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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.

Glucagon secretion is regulated by circulating glucose, but it has turned out that amino acids also play an important role and that hepatic amino acid metabolism and glucagon are linked in a mutual feedback cycle, the liver–α-cell axis. On the basis of this knowledge, we hypothesized that hepatic steatosis might impair glucagon’s action on hepatic amino acid metabolism and lead to hyperaminoacidemia and hyperglucagonemia. We subjected 15 healthy lean and 15 obese steatotic male participants to a pancreatic clamp with somatostatin and evaluated hepatic glucose and amino acid metabolism when glucagon was at basal levels and at high physiological levels. The degree of steatosis was evaluated from liver biopsy specimens. Total RNA sequencing of liver biopsy specimens from the obese steatotic individuals revealed perturbations in the expression of genes predominantly involved in amino acid metabolism. This group was characterized by fasting hyperglucagonemia, hyperaminoacidemia, and no lowering of amino acid levels in response to high levels of glucagon. Endogenous glucose production was similar between lean and obese individuals. Our results suggest that hepatic steatosis causes resistance to the effect of glucagon on amino acid metabolism. This results in increased amino acid concentrations and increased glucagon secretion, providing a likely explanation for fatty liver–associated hyperglucagonemia.

In type 1 diabetes (T1D), the counterregulatory glucagon response to hypoglycemia disappears over time. It remains unknown whether this is due to lack of glucagon production or represents a malfunctioning stimulus-secretion coupling in pancreatic alpha cells. Arginine test (5 g of arginine infused intravenously (iv) over 1 minute after an overnight fast) with frequent measurements of plasma glucagon and serum C-peptide concentrations over 30 minutes was performed in 80 patients with T1D (19/61 females/males, age 49 (22-74) years (median (range)), duration 20 (2-46) years, BMI 28 (22-44) kg/m2, HbA1c 8.2 (7.5-10) %). The interrelationship between the arginine-induced glucagon response and demographic, clinical and biochemical parameters was evaluated using a stepwise approach in two multiple linear regression analysis models with glucagon area under curve (AUC) and Cmax, respectively, as dependent parameter. Mean baseline plasma glucagon concentrations amounted to 10.6±5.5 pmol/L (mean±SD). Overall, robust arginine-induced glucagon responses were observed (AUC: 499±209 pmol/L × min; Cmax: 41.0±17.7 pmol/L) independently of diabetes duration, age, HbA1c and beta cell secretory capacity. Fasting plasma glucagon and waist-to-hip ratio predicted the glucagon response in both models. When leaving out fasting plasma glucagon of the models, fasting low-density lipoprotein cholesterol and alanine aminotransferase as well as eGFR also predicted the glucagon response. In conclusion, glucagon secretory capacity in patients with T1D as assessed by iv arginine test seems preserved independently of diabetes duration, age, HbA1c and beta cell secretory capacity positioning pharmaceutical restoration of the glucagon counterregulatory response to hypoglycemia as an attractive therapeutic strategy for the protection of insulin-induced hypoglycemia. Disclosure J. Warnøe: None. 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. 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. N. J. Johansen: Employee; Self; Novo Nordisk. A. Lund: Speaker's Bureau; Self; Novo Nordisk, Sanofi. J. I. Bagger: None. N. J. Wewer albrechtsen: Research Support; Self; Mercodia, Novo Nordisk A/S, Regeneron Pharmaceuticals Inc., Speaker's Bureau; Self; Merck & Co., Inc., Mercodia. 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. 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. H. U. Andersen: Stock/Shareholder; Self; Novo Nordisk A/S.

Hyperglucagonemia is a well-known contributor to diabetic hyperglycemia, and glucagon-like peptide 1 (GLP-1) suppresses glucagon secretion. Reduced inhibitory effects of glucose and GLP-1 on glucagon secretion may contribute to the hyperglucagonemia in diabetes and influence the success of GLP-1 receptor agonist therapy. We examined the dose-response relationship for GLP-1 on glucose-induced glucagon suppression in healthy individuals and patients with type 2 and type 1 diabetes. In randomized order, 10 healthy individuals with normal glucose tolerance, 10 patients with type 2 diabetes, and 9 C-peptide–negative patients with type 1 diabetes underwent 4 separate stepwise glucose clamps (five 30-min steps from fasting level to 15 mmol/L plasma glucose) during simultaneous intravenous infusions of saline or 0.2, 0.4, or 0.8 pmol GLP-1/kg/min. In healthy individuals and patients with type 2 diabetes, GLP-1 potentiated the glucagon-suppressive effect of intravenous glucose in a dose-dependent manner. In patients with type 1 diabetes, no significant changes in glucagon secretion were observed during the clamps whether with saline or GLP-1 infusions. In conclusion, the glucagonostatic potency of GLP-1 during a stepwise glucose clamp is preserved in patients with type 2 diabetes, whereas our patients with type 1 diabetes were insensitive to the glucagonostatic effects of both glucose and GLP-1.

