Showing papers by "Filip K. Knop published in 2022"

The Liver–α-Cell Axis in Health and in Disease

Abstract: Glucagon and insulin are the main regulators of blood glucose. While the actions of insulin are extensively mapped, less is known about glucagon. Besides glucagon’s role in glucose homeostasis, there are additional links between the pancreatic α-cells and the hepatocytes, often collectively referred to as the liver–α-cell axis, that may be of importance for health and disease. Thus, glucagon receptor antagonism (pharmacological or genetic), which disrupts the liver–α-cell axis, results not only in lower fasting glucose but also in reduced amino acid turnover and dyslipidemia. Here, we review the actions of glucagon on glucose homeostasis, amino acid catabolism, and lipid metabolism in the context of the liver–α-cell axis. The concept of glucagon resistance is also discussed, and we argue that the various elements of the liver–α-cell axis may be differentially affected in metabolic diseases such as diabetes, obesity, and nonalcoholic fatty liver disease (NAFLD). This conceptual rethinking of glucagon biology may explain why patients with type 2 diabetes have hyperglucagonemia and how NAFLD disrupts the liver–α-cell axis, compromising the normal glucagon-mediated enhancement of substrate-induced amino acid turnover and possibly fatty acid β-oxidation. In contrast to amino acid catabolism, glucagon-induced glucose production may not be affected by NAFLD, explaining the diabetogenic effect of NAFLD-associated hyperglucagonemia. Consideration of the liver–α-cell axis is essential to understanding the complex pathophysiology underlying diabetes and other metabolic diseases.

LEAP2 reduces postprandial glucose excursions and ad libitum food intake in healthy men

