, glucagon MCR associated positivelywith fasting plasma glucose and negatively with body weight. In conclusion, our results suggest that impaired glucagon clearance is not a fundamental part of the hyperglucagonemia observed in obesity and type 2 diabetes.

With the rising prevalence of type 2 diabetes (T2D), there is a substantial interest in novel, glucose-lowering drugs that may complement existing treatment options. Imeglimin is an oral antidiabetic agent currently in clinical development.This review is based on a literature search using PubMed and Embase including all published manuscripts and presentations concerning imeglimin. Supplementary information was retrieved from the manufacturer's official webpage. Preclinical and clinical data are summarized with a focus on mechanisms of action as well as clinical efficacy and safety in T2D.Imeglimin's mode of action seems to be improved mitochondrial function in pancreatic beta cells leading to improved insulin secretion and lowering of plasma glucose levels. In clinical trials of up to 24 weeks, imeglimin in doses of 1,000-1,500 mg twice daily conferred modest reductions in glycates hemoglobin A1c of 6-11 mmol/mol (0.5-1.0%) (placebo-adjusted) as a monotherapy and 7 mmol/mol (0.6%) as an add-on therapy to metformin or sitagliptin in patients with T2D. Reported adverse effects were mainly gastrointestinal discomfort. The position of imeglimin among other pharmacotherapies in the treatment of T2D will be determined based on future studies more clearly outlining the safety and long-term cardiovascular effects.AUC: area under the curve; BID: twice daily; DPP-4: dipeptidyl peptidase 4; GLP-1R: glucagon-like peptide-1 receptor; HbA1c: glycated hemoglobin A1c; HFHSD: high-fat high-sucrose diet; OAD: oral antidiabetic; OD: once daily; OGTT: oral glucose tolerance test; PPAR-γ: peroxisome proliferator-activated receptor gamma; PTP: permeability transition pore; SGLT-2: sodium-glucose transport protein 2; STZ: streptozotocin; T2D: type 2 diabetes.

OBJECTIVE Dual incretin receptor agonists in clinical development have shown reductions in body weight and hemoglobin A1c (HbA1c) in patients with type 2 diabetes, but the impact of glucose-dependent insulinotropic polypeptide (GIP) receptor activation remains unclear. Here, we evaluated the effects of high-dose exogenous GIP on energy intake, energy expenditure, plasma glucose, and glucose-regulating hormones in patients with type 2 diabetes treated with a long-acting glucagon-like peptide 1 receptor (GLP-1R) agonist. RESEARCH DESIGN AND METHODS In a randomized, double-blind design, men with type 2 diabetes (n = 22, mean ± SEM HbA1c 6.8 ± 0.1% [51 ± 1.5 mmol/mol]) treated with metformin and long-acting GLP-1R agonists were subjected to two 5-h continuous infusions (separated by a washout period of ≥3 days): one with GIP (6 pmol/kg/min) and another with saline (placebo). After 60 min of infusion, a liquid mixed-meal test was performed, and after 270 min of infusion, an ad libitum meal was served for evaluation of energy intake (primary end point). RESULTS Energy intake was similar during GIP and placebo infusion (648 ± 74 kcal vs. 594 ± 55 kcal, respectively; P = 0.480), as were appetite measures and energy expenditure. Plasma glucagon and glucose were higher during GIP infusion compared with placebo infusion (P = 0.026 and P = 0.017) as assessed by area under the curve. CONCLUSIONS In patients with type 2 diabetes, GIP infusion on top of treatment with metformin and a long-acting GLP-1R agonist did not affect energy intake, appetite, or energy expenditure but increased plasma glucose compared with placebo. These results indicate no acute beneficial effects of combining GIP and GLP-1.