Patients with type 2 diabetes (T2D) have a markedly altered cardiac metabolism and twice the risk of developing heart failure compared to individuals without diabetes. The effect of acute changes in plasma glucose (PG) on cardiac function is unclear. We evaluated the effect of acute hyperglycemia and hypoglycemia on cardiac function. Insulin-treated patients with T2D (N=21, [mean±SD] age 62.8±6.5 years, BMI 29.0±4.2 kg/m2, HbA1c 51.0±5.4 mmol/mol) and matched controls (N=21, age 62.2±8.3 years, BMI 29.2±3.5, HbA1c 34.3±3.3 mmol/l) with normal glucose tolerance underwent a 3-step glucose clamp day with 30 min of steady-state PG during each step: 1) fasting PG (FPG), 2) hyperglycemia (FPG+10 mmol/l), and 3) hyperinsulinemic hypoglycemia (PG Acute hyperglycemia increased left ventricular ejection fraction (LVEF) from baseline in T2D patients ([mean±SEM, P-value] 4.5±1.7%, P=0.0108) whereas no change was observed in controls (2.0±1.7%, P=0.2525). Furthermore, left ventricular systolic function measured by s’ increased during hyperglycemia in both patients and controls (0.4±0.1 m/s (P=0.0007) and 0.6±0.1 m/s (P In conclusion, we demonstrate that LVEF increases during acute hyperglycemia in insulin-treated patients with T2D and that acute hypoglycemia markedly increases all measures of left ventricular systolic function. These results point to the importance of glycemia when evaluating left ventricular systolic function by echocardiography in patients with T2D. Disclosure A. Andersen: None. P.G. Jørgensen: None. J.I. Bagger: Speaker’s Bureau; Self; Novo Nordisk A/S. M. Baldassarre: None. M.B. Christensen: None. K.U. Abelin: None. U. Pedersen-Bjergaard: Advisory Panel; Self; Novo Nordisk A/S, Sanofi. Research Support; Self; Novo Nordisk A/S. J.J. Holst: Advisory Panel; Self; AstraZeneca, Merck Sharp & Dohme Corp., Novo Nordisk A/S, Zealand Pharma A/S. Other Relationship; Spouse/Partner; Antag Therapeutics. T.B. Lindhardt: None. F.K. Knop: Advisory Panel; Self; AstraZeneca, Merck Sharp & Dohme Corp., Mundipharma International, Novo Nordisk A/S, Sanofi. Consultant; Self; Carmot Therapeutics, Inc., Eli Lilly and Company, Novo Nordisk A/S. Research Support; Self; AstraZeneca, Gubra, Novo Nordisk A/S, Sanofi, Zealand Pharma A/S. Speaker’s Bureau; Self; AstraZeneca, Lupin Pharmaceuticals, Inc., Merck Sharp & Dohme Corp., Norgine B.V., Novo Nordisk A/S. T. Vilsbøll: Advisory Panel; Self; AstraZeneca, Mundipharma International, Novo Nordisk A/S, Sun Pharmaceutical Industries Ltd. Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Lilly Diabetes, Medscape, Merck Sharp & Dohme Corp., Sanofi.