Abstract: •Exogenous LEAP2 lowers postprandial plasma glucose excursions•Exogenous LEAP2 suppresses ad libitum food intake•During fasting, exogenous LEAP2 increases insulin secretion and suppresses lipolysis•The GHSR is required for eliciting LEAP2 effects in mice 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 ad libitum food intake in a randomized, double-blind, placebo-controlled, crossover trial of 20 healthy men. We report that LEAP2 infusion lowers postprandial plasma glucose and growth hormone concentrations and decreases food intake during an ad libitum meal test. In wild-type mice, plasma glucose and food intake are reduced by LEAP2 dosing, but not in GHSR-null mice, pointing to GHSR as a potential mediator of LEAP2’s glucoregulatory and appetite-suppressing effects in mice. 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 ad libitum food intake in a randomized, double-blind, placebo-controlled, crossover trial of 20 healthy men. We report that LEAP2 infusion lowers postprandial plasma glucose and growth hormone concentrations and decreases food intake during an ad libitum meal test. In wild-type mice, plasma glucose and food intake are reduced by LEAP2 dosing, but not in GHSR-null mice, pointing to GHSR as a potential mediator of LEAP2’s glucoregulatory and appetite-suppressing effects in mice. The growth hormone (GH) secretagogue receptor (GHSR) modulates fundamental physiological functions, including regulation of food intake, glucose homeostasis, and GH release from the anterior pituitary gland.1Müller T.D. Nogueiras R. Andermann M.L. Andrews Z.B. Anker S.D. Argente J. Batterham R.L. Benoit S.C. Bowers C.Y. Broglio F. et al.Ghrelin.Mol. Metab. 2015; 4: 437-460Google Scholar The gastric hormone ghrelin, an endogenous GHSR agonist, stimulates food intake and gastrointestinal motility and increases plasma glucose.1Müller T.D. Nogueiras R. Andermann M.L. Andrews Z.B. Anker S.D. Argente J. Batterham R.L. Benoit S.C. Bowers C.Y. Broglio F. et al.Ghrelin.Mol. Metab. 2015; 4: 437-460Google Scholar,2Kojima M. Hosoda H. Date Y. Nakazato M. Matsuo H. Kangawa K. Ghrelin is a growth-hormone-releasing acylated peptide from stomach.Nature. 1999; 402: 656-660Google Scholar Ghrelin, a peptide hormone, requires an acylation to obtain full activity, and its expression is regulated according to energy status.1Müller T.D. Nogueiras R. Andermann M.L. Andrews Z.B. Anker S.D. Argente J. Batterham R.L. Benoit S.C. Bowers C.Y. Broglio F. et al.Ghrelin.Mol. Metab. 2015; 4: 437-460Google Scholar,2Kojima M. Hosoda H. Date Y. Nakazato M. Matsuo H. Kangawa K. Ghrelin is a growth-hormone-releasing acylated peptide from stomach.Nature. 1999; 402: 656-660Google Scholar Thus, plasma ghrelin concentrations rise during conditions with energy deficit, such as fasting and calorie restriction, and fall after food intake or with obesity.3Ariyasu H. Takaya K. Tagami T. Ogawa Y. Hosoda K. Akamizu T. Suda M. Koh T. Natsui K. Toyooka S. et al.Stomach is a major source of circulating ghrelin, and feeding state determines plasma ghrelin-like immunoreactivity levels in humans.J. Clin. Endocrinol. Metab. 2001; 86: 4753-4758Google Scholar,4Mani B.K. Puzziferri N. He Z. Rodriguez J.A. Osborne-Lawrence S. Metzger N.P. Chhina N. Gaylinn B. Thorner M.O. Thomas E.L. et al.LEAP2 changes with body mass and food intake in humans and mice.J. Clin. Invest. 2019; 129: 3909-3923Google Scholar Recently, liver-expressed antimicrobial peptide 2 (LEAP2), a 40-amino-acid peptide expressed in the liver and the small intestine, was identified as another GHSR ligand.5Ge X. Yang H. Bednarek M.A. Galon-Tilleman H. Chen P. Chen M. Lichtman J.S. Wang Y. Dalmas O. Yin Y. et al.LEAP2 is an endogenous antagonist of the ghrelin receptor.Cell Metab. 2018; 27: 461-469.e6Google Scholar LEAP2 is both an inverse agonist of GHSR that downregulates the constitutive activity of GHSR and a competitive antagonist that impairs ghrelin-induced activation of GHSR.4Mani B.K. Puzziferri N. He Z. Rodriguez J.A. Osborne-Lawrence S. Metzger N.P. Chhina N. Gaylinn B. Thorner M.O. Thomas E.L. et al.LEAP2 changes with body mass and food intake in humans and mice.J. Clin. Invest. 2019; 129: 3909-3923Google Scholar,6M’Kadmi C. Cabral A. Barrile F. Giribaldi J. Cantel S. Damian M. Mary S. Denoyelle S. Dutertre S. Péraldi-Roux S. et al.N-terminal liver-expressed antimicrobial peptide 2 (LEAP2) region exhibits inverse agonist activity toward the ghrelin receptor.J. Med. Chem. 2019; 62: 965-973Google Scholar,7Hagemann C.A. Zhang C. Hansen H.H. Jorsal T. Rigbolt K.T.G. Madsen M.R. Bergmann N.C. Heimbürger S.M.N. Falkenhahn M. Theis S. et al.Identification and metabolic profiling of a novel human gut-derived LEAP2 fragment.J. Clin. Endocrinol. Metab. 2021; 106: e966-e981Google Scholar Thus, the activity of GHSR is controlled at least in part by two circulating, gut-derived ligands with opposing actions. This type of dual regulation of receptor signaling properties is unusual in human physiology, but it has previously been described for the melanocortin receptors. For example, the melanocortin-4 receptor—an important receptor for appetite regulation—also displays constitutive activity, which is further activated by α-melanocyte-stimulating hormone and inhibited by agouti-related peptide.8Baldini G. Phelan K.D. The melanocortin pathway and control of appetite-progress and therapeutic implications.J. Endocrinol. 2019; 241: R1-R33Google Scholar LEAP2 is synthesized as a 77-amino-acid prepropeptide and is processed into several truncated forms, including the mature 40-amino-acid residue peptide (LEAP238–77; here called LEAP2), which is identical in mice and humans.5Ge X. Yang H. Bednarek M.A. Galon-Tilleman H. Chen P. Chen M. Lichtman J.S. Wang Y. Dalmas O. Yin Y. et al.LEAP2 is an endogenous antagonist of the ghrelin receptor.Cell Metab. 2018; 27: 461-469.e6Google Scholar Plasma LEAP2 concentrations are regulated inversely compared with plasma ghrelin in several metabolic settings.4Mani B.K. Puzziferri N. He Z. Rodriguez J.A. Osborne-Lawrence S. Metzger N.P. Chhina N. Gaylinn B. Thorner M.O. Thomas E.L. et al.LEAP2 changes with body mass and food intake in humans and mice.J. Clin. Invest. 2019; 129: 3909-3923Google Scholar Hence, LEAP2 concentrations have been reported to decrease during weight loss and increase with obesity.4Mani B.K. Puzziferri N. He Z. Rodriguez J.A. Osborne-Lawrence S. Metzger N.P. Chhina N. Gaylinn B. Thorner M.O. Thomas E.L. et al.LEAP2 changes with body mass and food intake in humans and mice.J. Clin. Invest. 2019; 129: 3909-3923Google Scholar Whether plasma concentrations of LEAP2 increase in response to food intake in humans as seen in rodents remains to be clarified.4Mani B.K. Puzziferri N. He Z. Rodriguez J.A. Osborne-Lawrence S. Metzger N.P. Chhina N. Gaylinn B. Thorner M.O. Thomas E.L. et al.LEAP2 changes with body mass and food intake in humans and mice.J. Clin. Invest. 2019; 129: 3909-3923Google Scholar,7Hagemann C.A. Zhang C. Hansen H.H. Jorsal T. Rigbolt K.T.G. Madsen M.R. Bergmann N.C. Heimbürger S.M.N. Falkenhahn M. Theis S. et al.Identification and metabolic profiling of a novel human gut-derived LEAP2 fragment.J. Clin. Endocrinol. Metab. 2021; 106: e966-e981Google Scholar Mani et al.4Mani B.K. Puzziferri N. He Z. Rodriguez J.A. Osborne-Lawrence S. Metzger N.P. Chhina N. Gaylinn B. Thorner M.O. Thomas E.L. et al.LEAP2 changes with body mass and food intake in humans and mice.J. Clin. Invest. 2019; 129: 3909-3923Google Scholar observed a postprandial rise in LEAP2 plasma concentration in obese individuals eligible for bariatric surgery, but not in lean individuals; however, we could not confirm a postprandial increase in LEAP2 plasma levels in a similar group of obese individuals.7Hagemann C.A. Zhang C. Hansen H.H. Jorsal T. Rigbolt K.T.G. Madsen M.R. Bergmann N.C. Heimbürger S.M.N. Falkenhahn M. Theis S. et al.Identification and metabolic profiling of a novel human gut-derived LEAP2 fragment.J. Clin. Endocrinol. Metab. 2021; 106: e966-e981Google Scholar Recently, we reported an increased expression level of LEAP2 following the bariatric surgical procedure Roux-en-Y gastric bypass (RYGB) and robust insulinotropic properties in vitro of another endogenous LEAP2 fragment, LEAP238–47, however without glucoregulatory effect in a clinical proof-of-concept trial.7Hagemann C.A. Zhang C. Hansen H.H. Jorsal T. Rigbolt K.T.G. Madsen M.R. Bergmann N.C. Heimbürger S.M.N. Falkenhahn M. Theis S. et al.Identification and metabolic profiling of a novel human gut-derived LEAP2 fragment.J. Clin. Endocrinol. Metab. 2021; 106: e966-e981Google Scholar Interestingly, LEAP238–47 retains the inverse agonistic properties on GHSR, suggesting that the insulinotropic characteristics of the fragment may be directly linked to downregulation of constitutive GHSR activity.6M’Kadmi C. Cabral A. Barrile F. Giribaldi J. Cantel S. Damian M. Mary S. Denoyelle S. Dutertre S. Péraldi-Roux S. et al.N-terminal liver-expressed antimicrobial peptide 2 (LEAP2) region exhibits inverse agonist activity toward the ghrelin receptor.J. Med. Chem. 2019; 62: 965-973Google Scholar,7Hagemann C.A. Zhang C. Hansen H.H. Jorsal T. Rigbolt K.T.G. Madsen M.R. Bergmann N.C. Heimbürger S.M.N. Falkenhahn M. Theis S. et al.Identification and metabolic profiling of a novel human gut-derived LEAP2 fragment.J. Clin. Endocrinol. Metab. 