Background Glucose-dependent insulinotropic polypeptide (GIP) has been suggested to stimulate the secretion of pancreatic polypeptide (PP), an islet hormone thought to regulate gut motility, appetite, and glycemia. Objective To determine whether human GIP1-42 (hGIP) stimulates PP secretion. Method As glycemia modulates the secretion of PP, we measured plasma PP concentrations from 2 studies in healthy men (n = 10) and in patients with type 2 diabetes (T2D) (n = 12), where hGIP1-42 had been administered intravenously during fasting glycemia, hyperglycemia (12 mmol/L), and insulin-induced hypoglycemia (targets: 2.5 mmol/L [healthy]; 3.5 mmol/L [T2D]). Porcine GIP1-42 (pGIP) was also infused intra-arterially in isolated porcine pancreata (n = 4). Results Mean fasting plasma glucose concentrations were approximately 5 mmol/L (healthy) and approximately 8 mmol/L (T2D). At fasting glycemia, PP concentrations were higher during intravenous hGIP1-42 infusion compared with saline in healthy men (mean [standard error of the mean, SEM], net incremental areas under the curves (iAUCs)[0-30min], 403 [116] vs –6 [57] pmol/L × min; P = 0.004) and in patients with T2D (905 [177] vs –96 [86] pmol/L × min; P = 0.009). During hyperglycemic clamping, mean [SEM] PP concentrations were significantly higher during hGIP1-42 infusion compared with saline in patients with T2D (771 [160] vs –183 [117] pmol/L × min; P = 0.001), but not in healthy individuals (–8 [86] vs –57 [53] pmol/L × min; P = 0.69). When plasma glucose levels were declining in response to exogenous insulin, mean [SEM] PP concentrations were higher during hGIP1-42 infusion compared with saline in healthy individuals (294 [88] vs –82 [53] pmol/L × min; P = 0.0025), but not significantly higher in patients with T2D (586 [314] vs –120 [53]; P = 0.070). At target hypoglycemia, PP levels surged in both groups during both hGIP1-42 and saline infusions. In isolated pancreata, pGIP1-42 increased mean [SEM] PP output in the pancreatic venous effluent (baseline vs infusion, 24[5] vs 79 [16] pmol/min x min; P = 0.044). Conclusion GIP1-42 increases plasma PP secretion in healthy individuals, patients with T2D, and isolated porcine pancreata. Hyperglycemia blunts the stimulatory effect of hGIP1-42 in healthy individuals, but not in patients with T2D.

Aims/hypothesis: Glucagon-like peptide 1 (GLP-1) reduces appetite and energy intake in humans, whereas the other incretin hormone, glucose-dependent insulinotropic polypeptide (GIP), seems to have no effect on eating behaviour. Interestingly, studies in rodents have shown that concomitant activation of GIP and GLP-1 receptors may potentiate the satiety-promoting effect of GLP-1, and a novel dual GLP-1/GIP receptor agonist was recently shown to trigger greater weight losses compared with a GLP-1 receptor agonist in individuals with type 2 diabetes. The aim of this study was to delineate the effects of combined GIP and GLP-1 receptor activation on energy intake, appetite and resting energy expenditure in humans. Methods: We examined 17 overweight/obese men in a crossover design with 5 study days. On day 1, a 50 g OGTT was performed; on the following 4 study days, the men received an isoglycaemic i.v. glucose infusion (IIGI) plus saline (154 mmol/l NaCl; placebo), GIP (4 pmol kg−1 min−1), GLP-1 (1 pmol kg−1 min−1) or GIP+GLP-1 (4 and 1 pmol kg−1 min−1, respectively). All IIGIs were performed in a randomised order blinded for the participant and the investigators. The primary endpoint was energy intake as measured by an ad libitum meal after 240 min. Secondary endpoints included appetite ratings and resting energy expenditure, as well as insulin, C-peptide and glucagon responses. Results: Energy intake was significantly reduced during IIGI+GLP-1 compared with IIGI+saline infusion (2715 ± 409 vs 4483 ± 568 kJ [mean ± SEM, n = 17], p = 0.014), whereas there were no significant differences in energy intake during IIGI+GIP (4062 ± 520 kJ) or IIGI+GIP+GLP-1 (3875 ± 451 kJ) infusion compared with IIGI+saline (p = 0.590 and p = 0.364, respectively). Energy intake was higher during IIGI+GIP+GLP-1 compared with IIGI+GLP-1 infusion (p = 0.039). Conclusions/interpretation: While GLP-1 infusion lowered energy intake in overweight/obese men, simultaneous GIP infusion did not potentiate this GLP-1-mediated effect. Trial registration: ClinicalTrials.gov NCT02598791 Funding: This study was supported by grants from the Innovation Fund Denmark and the Vissing Foundation.