Hyperglucagonemia is considered an important pathophysiological trait of type 2 diabetes and occurs also in individuals with obesity. The underlying mechanisms remain unclear. We hypothesized that hyperglucagonemia is a consequence of steatosis-induced glucagon resistance. We examined 15 healthy (BMI: 23.2±1.6 (mean±SD) kg/m2, age 40.9±12.8 years, hepatic steatosis 2:15) and 15 obese individuals (BMI: 33.6±2.1 kg/m2, age 35.8±9.4 years, hepatic steatosis 14:15) in a pancreatic somatostatin clamp with basal insulin (1 mU/kg/h) and low and high glucagon infusion rates (0.6 and 3.0 ng/kg/min). Glucagon sensitivity was assessed as changes in plasma amino acids (AA) and endogenous glucose production (EGP) and urea synthesis (U.S.) measured by tracer techniques. Basal glucagon and AA were significantly higher in obese compared to lean individuals, but no differences in basal EGP or U.S. were observed. In the lean group AA significantly dropped in response to glucagon infusion (p In conclusion, our results point to steatosis-induced hepatic glucagon resistance and compensatory glucagon secretion mediated by glucagonotropic amino acids as a likely explanation of obesity-associated hyperglucagonemia. Disclosure M.P. Suppli: None. J.I. Bagger: None. A.B. Lund: Other Relationship; Self; Novo Nordisk A/S. N.J. Wewer Albrechtsen: Speaker's Bureau; Self; Merck Sharp & Dohme Corp.. Other Relationship; Self; Mercodia, Alpco. J.J. Holst: Advisory Panel; Self; Novo Nordisk A/S. Board Member; Self; Zealand Pharma A/S. Speaker's Bureau; Self; Merck Sharp & Dohme Corp., AstraZeneca. Research Support; Self; Danish Diabetes Academy, Novo Nordisk Foundation. Other Relationship; Self; Antag Therapeutics. Other Relationship; Spouse/Partner; Antag Therapeutics. T. Vilsbøll: Advisory Panel; Self; Amgen Inc., Boehringer Ingelheim GmbH, Eli Lilly and Company, AstraZeneca, MSD K.K., Sanofi, Novo Nordisk A/S. Consultant; Self; Amgen Inc., Boehringer Ingelheim GmbH, Eli Lilly and Company, AstraZeneca, MSD K.K., Sanofi, Novo Nordisk A/S. Speaker's Bureau; Self; Amgen Inc., Boehringer Ingelheim GmbH, Eli Lilly and Company, AstraZeneca, MSD K.K., Sanofi, Novo Nordisk A/S. Research Support; Self; Eli Lilly and Company, Novo Nordisk A/S. F.K. Knop: Advisory Panel; Self; AstraZeneca. Consultant; Self; AstraZeneca. Research Support; Self; AstraZeneca. Speaker's Bureau; Self; AstraZeneca. Advisory Panel; Self; Eli Lilly and Company. Speaker's Bureau; Self; Eli Lilly and Company. Advisory Panel; Self; Amgen Inc.. Speaker's Bureau; Self; Merck Sharp & Dohme Corp.. Advisory Panel; Self; Novo Nordisk A/S. Consultant; Self; Novo Nordisk A/S. Speaker's Bureau; Self; Novo Nordisk A/S. Consultant; Self; Amgen Inc.. Advisory Panel; Self; MedImmune, Sanofi. Consultant; Self; Sanofi. Research Support; Self; Sanofi. Speaker's Bureau; Self; Sanofi.

More than half the world’s population lives in cities and two thirds of 425 million people with diabetes live in cities. That makes cities a focal point for tackling diabetes. As part of Cities Changing Diabetes (CCD) five diverse cities (Copenhagen, Houston, Mexico City, Shanghai, Tianjin) have implemented actions based on 740 individual interviews with people with type 2 diabetes or at increased risk of developing it. Based on participants’ perspectives on socio-cultural barriers to live a healthy life action plans were created relevant to the local diabetes challenge and city context and tailor-made interventions were designed. CCD is a partnership between Novo Nordisk A/S, University College London, and Steno Diabetes Center Copenhagen aiming to map the diabetes challenge, understand risk and vulnerability to type 2 diabetes, and design interventions tailor-made to the respective city context. In the cities the program is driven by local partnerships in a collaborative working approach bringing together city governments, academics, businesses, city planners, patient organizations, faith-based organizations, and other non-governmental organizations. The research insights led to four arenas for impactful interventions: Health promoting policies by incorporating awareness and understanding of type 2 diabetes into local policies to address the diabetes challenge and improve overall health. Urban planning by integrating health-promoting aspects such as walkability and bikeability in urban planning to increase the ability to live a healthy life. Community involvement by strengthening communities around citizens vulnerable to diabetes to build resilience, improve diabetes care and quality of life. Health system strengthening by building capacity into the local healthcare system to help vulnerable citizens to access it. In conclusion, insights from the research have directly guided development of city-specific tailor-made interventions within four arenas. Disclosure A. Napier: Consultant; Self; Novo Nordisk A/S. N. Lund: Employee; Self; Novo Nordisk A/S. Stock/Shareholder; Self; Novo Nordisk A/S. M. Bagger: Employee; Self; Novo Nordisk A/S. Stock/Shareholder; Self; Novo Nordisk A/S. Stock/Shareholder; Spouse/Partner; Novo Nordisk A/S. B.B. Jensen: None.