2021; 106: e966-e981Google Scholar Thus, the pharmacological potential of LEAP2 family peptides deserves to be further investigated. To date, bariatric surgery is the most effective treatment of obesity.9Maciejewski M.L. Arterburn D.E. Van Scoyoc L. Smith V.A. Yancy W.S. Weidenbacher H.J. Livingston E.H. Olsen M.K. Bariatric surgery and long-term durability of weight loss.JAMA Surg. 2016; 151: 1046Google Scholar Despite documented beneficial effects of individual gut hormones, such as glucagon-like peptide 1 (GLP-1) and peptide YY, on glycemic control and appetite regulation following RYGB surgery,10Moffett R.C. Docherty N.G. le Roux C.W. The altered enteroendocrine reportoire following roux-en-Y-gastric bypass as an effector of weight loss and improved glycaemic control.Appetite. 2021; 156: 104807Google Scholar,11Svane M.S. Jørgensen N.B. Bojsen-Møller K.N. Dirksen C. Nielsen S. Kristiansen V.B. Toräng S. Wewer Albrechtsen N.J. Rehfeld J.F. Hartmann B. et al.Peptide YY and glucagon-like peptide-1 contribute to decreased food intake after Roux-en-Y gastric bypass surgery.Int. J. Obes. 2016; 40: 1699-1706Google Scholar the exact mechanisms that regulate changes in gut-derived signals and link them with metabolic control are not well understood. GHSR and ghrelin regulate a wealth of metabolic functions connecting gut and brain and have been considered as possible neuroendocrine therapeutic targets. However, despite two decades of intensive research in the field, no viable clinical candidate has been developed. Consequently, the discovery of the endogenous inverse agonist LEAP2 may reveal a potential therapeutic target for ghrelin-related diseases, including type 2 diabetes and obesity, due to its reciprocal relationship with ghrelin4Mani B.K. Puzziferri N. He Z. Rodriguez J.A. Osborne-Lawrence S. Metzger N.P. Chhina N. Gaylinn B. Thorner M.O. Thomas E.L. et al.LEAP2 changes with body mass and food intake in humans and mice.J. Clin. Invest. 2019; 129: 3909-3923Google Scholar and elevated expression levels following RYGB.7Hagemann C.A. Zhang C. Hansen H.H. Jorsal T. Rigbolt K.T.G. Madsen M.R. Bergmann N.C. Heimbürger S.M.N. Falkenhahn M. Theis S. et al.Identification and metabolic profiling of a novel human gut-derived LEAP2 fragment.J. Clin. Endocrinol. Metab. 2021; 106: e966-e981Google Scholar The administration of ghrelin in rodents and humans stimulates food intake and increases plasma glucose.5Ge X. Yang H. Bednarek M.A. Galon-Tilleman H. Chen P. Chen M. Lichtman J.S. Wang Y. Dalmas O. Yin Y. et al.LEAP2 is an endogenous antagonist of the ghrelin receptor.Cell Metab. 2018; 27: 461-469.e6Google Scholar,12Cornejo M.P. Mustafá E.R. Cassano D. Banères J.L. Raingo J. Perello M. The ups and downs of growth hormone secretagogue receptor signaling.FEBS J. 2021; 288: 7213-7229Google Scholar,13Druce M.R. Wren A.M. Park A.J. Milton J.E. Patterson M. Frost G. Ghatei M.A. Small C. Bloom S.R. Ghrelin increases food intake in obese as well as lean subjects.Int. J. Obes. 2005; 29: 1130-1136Google Scholar Several groups have investigated the effect of exogenous LEAP2 on food intake and plasma glucose in rodents. A pioneering study demonstrated lower food intake in LEAP2-treated compared with vehicle-treated mice;5Ge X. Yang H. Bednarek M.A. Galon-Tilleman H. Chen P. Chen M. Lichtman J.S. Wang Y. Dalmas O. Yin Y. et al.LEAP2 is an endogenous antagonist of the ghrelin receptor.Cell Metab. 2018; 27: 461-469.e6Google Scholar however, this finding could not be confirmed in succeeding studies.6M’Kadmi C. Cabral A. Barrile F. Giribaldi J. Cantel S. Damian M. Mary S. Denoyelle S. Dutertre S. Péraldi-Roux S. et al.N-terminal liver-expressed antimicrobial peptide 2 (LEAP2) region exhibits inverse agonist activity toward the ghrelin receptor.J. Med. Chem. 2019; 62: 965-973Google Scholar,7Hagemann C.A. Zhang C. Hansen H.H. Jorsal T. Rigbolt K.T.G. Madsen M.R. Bergmann N.C. Heimbürger S.M.N. Falkenhahn M. Theis S. et al.Identification and metabolic profiling of a novel human gut-derived LEAP2 fragment.J. Clin. Endocrinol. Metab. 2021; 106: e966-e981Google Scholar,14Islam M.N. Mita Y. Maruyama K. Tanida R. Zhang W. Sakoda H. Nakazato M. Liver-expressed antimicrobial peptide 2 antagonizes the effect of ghrelin in rodents.J. Endocrinol. 2020; 244: 13-23Google Scholar Nevertheless, LEAP2 treatment has consistently been shown to impair ghrelin-induced food intake and hyperglycemia in rodents.5Ge X. Yang H. Bednarek M.A. Galon-Tilleman H. Chen P. Chen M. Lichtman J.S. Wang Y. Dalmas O. Yin Y. et al.LEAP2 is an endogenous antagonist of the ghrelin receptor.Cell Metab. 2018; 27: 461-469.e6Google Scholar,6M’Kadmi C. Cabral A. Barrile F. Giribaldi J. Cantel S. Damian M. Mary S. Denoyelle S. Dutertre S. Péraldi-Roux S. et al.N-terminal liver-expressed antimicrobial peptide 2 (LEAP2) region exhibits inverse agonist activity toward the ghrelin receptor.J. Med. Chem. 2019; 62: 965-973Google Scholar,14Islam M.N. Mita Y. Maruyama K. Tanida R. Zhang W. Sakoda H. Nakazato M. Liver-expressed antimicrobial peptide 2 antagonizes the effect of ghrelin in rodents.J. Endocrinol. 2020; 244: 13-23Google Scholar, 15Shankar K. Metzger N.P. Singh O. Mani B.K. Osborne-Lawrence S. Varshney S. Gupta D. Ogden S.B. Takemi S. Richard C.P. et al.LEAP2 deletion in mice enhances ghrelin’s actions as an orexigen and growth hormone secretagogue.Mol. Metab. 2021; 53: 101327Google Scholar, 16Barrile F. M’Kadmi C. De Francesco P.N. Cabral A. García Romero G. Mustafá E.R. Cantel S. Damian M. Mary S. Denoyelle S. et al.Development of a novel fluorescent ligand of growth hormone secretagogue receptor based on the N-Terminal Leap2 region.Mol. Cell. Endocrinol. 2019; 498: 110573Google Scholar Notably, only two studies besides the study of Ge et al. have demonstrated effects of LEAP2 administration alone, i.e., a decrease in plasma glucose after intraperitoneal LEAP2 administration in mice17Gupta D. Dowsett G.K.C. Mani B.K. Shankar K. Osborne-Lawrence S. Metzger N.P. Lam B.Y.H. Yeo G.S.H. Zigman J.M. High coexpression of the ghrelin and LEAP2 receptor GHSR with pancreatic polypeptide in mouse and human islets.Endocrinology. 2021; 162: bqab148Google Scholar and reduced binge-like eating after central administration of a truncated LEAP2 form in mice.18Cornejo M.P. Castrogiovanni D. Schiöth H.B. Reynaldo M. Marie J. Fehrentz J.A. Perello M. Growth hormone secretagogue receptor signalling affects high-fat intake independently of plasma levels of ghrelin and LEAP2, in a 4-day binge eating model.J. Neuroendocrinol. 2019; 31: e12785Google Scholar Whether exogenous LEAP2 affects food intake and glucose metabolism in humans has not been investigated. In the present study, we studied the effects of exogenous LEAP2 in healthy men and show that it lowers postprandial glucose excursions and suppresses food intake (effects that may be mediated via the GHSR as informed by experiments in GHSR-null mice). Whether the striking effects of exogenous LEAP2 in humans will revitalize the GHSR as a therapeutic target in metabolic diseases awaits further studies. To investigate the metabolic effects of LEAP2 in humans, we carried out an intravenous infusion of LEAP2 (∼25 pmol/kg/min), resulting in supraphysiological plasma concentrations in 20 lean, young men (see Table 1 for baseline characteristics and Figure 1 for an overview of the randomized, double-blind, placebo-controlled study design). Using an in-house radioimmunoassay directed against the N-terminal part of LEAP2, we determined LEAP2 plasma concentrations during LEAP2 and placebo infusions. During LEAP2 and placebo infusions, the baseline concentrations of LEAP2 plasma concentrations were similar (Figure 2A ). During LEAP2 infusion, plasma concentrations of LEAP2 reached steady state after 45 min of infusion with a mean concentration of 41.2 ± 1.1 ng/mL (Figure 2A), ∼2.6-fold higher than the mean plasma LEAP2 concentration during placebo infusion (Figure 2A). During placebo infusion, no change in LEAP2 concentration was found in response to the liquid mixed meal (Figure 2A), suggesting that endogenous LEAP2 concentrations are not acutely affected by food intake in lean, young men. The participants reported no adverse events during the infusions.Table 1Baseline characteristics of study participantsMale/female (n/n)20/0Age (years)23 (20–25)Weight (kg)80.3 (74.9–88.2)Height (m)1.87 (1.81–1.92)BMI (kg/m2)23.1 (22.3–25.0)Fasting plasma glucose (mmol/L)5.2 (5.0–5.3)HbA1c (mmol/mol)32 (29–33)Data are presented as median (interquartile range [IQR]). BMI, body mass index; HbA1c, glycated hemoglobin A1c. Open table in a new tab Figure 2LEAP2 alters postprandial plasma concentrations of glucose, glucagon, and growth hormone during a liquid mixed meal test and fasting plasma concentrations of insulin, C-peptide, C-peptide/glucose ratio, glucagon, and glycerol in healthy, young menShow full captionPlasma concentrations of LEAP2 (A), glucose (B), insulin (C), C-peptide (D), C-peptide/glucose ratio (E), glucagon (F), free fatty acids (G), glycerol (H), triglycerides (I), acetaminophen (J), growth hormone (K), and acyl ghrelin (L). Bold dotted line, infusion start (0 min); thin dotted line, liquid mixed meal test (65 min); blue square symbols, LEAP2 infusion; gray round symbols, placebo infusion (n = 20). Data are presented as mean ± SEM. Student’s paired t test of AUC60–255 min: p = 0.017 (B), p < 0.001 (F), and p < 0.001 (K). Student’s paired t test of AUC0–60 min: p < 0.001 (C), p = 0.018 (D), p = 0.003 (E), p = 0.038 (F), and p = 0.039 (H). AUC, area under the curve.View Large Image Figure ViewerDownload Hi-res image Download (PPT) Data are presented as median (interquartile range [IQR]). BMI, body mass index; HbA1c, glycated hemoglobin A1c. Plasma concentrations of LEAP2 (A), glucose (B), insulin (C), C-peptide (D), C-peptide/glucose ratio (E), glucagon (F), free fatty acids (G), glycerol (H), triglycerides (I), acetaminophen (J), growth hormone (K), and acyl ghrelin (L). Bold dotted line, infusion start (0 min); thin dotted line, liquid mixed meal test (65 min); blue square symbols, LEAP2 infusion; gray round symbols, placebo infusion (n = 20). Data are presented as mean ± SEM. Student’s paired t test of AUC60–255 min: p = 0.017 (B), p < 0.001 (F), and p < 0.001 (K). Student’s paired t test of AUC0–60 min: p < 0.001 (C), p = 0.018 (D), p = 0.003 (E), p = 0.038 (F), and p = 0.039 (H). AUC, area under the curve. First, we assessed the effect of exogenous LEAP2 on postprandial glucose metabolism in healthy men. For this purpose, participants were given a standardized liquid mixed meal (65 min after infusion start). During LEAP2 infusion, the postprandial plasma glucose peaks were lower than during placebo infusion (Figure 2B; Table 2). Furthermore, the area under the curve (AUC) for the entire infusion period (AUC0–255 min) and the postprandial AUC (AUC60–255 min) were lower during LEAP2 infusion compared with placebo (Table 2), demonstrating a reduced postprandial glucose response during LEAP2 infusion.Table 2Overview of plasma measurements in the clinical studyLEAP2Placebo (saline)p value (paired t test)Glucose Baseline (mmol/L)5.02 ± 0.065.01 ± 0.070.900 Peak (mmol/L)6.21 ± 0.126.58 ± 0.130.005 Time to peak (min)140 ± 12.7137 ± 10.70.808 Postprandial baseline (mmol/L)4.96 ± 0.055.10 ± 0.080.077 Postprandial end (mmol/L)4.48 ± 0.114.75 ± 0.120.056 AUC (mmol/L × min)1,288 ± 13.41,336 ± 18.50.013 –60 min (mmol/L × min)295 ± 3.02300 ± 3.670.198 AUC60–255 min (mmol/L × min)992 ± 12.41,037 ± 16.90.017Insulin Baseline (pmol/L)36.4 ± 1.7036.3 ± 2.080.984 Peak (pmol/L)347 ± 38.6356 ± 35.40.734 Time to peak (min)110 ± 6.28120 ± 9.230.433 Postprandial baseline (pmol/L)38.6 ± 2.0931.1 ± 2.080.017 AUC (nmol/L × min)33.8 ± 2.6333.3 ± 2.340.775 AUC0–60 min (nmol/L × min)2.39 ± 0.091.92 ± 0.13<0.001 AUC60–255 min (nmol/L × min)31.5 ± 2.6031.4 ± 2.280.985C-peptide Baseline (pmol/L)360 ± 21.4350 ± 15.80.673 Peak (pmol/L)1,524 ± 1061,647 ± 1250.317 Time to peak (min)136 ± 9.01160 ± 11.20.028 Postprandial baseline (pmol/L)365 ± 20.2313 ± 15.90.010 AUC (nmol/L × min)218 ± 11.7222 ± 11.50.697 AUC0–60 min (nmol/L × min)22.5 ± 1.1819.7 ± 1.000.018 AUC60–255 min (nmol/L × min)196 ± 11.2202 ± 10.90.490C-peptide/glucose ratio Baseline (pmol/mmol)71.4 ± 3.9369.8 ± 2.820.675 Peak (pmol/mmol)269 ± 17.9268 ± 17.60.959 Time to peak (min)140 ± 9.24153 ± 10.30.179 Postprandial baseline (pmol/mmol)73.6 ± 4.0361.4 ± 3.030.002 AUC (nmol/mmol × min)41.4 ± 2.3440.8 ± 1.890.705 AUC0–60 min (nmol/mmol × min)4.57 ± 0.233.92 ± 0.180.003 AUC60–255 min (nmol/mmol × min)36.8 ± 2.2336.8 ± 1.781.000Glucagon Baseline (pmol/L)6.57 ± 0.767.23 ± 0.680.237 Peak (pmol/L)13.0 ± 0.9411.2 ± 0.720.003 Time to peak (min)116 ± 12.5117 ± 17.10.926 Postprandial baseline (pmol/L)7.35 ± 0.825.35 ± 0.670.005 AUC (nmol/L × min)2.26 ± 0.201.74 ± 0.14<0.001 AUC0–60 min (nmol/L × min)0.446 ± 0.0440.375 ± 0.0350.038 AUC60–255 min (nmol/L × min)1.82 ± 0.171.36 ± 0.13<0.001Free fatty acids Baseline (μmol/L)339 ± 18.4361 ± 20.90.419 Nadir (μmol/L)58.4 ± 3.9457.7 ± 3.700.860 Time to nadir (min)155 ± 7.63168 ± 11.10.317 Postprandial baseline (μmol/L)272 ± 16.4360 ± 28.00.013 AUC (mmol/L × min)43.2 ± 2.4948.1 ± 2.740.171 AUC0–60 min (mmol/L × min)18.9 ± 1.1820.9 ± 1.430.258 AUC60–255 min (mmol/L × min)24.4 ± 1.5127.2 ± 1.540.150Glycerol Baseline (μmol/L)26.6 ± 2.4528.4 ± 3.120.379 Nadir (μmol/L)11.7 ± 2.1212.1 ± 2.440.761 Time to nadir (min)144 ± 10.2164 ± 11.80.201 Postprandial baseline (μmol/L)22.9 ± 2.1231.4 ± 3.650.007 AUC (mmol/L × min)4.87 ± 0.575.49 ± 0.700.080 AUC0–60 min (mmol/L × min)1.65 ± 0.151.95 ± 0.190.039 AUC60–255 min (mmol/L × min)3.22 ± 0.443.54 ± 0.540.211Triglycerides Baseline (μmol/L)920 ± 62.2953 ± 70.40.539 Peak (μmol/L)1,275 ± 84.81,353 ± 1130.279 Time to peak (min)195 ± 5.33192 ± 6.850.725 Postprandial baseline (μmol/L)847 ± 48.3916 ± 73.20.159 AUC (mmol/L × min)263 ± 16.7279 ± 22.10.251 AUC0–60 min (mmol/L × min)53.5 ± 3.1456.8 ± 4.410.284 AUC60–255 min (mmol/L × min)210 ± 13.8222 ± 17.90.258Growth hormone Baseline (ng/mL)0.594 ± 0.3000.299 ± 0.1060.372 Nadir (ng/mL)0.042 ± 0.0040.084 ± 0.0120.001 Time to nadir (min)116 ± 17.2128 ± 13.90.592 Postprandial baseline (ng/mL)0.121 ± 0.0480.432 ± 0.1330.014 AUC (ng/mL × min)33.8 ± 11.8106 ± 18.30.001 AUC0–60 min (ng/mL × min)20.2 ± 9.7632.0 ± 9.570.312 AUC60–255 min (ng/mL × min)13.6 ± 2.3273.7 ± 14.5<0.001Acyl ghrelin Baseline (ng/mL)0.155 ± 0.0110.158 ± 0.0100.730 Nadir (ng/mL)0.088 ± 0.0060.084 ± 0.0040.343 Postprandial baseline (ng/mL)0.161 ± 0.0120.172 ± 0.0130.264 AUC (ng/mL × min)31.2 ± 1.9431.7 ± 1.960.634 AUC0–60 min (ng/mL × min)9.50 ± 0.679.90 ± 0.650.387 AUC60–255 min (ng/mL × min)21.7 ± 1.3321.8 ± 1.340.875Acetaminophen Peak (μmol/L)65.1 ± 2.5266.3 ± 2.750.548 Time to peak (min)209 ± 6.34215 ± 7.930.297Data are presented as mean ± SEM. AUC, area under the curve; LEAP2, liver-expressed antimicrobial peptide 2. Open table in a new tab Data are presented as mean ± SEM. AUC, area under the curve; LEAP2, liver-expressed antimicrobial peptide 2. We measured plasma concentrations of insulin, C-peptide, glucagon, and calculated C-peptide/glucose ratio—the latter as a measure of pancreatic beta cell secretion—before and after the liquid mixed meal test (i.e., during fasting and postprandial conditions) in the healthy, young men. In the fasting state, the circulating concentrations of insulin and C-peptide and C-peptide/glucose ratio were higher during LEAP2 infusion compared with placebo, as assessed by AUC0–60 min (Figures 2C–2E; Table 2). Accordingly, postprandial baseline values (i.e., at the end of the fasting period, time = 60 min) were higher for both insulin, C-peptide, and C-peptide/glucose ratio (Figures 2C–2E; Table 2). The insulinotropic effect of LEAP2 during fasting was supported by a shorter time to peak for C-peptide during LEAP2 infusion (Table 2). An increase of ∼2 pmol/L in glucagon concentrations was observed both in the fasting state and postprandially during LEAP2 infusion (Figure 2F; Table 2). Plasma concentrations of free fatty acids, glycerol, and triglycerides were measured during fasting and postprandial conditions (Figures 2G–2I; Table 2). In the fasting state, circulating glycerol (AUC0–60 min) concentrations were lower during LEAP2 infusion compared with placebo infusion (Figure 2H; Table 2), suggesting a decreased lipolytic activity. No differences in AUC0–60 min values were found for free fatty acids or triglycerides, but postprandial baseline concentrations (time = 60 min) of free fatty acids and glycerol were lower during LEAP2 infusion (Table 2). Because ghrelin is known to increase the gastric emptying rate,19Levin F. Edholm T. Schmidt P.T. Grybäck P. Jacobsson H. Degerblad M. Höybye C. Holst J.J. Rehfeld J.F. Hellström P.M. et al.Ghrelin stimulates gastric emptying and hunger in normal-weight humans.J. Clin. Endocrinol. Metab. 2006; 91: 3296-3302Google Scholar we admixed acetaminophen to the liquid mixed meal in order to evaluate postprandial plasma excursions of acetaminophen as an indirect marker of gastric emptying, as previously validated.20Willems M. Otto Quartero A. Numans M.E. How useful is paracetamol absorption as a marker of gastric emptying? A systematic literature study.Dig. Dis. Sci. 2001; 46: 2256-2262Google Scholar Peak plasma acetaminophen concentrations and time to peak plasma acetaminophen concentrations revealed no difference between LEAP2 and placebo infusions (Figure 2J; Table 2), suggesting that exogenous LEAP2 does not alter gastric emptying rate of a liquid mixed meal. GH release reflects activity of the GHSR and is stimulated by acute administration of ghrelin.21Takaya K. Ariyasu H. Kanamoto N. Iwakura H. Yoshimoto A. Harada M. Mori K. Komatsu Y. Usui T. Shimatsu A. et al.Ghrelin strongly stimulates growth hormone (GH) release in humans.J. Clin. Endocrinol. Metab. 2000; 85: 4908-4911Google Scholar To test whether exogenous LEAP2 reduces the production or secretion of GH and ghrelin, we measured plasma concentrations of both hormones (Figures 2K and 2L; Table 2). Notably, GH concentrations were suppressed during LEAP2 infusion compared with placebo, as assessed by AUC (Table 2). When assessing the fasting (AUC0–60 min) and postprandial (AUC60–255 min) periods separately, only the postprandial period was lower during LEAP2 infusion compared with placebo (Table 2), suggesting that LEAP2 mainly suppresses GH postprandially. The postprandial GH suppression was supported by a lower nadir during LEAP2 infusion compared with placebo infusion (Table 2). Plasma concentrations of ghrelin (measured as active acylated ghrelin) were unaffected by LEAP2 infusion (Table 2); hence, the metabolic effects of exogenous LEAP2 in healthy men do not seem to be a result of altered plasma concentrations of ghrelin. Together, these results support previous findings on suppression of ghrelin-induced GH release in a dose-dependent manner in rodents5Ge X. Yang H. Bednarek M.A. Galon-Tilleman H. Chen P. Chen M. Lichtman J.S. Wang Y. Dalmas O. Yin Y. et al.LEAP2 is an endogenous antagonist of the ghrelin receptor.Cell Metab. 2018; 27: 461-469.e6Google Scholar,14Islam M.N. Mita Y. Maruyama K. Tanida R. Zhang W. Sakoda H. Nakazato M. Liver-expressed antimicrobial peptide 2 antagonizes the effect of ghrelin in rodents.J. Endocrinol. 2020; 244: 13-23Google Scholar and suggest that LEAP2 may reduce GH release independently of plasma concentrations of ghrelin in humans. As ghrelin infusion in humans has been reported to increase appetite sensations,13Druce M.R. Wren A.M. Park A.J. Milton J.E. Patterson M. Frost G. Ghatei M.A.