Introduction: Obesity is a growing threat to public health, increasing risks of numerous diseases and mortality, and impairing quality of life. If current trends continue, more than 1.1 billion individuals will have obesity in 2030, corresponding to almost 2.5 times the number of adults currently living with diabetes. There is a strong interest in developing obesity treatments based on glucagon-like peptide-1 (GLP-1) agonism, which have proved to limit morbidity and mortality in type 2 diabetes.Areas covered: This review provides an overview of current compounds containing GLP-1 receptor agonism in clinical development for obesity, with mono-activity at the GLP-1 receptor (PF-0688296, glutazumab, semaglutide) or engaging one or more other endogenous hormonal systems involved in energy balance and metabolism, including glucagon, oxyntomodulin, glucose-dependent inhibitory peptide and amylin (CT-868, CT-388, AMG 133, tirzepatide, NNC9204-1177, JNJ-54,728,518, SAR425899, pegapamodutide, MK8521, cotadutide, efinopegdutide, BI-456,906, cagrilintide + semaglutide 2,4 mg, HM15211, NNC9204-1706).Expert opinion: Many novel compounds employing GLP-1 receptor agonism are in clinical development. Semaglutide is farthest in clinical development and will presumably become a benchmark for this class of novel anti-obesity compounds.

Secretin is best known for its effect on pancreatic exocrine secretion. It also has osmoregulatory effects and was recently identified as a potential target for the treatment of obesity. We investigated the effects of a 5-hour intravenous (iv) secretin infusion on postprandial plasma glucose and lipids and gallbladder motility as well as hemodynamics in healthy males. In a randomized, double-blind, placebo-controlled, crossover study, 25 healthy males (25.7 ± 6.1 (mean ± SD) years; BMI 23.4 ± 1.8 kg/m2) underwent two 5-hour iv infusions of secretin (1 pmol/kg/min) or placebo (saline), with an interposed 8-week washout period. After 30 minutes of infusion, a standardized liquid mixed meal was ingested. Prior to and with regular intervals during the 5-hour infusions, blood samples were drawn, ultrasonography of the gallbladder performed, and hemodynamics measured. Steady-state plasma concentrations of secretin amounted to 113 ± 2 pmol/L, i.e., ~20-fold higher than physiological levels. Postprandial plasma triglyceride excursions were higher during secretin than placebo infusions (baseline-subtracted area under curve: 111 ± 49 vs. 83 ± 36 min × pmol/L [P = 0.012]), whereas excursions in glucose, glycerol and free fatty acids were similar during placebo and secretin infusions. Compared to placebo, secretin reduced maximum gallbladder ejection fraction by 32 ± 27% (P We conclude that a 5-hour iv infusion of secretin in healthy males has no effect on fasting and postprandial glucose levels, but reduces postprandial gallbladder contraction, while increasing plasma triglycerides, blood pressure and pulse. Disclosure M. J. Bentzen: None. S. M. Nguyen heimbürger: Speaker’s Bureau; Self; AstraZeneca. B. Hartmann: None. 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.

Glucose-dependent insulinotropic polypeptide (GIP) contributes importantly to postprandial insulin secretion, and - perhaps primarily due to this insulinotropic effect - affects glucose and lipid metabolism. We investigated the effects of exogenous GIP on lipid metabolism during hyperglycemia and stable insulin levels. Ten male patients with type 1 diabetes without endogenous insulin secretion (C-peptide negative), aged [mean±SD: 26±4 years; BMI: 24±2 kg/m2; HbA1c 7.3±0.8%) were studied in a randomized, double-blind, crossover study with continuous intravenous infusions of GIP (4 pmol/kg/min) or placebo (saline), during two separate 90-minute hyperglycemic (12 mmol/L) clamps with basal insulin substitution (0.1-0.2 mU/kg/min). Plasma glycerol concentrations increased from baseline during GIP infusions and decreased during placebo infusions (baseline-subtracted area under the curve (bsAUC): 703±407 vs. -262±240 µmol/L × min, respectively, P Disclosure C. N. Nielsen: None. S. M. Nguyen heimbürger: Speaker’s Bureau; Self; AstraZeneca. S. Calanna: Employee; Self; Novo Nordisk A/S. 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. 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. 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. M. B. Christensen: None.