The molecular events underlying the development and progression of nonalcoholic fatty liver disease (NAFLD), covering a wide spectrum from simple hepatic steatosis to the more aggressive inflammatory manifestation, nonalcoholic steatohepatitis (NASH), remain elusive. To promote the understanding of the pathophysiology behind this disease spectrum we characterized lean controls vs. individuals with simple NAFLD and NASH, respectively, by standard clinical measures, histopathology and global mRNA profiling of liver biopsies. The study included 11 patients with simple NAFLD, 11 patients with NASH (based on the FLIP/Bedossa score) and 15 lean healthy individuals. Liver biopsies from all subjects were evaluated using diagnostic histopathological scoring of steatosis, inflammation, fibrosis and ballooning degeneration of hepatocytes. Global mRNA quantification of liver biopsies was performed by RNA-sequencing. No steatosis was seen in the lean healthy individuals, whereas all patients with simple NAFLD and NASH displayed moderate steatosis, and to some degree inflammation and fibrosis. Only NASH patients had ballooning degeneration of hepatocytes. Several marker genes such as collagens and galectin-3 showed good correlation with disease severity being markedly upregulated in the NAFLD and NASH groups compared to healthy controls. However, the histopathological categorization of patient samples into NAFLD and NASH did not correlate well with gene expression levels. We here provide a unique characterization of a cohort of individuals covering the spectrum from healthy lean subjects over individuals with simple NAFLD to patients with NASH. Clinical markers as well as hepatic pathology and gene expression clearly discriminate NAFLD/NASH patients from healthy individuals, but NAFLD and NASH patients appear highly similar at all parameters, except for histopathological scoring of ballooning. Disclosure K. Rigbolt: Employee; Self; Gubra. Stock/Shareholder; Self; Gubra. S. Veidal: None. S. Heebøll: None. M. Demant: None. J.I. Bagger: None. A.B. Lund: Other Relationship; Self; Novo Nordisk A/S. T. Vilsbøll: Advisory Panel; Self; Amgen Inc., Boehringer Ingelheim GmbH, Eli Lilly and Company, AstraZeneca, MSD K.K., Sanofi, Novo Nordisk A/S. Consultant; Self; Amgen Inc., Boehringer Ingelheim GmbH, Eli Lilly and Company, AstraZeneca, MSD K.K., Sanofi, Novo Nordisk A/S. Speaker's Bureau; Self; Amgen Inc., Boehringer Ingelheim GmbH, Eli Lilly and Company, AstraZeneca, MSD K.K., Sanofi, Novo Nordisk A/S. Research Support; Self; Eli Lilly and Company, Novo Nordisk A/S. N. Vrang: Board Member; Self; Gubra. Employee; Self; Gubra. Stock/Shareholder; Self; Gubra. J. Jelsing: Stock/Shareholder; Self; Gubra. Research Support; Self; Sanofi. F.K. Knop: Advisory Panel; Self; AstraZeneca. Consultant; Self; AstraZeneca. Research Support; Self; AstraZeneca. Speaker's Bureau; Self; AstraZeneca. Advisory Panel; Self; Eli Lilly and Company. Speaker's Bureau; Self; Eli Lilly and Company. Advisory Panel; Self; Amgen Inc.. Speaker's Bureau; Self; Merck Sharp & Dohme Corp.. Advisory Panel; Self; Novo Nordisk A/S. Consultant; Self; Novo Nordisk A/S. Speaker's Bureau; Self; Novo Nordisk A/S. Consultant; Self; Amgen Inc.. Advisory Panel; Self; MedImmune, Sanofi. Consultant; Self; Sanofi. Research Support; Self; Sanofi. Speaker's Bureau; Self; Sanofi.