Semaglutide for the treatment of overweight and obesity: A review

Abstract: Obesity is a chronic, relapsing disease associated with multiple complications and a substantial morbidity, mortality and health care burden. Pharmacological treatments for obesity provide a valuable adjunct to lifestyle intervention, which often achieves only limited weight loss that is difficult to maintain. The Semaglutide Treatment Effect in People with obesity (STEP) clinical trial programme is evaluating once‐weekly subcutaneous semaglutide 2.4 mg (a glucagon‐like peptide‐1 analogue) in people with overweight or obesity. Across STEP 1, 3, 4 and 8, semaglutide 2.4 mg was associated with mean weight losses of 14.9%‐17.4% in individuals with overweight or obesity without type 2 diabetes from baseline to week 68; 69%‐79% of participants achieved ≥10% weight loss with semaglutide 2.4 mg (vs. 12%‐27% with placebo) and 51%‐64% achieved ≥15% weight loss (vs. 5%‐13% with placebo). In STEP 5, mean weight loss was −15.2% with semaglutide 2.4 mg versus −2.6% with placebo from baseline to week 104. In STEP 2 (individuals with overweight or obesity, and type 2 diabetes), mean weight loss was −9.6% with semaglutide 2.4 mg versus −3.4% with placebo from baseline to week 68. Improvements in cardiometabolic risk factors, including high blood pressure, atherogenic lipids and benefits on physical function and quality of life were seen with semaglutide 2.4 mg. The safety profile of semaglutide 2.4 mg was consistent across trials, primarily gastrointestinal adverse events. The magnitude of weight loss reported in the STEP trials offers the potential for clinically relevant improvement for individuals with obesity‐related diseases.

Long-acting amylin analogues for the management of obesity

Abstract: Purpose of review To summarize recent developments of long-acting amylin analogues for the treatment of obesity and to outline their mode of action. Recent findings Amylin is a pancreatic hormone acting to control energy homeostasis and body weight. Activity at the calcitonin and amylin receptors in the area postrema seems to – at least partly – be responsible for these effects of amylin. Both preclinical and early-stage clinical studies investigating long-acting amylin receptor analogues demonstrate beneficial effects on body weight in obesity. Cagrilintide, a novel amylin analogue suitable for once-weekly administration, is in phase II clinical development and has shown promising body weight reducing effects alone and in combination with the glucagon-like peptide 1 receptor agonist semaglutide. Summary Long-acting amylin analogues have emerged as a possible pharmacotherapy against obesity, but more studies are needed to support the utility and long-term effects of this strategy in relevant populations.

Beta-Hydroxybutyrate Suppresses Hepatic Production of the Ghrelin Receptor Antagonist LEAP2

Abstract: Abstract Introduction Liver-expressed antimicrobial peptide-2 (LEAP2) is an endogenous ghrelin receptor antagonist, which is upregulated in the fed state and downregulated during fasting. We hypothesized that the ketone body beta-hydroxybutyrate (BHB) is involved in the downregulation of LEAP2 during conditions with high circulating levels of BHB. Methods Hepatic and intestinal Leap2 expression were determined in 3 groups of mice with increasing circulating levels of BHB: prolonged fasting, prolonged ketogenic diet, and oral BHB treatment. LEAP2 levels were measured in lean and obese individuals, in human individuals following endurance exercise, and in mice after BHB treatment. Lastly, we investigated Leap2 expression in isolated murine hepatocytes challenged with BHB. Results We confirmed increased circulating LEAP2 levels in individuals with obesity compared to lean individuals. The recovery period after endurance exercise was associated with increased plasma levels of BHB levels and decreased LEAP2 levels in humans. Leap2 expression was selectively decreased in the liver after fasting and after exposure to a ketogenic diet for 3 weeks. Importantly, we found that oral administration of BHB increased circulating levels of BHB in mice and decreased Leap2 expression levels and circulating LEAP2 plasma levels, as did Leap2 expression after direct exposure to BHB in isolated murine hepatocytes. Conclusion From our data, we suggest that LEAP2 is downregulated during different states of energy deprivation in both humans and rodents. Furthermore, we here provide evidence that the ketone body, BHB, which is highly upregulated during fasting metabolism, directly downregulates LEAP2 levels. This may be relevant in ghrelin receptor–induced hunger signaling during energy deprivation.

GIP affects hepatic fat and brown adipose tissue thermogenesis, but not white adipose tissue transcriptome in T1D.

Abstract: AIMS/HYPOTHESIS Glucose-dependent insulinotropic polypeptide (GIP) has been proposed to exert insulin-independent effects on lipid and bone metabolism. We investigated the effect of a 6-day s.c. 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 s.c. 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; HbA1c 51 ± 10 mmol/mol [6.8 ± 3.1%]) experienced transiently increased circulating concentrations of 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 to placebo. After six 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 to placebo. WAT transcriptomic profile as well as circulating lipid species, proteome, markers of inflammation, and bone homeostasis were unaffected. CONCLUSIONS/INTERPRETATION Six days s.c. 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.

