BACKGROUND:Glycaemic dysregulation is associated with clinically diagnosed atrial fibrillation (AF), but prior studies have largely relied on limited monitoring of heart rhythm and glucose levels. We investigated whether periods with higher glucose exposure were associated with AF burden and progression in individuals undergoing long-term continuous monitoring and serial haemoglobin A1c (HbA1c) measurements. METHODS:Post-hoc analysis of 884 LOOP Study participants without diabetes undergoing implantable loop recorder (ILR) screening for AF and repeated HbA1c measurements. AF burden, defined as percentage of time in AF, was calculated in the 60-days prior to blood sampling and analysed in groups by highest HbA1c level and using a two-part mixed-effects model, while AF progression was assessed by cumulative AF duration and burden over time. RESULTS:The dataset combined >1 million days of heart rhythm monitoring (including 34,852 with AF) with 3079 HbA1c measurements. The AF burden was 0.52% [0.09-3.45%], 0.78% [0.25-4.07%], and 4.42% [0.98-13.1%], for HbA1c measurements in the normal (≤38 mmol/mol), prediabetic (39-47 mmol/mol), and diabetic (≥48 mmol/mol) range, respectively. A 1 mmol/mol increase in HbA1c was associated with a 5% relative increase in AF burden (adjusted estimate 1.05 [1.00-1.09], p = 0.039). Participants reaching prediabetes or diabetes accumulated longer AF durations and higher AF burden over time compared to participants with consistently normal HbA1c. CONCLUSION:Higher HbA1c levels were associated with higher AF burden and lower HbA1c levels were associated with lower AF burden and less accumulation of AF over time. TRIAL REGISTRATION:ClinicalTrials.gov, identifier: NCT02036450.

OBJECTIVE:Maturity-onset diabetes of the young (MODY) caused by pathogenic variants in HNF1A is a common form of monogenic diabetes. Sulfonylurea drugs are considered first-line treatment of HNF1A-MODY (MODY3), but intensified treatment is often needed. HNF1A encodes a transcription factor involved in the regulation of the sodium-glucose cotransporter 2 (SGLT2). Accordingly, the glucose-lowering efficacy of SGLT2 inhibitors in HNF1A-MODY is questionable. Here, we assess the glucose-lowering effect of the SGLT2 inhibitor empagliflozin as an add-on for treatment of individuals with HNF1A-MODY. RESEARCH DESIGN AND METHODS:MOD3ST-TRIAL was a randomized, double-blind, placebo-controlled crossover trial. Adults with HNF1A-MODY treated with at least one glucose-lowering drug were randomized to be treated with empagliflozin 25 mg for 4 weeks followed by a 2-week washout period and then received placebo for 4 weeks or the opposite sequence. The primary outcome was mean glucose concentration assessed by 10 days of continuous glucose monitoring (CGM). RESULTS:Nineteen individuals were randomized and 18 participants (n = 10 women [56%]; median [Q1, Q3] HbA1c 7.5% [7.0, 8.4] or 58 [53, 68] mmol/mol, mean [SD] CGM glucose concentration 10.4 [2.5] mmol/L) completed the study. Compared with placebo, empagliflozin lowered the mean glucose level 2.3 mmol/L (95% CI 1.3 to 3.3; P = 0.0001). There were no significant differences in hypoglycemic outcomes. Adverse events were generally mild and transient, and no severe adverse events or study drug discontinuations were attributable to empagliflozin. CONCLUSIONS:Empagliflozin used for 4 weeks in adjunction with other glucose-lowering treatments markedly improved glycemia compared with placebo in individuals with HNF1A-MODY without significantly increasing risk of hypoglycemia or unexpected adverse effects.