Glucagon is believed to be a pancreas-specific hormone, and hyperglucagonemia has been shown to contribute significantly to the hyperglycemic state of patients with diabetes. This hyperglucagonemia has been thought to arise from α-cell insensitivity to suppressive effects of glucose and insulin combined with reduced insulin secretion. We hypothesized that postabsorptive hyperglucagonemia represents a gut-dependent phenomenon and subjected 10 totally pancreatectomized patients and 10 healthy control subjects to a 75-g oral glucose tolerance test and a corresponding isoglycemic intravenous glucose infusion. We applied novel analytical methods of plasma glucagon (sandwich ELISA and mass spectrometry–based proteomics) and show that 29–amino acid glucagon circulates in patients without a pancreas and that glucose stimulation of the gastrointestinal tract elicits significant hyperglucagonemia in these patients. These findings emphasize the existence of extrapancreatic glucagon (perhaps originating from the gut) in man and suggest that it may play a role in diabetes secondary to total pancreatectomy.

Maturity-onset diabetes of the young (MODY) is a clinically and genetically heterogeneous subgroup of non-autoimmune diabetes, constituting 1-2% of all diabetes. Because little is known about incretin function in patients with MODY, we studied the incretin effect and hormone responses to oral and intravenous glucose loads in patients with glucokinase (GCK)-diabetes (MODY2) and hepatocyte nuclear factor 1 alpha (HNF1A)-diabetes (MODY3), respectively, and in matched healthy control subjects. Both MODY groups exhibited glucose intolerance after oral glucose (most pronounced in patients with HNF1A-diabetes), but only patients with HNF1A-diabetes had impaired incretin effect and inappropriate glucagon responses to OGTT. Both groups of patients with diabetes showed normal suppression of glucagon in response to intravenous glucose. Thus, HNF1A-diabetes, similar to type 2 diabetes, is characterized by an impaired incretin effect and inappropriate glucagon responses, whereas incretin effect and glucagon response to oral glucose remain unaffected in GCK-diabetes, reflecting important pathogenetic differences between the two MODY forms. Maturity-onset diabetes of the young (MODY) is a clinically and genetically heterogeneous subgroup of non-autoimmune diabetes, constituting 1-2% of all diabetes. Because little is known about incretin function in patients with MODY, we studied the incretin effect and hormone responses to oral and intravenous glucose loads in patients with glucokinase (GCK)-diabetes (MODY2) and hepatocyte nuclear factor 1a (HNF1A)-diabetes (MODY3), respectively, and in matched healthy control subjects. Both MODY groups exhibited glucose intolerance after oral glucose (most pronounced in patients with HNF1A-diabetes), but only patients with HNF1A-diabetes had impaired incretin effect and inappropriate glucagon responses to OGTT. Both groups of patients with diabetes showed normal suppression of glucagon in response to intravenous glucose. Thus, HNF1A-diabetes, similar to type 2 diabetes, is characterized by an impaired incretin effect and inappropriate glucagon responses, whereas incretin effect and gluca-gon response to oral glucose remain unaffected in GCK-diabetes, reflecting important pathogenetic differences between the two MODY forms.

To assess the effects of insulin in stable coronary artery disease (CAD), 2 U i.v. insulin was given to 9 control and 10 CAD patients during coronary sinus catheterization. Hemodynamic and metabolic data were obtained before and for 90 min after insulin injection. Insulin induced no changes in heart rate, mean aortic pressure, rate-pressure product, coronary sinus flow, or coronary resistance. Metabolic changes were similar in both groups and included 1) 30% decrease of arterial glucose (P < .001) and 3-fold increase of myocardial glucose uptake (P < .001), 2) 1.5- to 2.5-fold elevation of arterial lactate (P < .001) and myocardial lactate usage (P < .001), respectively, 3) 50–70% suppression of arterial levels (P < .001) and myocardial uptake of free fatty acids (P < .01), and 4) 10% reduction of myocardial net oxygen consumption (P < .05). Myocardial citrate efflux increased in the CAD patients (P < .05), whereas alanine release rose only in control patients (P < .01), suggesting that glucose enters glycogen production in the CAD patients and pyruvate production in the control patients to a high degree. Myocardial glutamate uptake remained unchanged. In conclusion, insulin sensitivity was not altered in CAD. The insulin-induced shift from myocardial free fatty acid to carbohydrate usage may be beneficial to the ischemie heart by increasing glycogen stores, saving oxygen, and inhibiting an excess free-fatty acid concentration, which may be toxic during ischemia.