Enterohepatic, Gluco-metabolic, and Gut Microbial Characterization of Individuals With Bile Acid Malabsorption

Abstract: Background and AimsBile acid malabsorption (BAM) is a debilitating disease characterized by loose stools and high stool frequency. The pathophysiology of BAM is not well-understood. We investigated postprandial enterohepatic and gluco-metabolic physiology, as well as gut microbiome composition and fecal bile acid content in patients with BAM.MethodsTwelve participants with selenium-75 homocholic acid taurine test–verified BAM and 12 healthy controls, individually matched on sex, age, and body mass index, were included. Each participant underwent 2 mixed meal tests (with and without administration of the bile acid sequestrant colesevelam) with blood sampling and evaluation of gallbladder motility; bile acid content and microbiota composition were evaluated in fecal specimens.ResultsPatients with BAM were characterized by increased bile acid synthesis as assessed by circulating 7-alpha-hydroxy-4-cholesten-3-one, fecal bile acid content, and postprandial concentrations of glucose, insulin, C-peptide, and glucagon. The McAuley index of insulin sensitivity was lower in patients with BAM than that in healthy controls. In patients with BAM, colesevelam co-administered with the meal reduced postprandial concentrations of bile acids and fibroblast growth factor 19 and increased 7-alpha-hydroxy-4-cholesten-3-one concentrations but did not affect postprandial glucagon-like peptide 1 responses or other gluco-metabolic parameters. Patients with BAM were characterized by a gut microbiome with low relative abundance of bifidobacteria and high relative abundance of Blautia, Streptococcus, Ruminococcus gnavus, and Akkermansia muciniphila.ConclusionPatients with BAM are characterized by an overproduction of bile acids, greater fecal bile acid content, and a gluco-metabolic profile indicative of a dysmetabolic prediabetic-like state, with changes in their gut microbiome composition potentially linking their enterohepatic pathophysiology and their dysmetabolic phenotype. ClinicalTrials.gov number NCT03009916. Bile acid malabsorption (BAM) is a debilitating disease characterized by loose stools and high stool frequency. The pathophysiology of BAM is not well-understood. We investigated postprandial enterohepatic and gluco-metabolic physiology, as well as gut microbiome composition and fecal bile acid content in patients with BAM. Twelve participants with selenium-75 homocholic acid taurine test–verified BAM and 12 healthy controls, individually matched on sex, age, and body mass index, were included. Each participant underwent 2 mixed meal tests (with and without administration of the bile acid sequestrant colesevelam) with blood sampling and evaluation of gallbladder motility; bile acid content and microbiota composition were evaluated in fecal specimens. Patients with BAM were characterized by increased bile acid synthesis as assessed by circulating 7-alpha-hydroxy-4-cholesten-3-one, fecal bile acid content, and postprandial concentrations of glucose, insulin, C-peptide, and glucagon. The McAuley index of insulin sensitivity was lower in patients with BAM than that in healthy controls. In patients with BAM, colesevelam co-administered with the meal reduced postprandial concentrations of bile acids and fibroblast growth factor 19 and increased 7-alpha-hydroxy-4-cholesten-3-one concentrations but did not affect postprandial glucagon-like peptide 1 responses or other gluco-metabolic parameters. Patients with BAM were characterized by a gut microbiome with low relative abundance of bifidobacteria and high relative abundance of Blautia, Streptococcus, Ruminococcus gnavus, and Akkermansia muciniphila. Patients with BAM are characterized by an overproduction of bile acids, greater fecal bile acid content, and a gluco-metabolic profile indicative of a dysmetabolic prediabetic-like state, with changes in their gut microbiome composition potentially linking their enterohepatic pathophysiology and their dysmetabolic phenotype. ClinicalTrials.gov number NCT03009916.

Mapping prohormone processing by proteases in human enteroendocrine cells using genetically engineered organoid models

Abstract: Significance Enteroendocrine cells control key physiological processes such as appetite and insulin secretion through the secretion of neurotransmitters and peptide hormones. The bioactive peptides are subject to complex proteolytic processing essential for their activation or inactivation. Moreover, alternative processing allows for the generation of different peptides from the same precursor protein. We use human organoid cultures combined with CRISPR-Cas9–mediated loss of function and peptidomics to assay the peptide spectrum of gut proteases. We identify substrates of these enzymes and identify the production of intestinal glucagon in organoids. A more complete understanding of hormone processing could allow a rational design of therapeutic interventions targeting these proteases.

Dasiglucagon Effectively Mitigates Postbariatric Postprandial Hypoglycemia: A Randomized, Double-Blind, Placebo-Controlled, Crossover Trial.

Abstract: OBJECTIVE To investigate the efficacy and safety of dasiglucagon, a novel stable glucagon analog in a liquid formulation, in Roux-en-Y gastric bypass (RYGB)-operated individuals suffering from postbariatric hypoglycemia (PBH). RESEARCH DESIGN AND METHODS In a randomized, double-blind, placebo-controlled, crossover trial, 10 RYGB-operated participants with continuous glucose monitoring-verified PBH were randomly assigned to 3 trial days, each consisting of a 240-min standardized liquid mixed-meal test with the subcutaneous injection of placebo or 80 μg or 200 μg dasiglucagon. RESULTS Compared with placebo, treatment with both 80 and 200 µg dasiglucagon raised nadir plasma glucose (PG) (placebo: 3.0 ± 0.2 mmol/L [mean ± SEM]; 80 μg dasiglucagon: 3.9 ± 0.3 mmol/L, P = 0.002; 200 μg dasiglucagon: 4.5 ± 0.2 mmol/L, P = 0.0002) and reduced time in hypoglycemia (PG <3.9 mmol/L) by 70.0 min (P = 0.030 and P = 0.008). CONCLUSIONS Single-dose administration of dasiglucagon effectively mitigated postprandial hypoglycemia.

The effect of curcumin on hepatic fat content in individuals with obesity

Abstract: To evaluate the effect of curcumin treatment on hepatic fat content in obese individuals.

Acute concomitant glucose‐dependent insulinotropic polypeptide receptor antagonism during glucagon‐like peptide 1 receptor agonism does not affect appetite, resting energy expenditure or food intake in patients with type 2 diabetes and overweight/obesity

Abstract: AIMS When combined with glucagon-like peptide 1 (GLP-1) receptor (GLP-1R) agonism, antagonising the glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR) reduces body weight in rodent models of obesity. Here, we investigated the acute effects of GIPR antagonism combined with a GLP-1 infusion on determinants of body weight in patients with type 2 diabetes and overweight/obesity. MATERIALS AND METHODS In a randomised, double-blind, placebo-controlled, crossover design, human synthetic GLP-1(7-36)NH2 (0.75 pmol/kg/min) was infused together with the selective GIPR antagonist GIP(3-30)NH2 (1,200 pmol/kg/min) or placebo for 320 minutes on two separate days covering an initial oral liquid mixed meal test and a terminal ad libitum meal. Appetite sensations, resting energy expenditure (REE) and food intake were evaluated, and subcutaneous adipose tissue (SAT) biopsies were analysed for triglyceride content. RESULTS Ten patients with type 2 diabetes and overweight/obesity (mean±SD; HbA1c 52±9 mmol/mol (7±1%); BMI 32.5±4.8 kg/m2 ) were included. Compared to placebo, infusion of the GIPR antagonist GIP(3-30)NH2 added to a GLP-1 infusion had no effect on appetite sensations, REE, food intake, or SAT triglyceride content during an ad libitum meal. Compared to placebo, GIP(3-30)NH2 lowered plasma glucagon by -12.4±5.9% (p=0.037), and reduced serum insulin by -32.5±8.0% (p=0.027). CONCLUSIONS During short term infusion, we found no effect of GIPR antagonism added to GLP-1R agonism on appetite sensations, REE, SAT triglyceride content or food intake in patients with type 2 diabetes and overweight/obesity. This article is protected by copyright. All rights reserved.

MYC mRNA expression throughout the intestine is not associated with body mass index or type 2 diabetes

Abstract: Inspired by the prospect of intestinal MYC reduction as a putative drug target against metabolic disorders, we investigated MYC mRNA expression in intestinal mucosa biopsies sampled using double-balloon enteroscopy along the entire intestinal tract of 12 patients with type 2 diabetes and 12 matched healthy controls. In these individuals with body mass index (BMI) ranging from 20 to 31 kg/m2 , the mean MYC mRNA expression varied along the intestine with the lowest level observed at the distal small intestine and the greatest expression levels in the proximal small intestine and in the colon. We do not see a correlation between intestinal mucosal MYC mRNA expression and BMI or glycaemic control, and thus, our findings do not support the hypothesis of intestinal MYC as a putative drug target against obesity and metabolic diseases.

The Glucagon Receptor Antagonist LY2409021 does not affect gastrointestinal-mediated glucose disposal or the incretin effect in individuals with and without type 2 diabetes.