To determine whether the glucagonotropic gut-derived hormone glucagon-like peptide 2 (GLP-2) might be exploited as a safeguard against insulin-induced hypoglycemia, we evaluated the effects of exogenous GLP-2 during hypoglycemia, euglycemia and hyperglycemia. Ten healthy, young men underwent six randomized study days: two insulin-induced hypoglycemic clamps (2.5 mmol/L), two euglycemic clamps, and two hyperglycemic clamps (10 mmol/L). At each glycemic level, double-blinded intravenous infusion with GLP-2 (6 pmol/kg/minfrom −10 to 0 min, and 2 pmol/kg/min from 0 to 90 min) or placebo was given. Compared to placebo, exogenous GLP-2 increased glucagon secretion (assessed by baseline-subtracted area under curve) during euglycemia ([mean ± SD] −141±159 pmol/L×min vs. 261±200 pmol/L×min, P=0.0005), but not during hypo- and hyperglycemia. However, compared to placebo, GLP-2 increased glucagon secretion during the initial 40 minutes of the hypoglycemic clamp (38±81 pmol/L×min vs. 174±82 pmol/L×min, P=0.0007). In conclusion, the glucagonotropic effect of GLP-2 is evident at euglycemia and - to a lesser extent - during hypoglycemia, but not during hyperglycemia; positioning GLP-2 as a potential plasma glucose-stabilizer, which perhaps may be utilized therapeutically as a safeguard against insulin-induced hypoglycemia. Disclosure N. L. Hansen: None. T. Magnussen: None. 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. B. Hartmann: None. M. B. Christensen: None. A. Lund: Speaker’s Bureau; Self; Novo Nordisk, Sanofi. 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.

Glucose-dependent insulinotropic polypeptide (GIP) has been proposed to increase adipose tissue lipolysis (at low insulin levels), adipokine secretion and circulating levels of inflammation markers via the GIP receptor (GIPR) in adipose tissue. We investigated the effect of a 6-day subcutaneous (sc) GIP infusion on circulating lipids and inflammation markers, the adipose tissue transcriptome and the presence of GIPR mRNA (ISH) in adipose tissue in patients with type 1 diabetes (T1D). In a randomized, placebo-controlled, double-blind, crossover study, 20 men with T1D (age [mean± SD] 26±8 years, BMI 23.8±1.8 kg/m2, HbA1c 51±10 mmol/mol (6.8±3.1%) underwent 2 × 6 days of continuous sc GIP (6 pmol/kg/min) infusion and placebo (saline) infusion, with an interposed 7-day washout period. Fasting blood samples were drawn frequently within the initial 3 hours and after 1 and 6 days of infusion. Adipose tissue biopsies were collected before and after 6 days of infusion. During the initial 3 hours of infusion, but not at day 1 and 6, GIP increased baseline-subtracted area under the curve of plasma free fatty acids (FFA) compared to placebo (16.8±10.4 vs. 4.4±9.2 min × mmol/L, P Disclosure S. M. Nguyen heimbürger: Speaker’s Bureau; Self; AstraZeneca. T. F. Dejgaard: Advisory Panel; Self; Novo Nordisk, Consultant; Self; Boehringer Ingelheim International GmbH, Research Support; Self; AstraZeneca, Novo Nordisk, Speaker’s Bureau; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Novo Nordisk. C. Pyke: Employee; Self; Novo Nordisk A/S, Stock/Shareholder; Self; Novo Nordisk A/S. 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. B. Hoe: None. C. N. Nielsen: None. B. Hartmann: None. 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. F. Dela: None. A. Overgaard: Stock/Shareholder; Self; Novo Nordisk A/S. J. Størling: 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. Funding The Leona M. and Harry B. Helmsley Charitable Trust (2018PG-T1D037)