Abstract: OBJECTIVE Gastrointestinal-mediated glucose disposal (GIGD) during oral glucose tolerance test (OGTT) reflects the percentage of glucose disposal caused by mechanisms elicited by the oral route of glucose administration. GIGD is reduced in patients with type 2 diabetes (T2D) due to a reduced incretin effect, but possibly also due to inappropriate suppression of glucagon after oral glucose. We investigated the effect of glucagon receptor antagonism on GIGD, the incretin effect and glucose excursions in patients with T2D and controls without diabetes. DESIGN A double-blind, randomised, placebo-controlled crossover study was conducted. METHODS Ten patients with T2D and 10 gender, age and BMI-matched controls underwent two 50 g OGTTs and two isoglycaemic IV glucose infusions, succeeding (~10 hours) single-dose administration of 100 mg of the glucagon receptor antagonist LY2409021 or placebo, respectively. RESULTS Compared to placebo, LY2409021 reduced fasting plasma glucose in patients with T2D and controls. Plasma glucose excursions after oral glucose assessed by baseline-subtracted AUC were increased by LY2409021 compared to placebo in both groups, but no effect of LY2409021 on GIGD or the incretin effect was observed. LY2409021 increased fasting glucagon concentrations three-fold compared to placebo concentrations. CONCLUSIONS Glucagon receptor antagonism with LY2409021 had no effect on the impaired GIGD or the impaired incretin effect in patients with T2D and did also not affect these parameters in the controls. Surprisingly, we observed reduced oral glucose tolerance with LY2409021 which may be specific for this glucagon receptor antagonist.

Hypoglycaemia and rebound hyperglycaemia increase left ventricular systolic function in patients with type 1 diabetes

Abstract: To investigate echocardiographic changes during acute hypoglycaemia followed by recovery to hyperglycaemia or euglycaemia in patients with type 1 diabetes.

Acute changes in plasma glucose increases left ventricular systolic function in insulin‐treated patients with type 2 diabetes and controls

Abstract: 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.

235-OR: Sustained QTc Prolongation during Recovery from Hypoglycemia in Patients with Type 1 Diabetes

Abstract: Hypoglycemia and increased glycemic variability have been associated with cardiac arrhythmias and sudden cardiac death. We investigated cardiac repolarization during acute hypoglycemia followed by recovery to hyperglycemia or euglycemia in patients with type 1 diabetes. In a randomized crossover study, patients with type 1 diabetes (N=24, (mean±SD) age 53±years, HbA1c 7.5±0.8% [57.6±8.9 mmol/mol], diabetes duration 23±14 years, BMI 25.7± 3.1 kg/m2) underwent two clamps with three steady-state phases: 1) a hyperinsulinemic-euglycemic phase for 45 minutes, 2) a hyperinsulinemic-hypoglycemic phase for 60 minutes, and 3) a recovery phase in hyperglycemia (clamp A) or euglycemia (clamp B) for 60 minutes. Continuous ECG (Holter) monitoring and blood samples for counterregulatory hormones and plasma potassium were obtained. Linear mixed models were used to assess the impact of hypoglycemia and recovery to hyperglycemia vs. euglycemia on cardiac repolarization. Heart rate-corrected QT (QTc) (Fridericia’s formula) progressively increased from baseline (mean (95% CI) , clamp A: 415 msec (409;421) ; clamp B: 418 msec (412;424)) during hypoglycemia on both clamp days (∆mean (95% CI) , clamp A: 21 msec (11;31) ; clamp B: 22 msec (12;31)) . In the recovery phase, QTc remained increased during hyperglycemia and euglycemia (17 msec (11;21) vs. 14 msec (10;20)) with no difference in change between recovery to hyperglycemia compared to euglycemia (3 msec (-6;11) , P=0.5442) . No significant changes from baseline were observed in QTc dispersion (heterogeneity of myocardial repolarization) during hypoglycemia or in the recovery phases. We conclude that clinically significant QTc prolongations during insulin-induced hypoglycemia remain during a 60-minute recovery period independently of recovery to hyperglycemia or euglycemia in patients with type 1 diabetes. Thus, vulnerability for serious cardiac arrhythmias and sudden cardiac death may extend beyond a hypoglycemic event itself. C.R.Andreasen: None. A.Andersen: n/a. P.G.Hagelqvist: None. J.V.Lauritsen: None. S.Engberg: Employee; Novo Nordisk A/S. J.J.Holst: Advisory Panel; Novo Nordisk, Board Member; Antag Therapeutics, Bainan Biotech. U.Pedersen-bjergaard: Advisory Panel; Novo Nordisk A/S, Sanofi. 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. 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. Danish Diabetes Academy (NNF17SA0031406)

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

Abstract: 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.

Amylin and calcitonin - physiology and pharmacology.

Abstract: Type 2 diabetes is a common manifestation of metabolic dysfunction due to obesity and constitutes a major burden for modern health care systems, in concert with the alarming rise in obesity worldwide. In recent years, several successful pharmacotherapies improving glucose metabolism have emerged, and some of these also promote weight loss, thus, ameliorating insulin resistance. However, the progressive nature of type 2 diabetes is not halted by these new anti-diabetic pharmacotherapies. Therefore, novel therapies promoting weight loss further and delaying diabetes progression are needed. Amylin, a beta cell hormone, has satiating properties and it also delays gastric emptying and inhibits postprandial glucagon secretion with the net result of reducing postprandial glucose excursions. Amylin acts through the three amylin receptors, which have partial identity to the calcitonin receptor. Calcitonin, derived from thyroid C cells, is best known for its role in humane calcium metabolism, where it inhibits osteoclasts and reduces circulating calcium. However, calcitonin, particularly of salmon origin, has also been shown to affect insulin sensitivity, reduce gastric emptying rate and promote satiation. Pre-clinical trials with agents targeting the calcitonin receptor and the amylin receptors, which are based on the calcitonin core receptor, show improvements in several parameters of glucose metabolism including insulin sensitivity and some of these agents are currently undergoing clinical trials. Here, we review the physiological and pharmacological effects of amylin and calcitonin and discuss the future potential of amylin and calcitonin-based treatments for patients with type 2 diabetes and obesity.

Residual inflammatory risk appeared related to weight, atherogenic lipid profile and biomarkers of inflammation, but not to glycaemic control in type 1 diabetes

Abstract: Mortality associated with atherosclerotic cardiovascular disease reduces average life expectancy by more than a decade in type 1 diabetes. Systemic inflammation drives atherosclerosis, and the concept of residual inflammatory risk (defined by high-sensitivity C-reactive protein (hsCRP) ≥2 mg/l) poses a potential, new therapeutic target for lowering residual cardiovascular risk in type 1 diabetes. However, the characteristics of individuals with residual inflammatory risk in type 1 diabetes are unknown. Identify differences in relevant demographics, clinical and paraclinical parameters for individuals with residual inflammatory risk as compared to those without in type 1 diabetes. Baseline characteristics as stratified for CRP ≥2 mg/l were analysed in 105 patients with type 1 diabetes participating in a previously published clinical trial. The study population was sampled to represent the broad background population struggling with glycaemic control and with a high cardiovascular risk. Residual inflammatory risk was seen in 39.1% of the study population. Compared to individuals without residual inflammatory risk, individuals with residual inflammatory risk were more frequently women, had increased body weight, body mass index and dual-energy X-ray absorptiometry (DXA)-assessed fat mass and exhibited elevated levels of low-density lipoprotein (LDL), very low-density lipoprotein (VLDL) and total cholesterol as well as triglycerides, interleukin 6 and tumour necrosis factor alpha (Table 1). Glycated haemoglobin, blood pressure and markers of renal function were similar between groups (Table 1). In the present cohort of individuals with type 1 diabetes, residual inflammatory risk was seen in 39.1% (similar to what is observed outside of type 1 diabetes) and appeared related to overweight/obesity, an atherogenic lipid profile and circulating biomarkers of inflammation but not to glycaemic control, blood pressure or renal function. Type of funding sources: Private company. Main funding source(s): AstraZenecaHerlev Gentofte Hospital

182-OR: Clinical Effects of SGLT2 Inhibitors in HNF1A-Diabetes (MODY3) : A Case Series

Abstract: Mutations in hepatocyte nuclear factor 1-alpha (HNF1A) cause HNF1A-diabetes (or maturity-onset diabetes of the young type 3 (MODY3)) . Treatment of HNF1A-diabetes is primarily based on sulphonylureas (SU) and secondarily insulins, glucagon-like peptide 1 receptor agonists (GLP1-RA) and dipeptidyl peptidase-4 inhibitors (DPP4i) . Sodium-glucose cotransporter-2 inhibitors (SGLT2i) are effective glucose-lowering agents, cause body weight loss and protect from chronic kidney disease, heart failure and major adverse cardiovascular events. The utility of SGLT2i in patients with HNF1A-diabetes is unknown. Here, we describe a case series of five patients with HNF1A-diabetes treated with SGLT2i. Patient characteristics (median [range]) : age: 52 [35; 68] years; men/women: n=4/1; diabetes duration: 23 [9; 55] years; age at diabetes onset: 18 [13; 44] years; HbA1c: 6.9 [6.0; 7.4]% (52 [42; 57] mmol/mol) ; body weight: 92.3 [65.5; 95.1] kg; BMI: 25.6 [23.8; 29.4] kg/m2. At baseline, patients were treated with SU (n=5) , insulin (n=3; total daily dose: 15 [6; 25] IE divided into 1-4 injections/day) , DPP-4i (n=3) , GLP1-RA (n=2) , metformin (n=1) . All patients were started on empagliflozin mg QD. Follow-up was 1.5 [0.7; 1.8] years (total 6.2 patient years) . After three to six months of SGLT2i therapy, HbA1c was 6.1 [5.5; 7.5]% (43 [37; 59] mmol/mol) and had decreased in four patients (HbA1c change: -0.5 [-1.3; 0.7]% (-5 [-14; 8] mmol/mol)) , while body weight had decreased in all patients (change: -3.4 [-5.9; -1.5] kg) . During SGLT2i treatment, insulin was fully ceased in two patients and insulin dose was reduced from 15 IE/day to 3 IE/day in one patient. No serious adverse events were reported. Our data suggest that SGLT2i is safe, have glucose-lowering effects and is well-tolerated in HNF1A-diabetes, but randomized controlled trials are needed. H.Maagensen: None. S.Haedersdal: None. J.Krogh: None. T.Hansen: 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. 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.

Abstract 34: Time spent in glycemic control after initiating treatment with oral semaglutide versus empagliflozin: An exploratory analysis of the PIONEER 2 trial

Abstract: A standard objective in the management of T2D is the achievement and maintenance of HbA1C targets, but the duration of time that patients spend within glycemic control targets has not been previously reported for oral semaglutide (sema). In this exploratory analysis, the duration of time that patients were in glycemic control (HbA1C <7.0% and <6.5%) during the 52-week PIONEER 2 trial (NCT02863328) was assessed. Patients with uncontrolled T2D (N=822; HbA1C 7.0─10.5%) were randomized to oral sema 14 mg once daily or empagliflozin (empa) 25 mg once daily. Both drugs underwent dose escalation, with oral sema starting at 3 mg, increasing to 7 mg after 4 weeks, and 14 mg after 8 weeks. Empa was initiated at 10 mg and escalated to 25 mg after 8 weeks. For this analysis, outcomes were evaluated using the on-treatment without rescue medication observation period, in all randomized patients. Baseline characteristics were similar between treatment arms. Mean baseline HbA1C for both arms was 8.1%. A greater proportion of patients receiving oral sema vs. empa achieved HbA1C <7.0% at some point during the study (78% vs. 60%), and for the following lengths of time that HbA1C remained <7%: ≥14 weeks (65% vs. 48%); ≥26 weeks (56% vs. 38%); and ≥38 weeks (46% vs. 28%). During treatment, the overall mean duration of time spent at HbA1C <7.0% and <6.5% was 27 weeks and 16 weeks, respectively, for oral sema, and 19 weeks and 7 weeks for empa. Based on the trial product estimand, the odds of patients achieving HbA1C <7.0% at both week 26 and 52 were significantly greater with oral sema vs. empa (estimated odds ratio 4.12 [95% CI 2.94, 5.76]; p<0.0001). In conclusion, despite an 8-week dose escalation schedule and a mean baseline HbA1C of 8.1%, nearly half of patients receiving oral sema achieved glycemic control (HbA1C <7.0%) for more than 70% of the 52-week treatment duration. These data suggest that patients spend more time in glycemic control during treatment with oral sema vs. empa.

Protocol for a 30-day randomised, parallel-group, non-inferiority, controlled trial investigating the effects of discontinuing renin-angiotensin system inhibitors in patients with and without COVID-19: the RASCOVID-19 trial

Abstract: Introduction The COVID-19 pandemic caused by the virus SARS-CoV has spread rapidly and caused damage worldwide. Data suggest a major overrepresentation of hypertension and diabetes among patients experiencing severe courses of COVID-19 including COVID-19-related deaths. Many of these patients receive renin-angiotensin system (RAS) inhibiting therapy, and evidence suggests that treatment with angiotensin II receptor blockers (ARBs) could attenuate SARS-CoV-induced acute respiratory distress syndrome, and ACE inhibitors and ARBs have been suggested to alleviate COVID-19 pulmonary manifestations. This randomised clinical trial will address whether RAS inhibiting therapy should be continued or discontinued in hospitalised patients with COVID-19. Methods and analysis This trial is a 30-day randomised parallel-group non-inferiority clinical trial with an embedded mechanistic substudy. In the main trial, 215 patients treated with a RAS inhibitor will be included. The participants will be randomly assigned in a 1:1 ratio to either discontinue or continue their RAS inhibiting therapy in addition to standard care. The patients are included during hospitalisation and followed for a period of 30 days. The primary end point is number of days alive and out of hospital within 14 days after recruitment. In a mechanistic substudy, 40 patients treated with RAS inhibition, who are not in hospital and not infected with COVID-19 will be randomly assigned to discontinue or continue their RAS inhibiting therapy with the primary end point of serum ACE2 activity. Ethics and dissemination This trial has been approved by the Scientific-Ethical Committee of the Capital Region of Denmark (identification no. H-20026484), the Danish Medicines Agency (identification no. 2020040883) and by the Danish Data Protection Agency (P-2020-366). The results of this project will be compiled into one or more manuscripts for publication in international peer-reviewed scientific journals. Trial registration number 2020-001544-26; NCT04351581.

The impact of statins and RAS inhibitors on the association between delayed antidiabetic treatment and the risk of cardiovascular event in patients with a first HbA1c between 48–57 mmol/mol

Abstract: In addition to lifestyle intervention, guidelines recommend initiation of antidiabetic (AD) treatment within 3 months of diagnosing type 2 diabetes (T2D). Yet, patients with an initial HbA1c level between 48 and 57 mmol/mol may await effects of lifestyle intervention up to 6 months. Omitting initial AD treatment and any lifestyle-induced remission, may affect initiation of statins and renin-angiotensin system inhibitors (RASi) and, thus, cardiovascular risk. To examine whether omission of initial AD treatment is associated with an increased 5-year risk of first-time major cardiovascular event (MACE: myocardial infarction/stroke/all-cause death) compared with well-controlled patients on AD. Further, whether lower initial use of statins and RASi could explain this excess risk of MACE. We used Danish registers to identify patients with a first-measured HbA1c of 48–57 mmol/mol between 2014 and 2020. We included patients aged 40–80 years without prior atherosclerotic disease that were alive the following 180 days (the index date). At date of index, we divided patients into four groups according to AD treatment and achieved HbA1c (mmol/mol): well-controlled (HbA1c ≤47) on AD; poorly controlled (HbA1c ≥48) on AD; remission (HbA1c ≤47) not on AD; poorly controlled (HbA1c ≥48) not on AD. Based on a Cox-regression model and imputations of treatment values of statins and RASi from two logistic regression models, we examined to what extent the observed standardised 5-year risk of MACE within each group could be reduced if each group had the same probability of treatment initiation with statin and RASi as well-controlled patients on AD. We included 14,206 patients (median age 59 [IQR 51–68] years; 52.0% men) with the following distribution according to AD group: well-controlled on AD: 22.3%; poorly controlled on AD: 14.7%; remission not on AD: 38.3%; poorly controlled not on AD: 24.6%. Patients not on AD had lower probabilities of initiation of statins and RASi compared with patients on AD (Figure 1). Compared with well-controlled on AD, the absolute 5-year risk of MACE was increased with 3.7% (95% CI 1.6–6.1) in poorly controlled on AD; 2.1% (95% CI 0.3–3.8) in remission not on AD; 3.4% (95% CI 1.6–5.3) in poorly controlled not on AD (Figure 1 and 2). If initiation of statins and RASi were the same as in the well-controlled group on AD, patients not on AD could reduce their risk of MACE with 1.0% (95% CI 0.2–1.8) in the remission group and with 2.2% (95% CI 1.2–3.2) in the poorly controlled group (Figure 2). Patients not on initial AD treatment had an increased 5-year risk of MACE, even among those who experienced remission of T2D. Lower initial use of statin and RASi seem to explain some of the excess risk of MACE in patients not on initial AD treatment. This study emphasizes the need for greater focus on primary prevention with statins and RASi in T2D, especially among patients not on AD treatment. Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): Research Grant from Steno Diabetes Center Sjaelland

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

Abstract: 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. 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. The Novo Nordisk Foundation

Ckd. pathophysiology, progression and risk factors

Abstract: i295