To address the clinical dilemma of how best to counsel women with type 2 diabetes (T2D) using glucagon-like peptide-1 receptor agonists (GLP-1RA) regarding pregnancy. Animal studies raise concern for fetal loss, malformations and adverse fetal growth after GLP-1RA exposure. Nonetheless, three cohort studies and one prospective study including 2,994 women with T2D exposed to GLP-1RA in early pregnancy indicate no increased risk of malformations compared with unexposed pregnancies, and observational data in 168 GLP-1RA exposed pregnancies are reassuring regarding miscarriage and fetal growth. Women with T2D are advised to use contraception and to discontinue GLP-1RAs two months before planned pregnancy. Despite concerns in animal studies, GLP-1RA exposure in early T2D pregnancy has not been associated with increased risk of malformations. If a woman with T2D inadvertently becomes pregnant while using GLP-1RA, the existing human evidence does not support a recommendation of terminating pregnancy.

Previous studies have indicated that 29-amino-acid glucagon (i.e. ‘pancreatic’ glucagon) circulates in totally pancreatectomised individuals and that a postprandial glucagon response can be detected. Using a glucagon receptor antagonist (GRA), we investigated the possible role of extrapancreatic glucagon on glucose, lipid and amino acid metabolism in totally pancreatectomised individuals. In a randomised, crossover study, nine totally pancreatectomised individuals and nine matched healthy control individuals were given, in randomised order (planned on the website www.random.org ), 300 mg GRA (LY2409021; Eli Lilly) or placebo 10 h before two 3 h OGTTs. The experiment was double-masked (i.e. both participants and investigator were masked for the type of the experimental day [day A vs day B]). The key inclusion criteria for the healthy control participants were age >18 years, normal fasting plasma glucose and HbA1c 31–44 mmol/mol (5.0–6.2

Obesity in fertile women is associated with decreased fertility and complications during pregnancy and delivery. As discussed in this review, lifestyle interventions during pregnancy in women with obesity show limited effect, highlighting the need for pre-conceptional intervention studies. Bariatric surgery could be used on an individual basis when obesity risks outweigh the risk of giving birth to weight-restricted babies and when managed carefully by specialists. Due to insufficient knowledge of perinatal consequences, GLP-1-based therapies should be stopped months prior to conception and not used during pregnancy.

Objective: Pathogenic variants of HNF1A cause maturity-onset diabetes of the young type 3 (HNF1A-MODY). Individuals with HNF1A-MODY are primarily treated with sulfonylureas, while little is known about the effect of sodium-glucose cotransporter 2 (SGLT2) inhibitors in HNF1A-MODY. Interestingly, HNF1A-MODY is associated with increased glucosuria that has been attributed to lower expression of SGLT2 as observed in HNF1A knockout mice. Here, we investigated the impact of acute SGLT2 inhibition on glucosuria in individuals with HNF1A-MODY and type 2 diabetes, respectively. Research Design and Methods: In a randomized, double-blind, crossover study, individuals with HNF1A-MODY and type 2 diabetes underwent two three-step hyperglycemic clamps targeted at one-hour periods of 10, 14, and 18 mM glucose with and without acute SGLT2 inhibition (25 mg empagliflozin or placebo administrated 2 hours before clamp procedures). Results: Eleven individuals with HNF1A-MODY (age [mean ± SD]: 49 ± 15 years, GFR: 113 ± 18 mL/min) and ten individuals with type 2 diabetes (age: 63 ± 7 years, GFR: 103 ± 27 mL/min) were included. During the 3-hour hyperglycemic clamp, SGLT2 inhibition increased urinary glucose excretion in both groups (HNF1A-MODY: 24.5 g [95% CI 20.6; 28.3], type 2 diabetes: 23.5 g [95% CI 20.4; 26.5]). The effect of SGLT2 inhibition was not significantly different between the groups (1.0 g [95% CI -3.5; 5.6], P = 0.6). Conclusions: The robust effect of SGLT2 inhibition on urinary glucose excretion in individuals with HNF1A-MODY observed here point to SGLT2 inhibition as a relevant glucose-lowering treatment strategy in people with HNF1A-MODY.

This review summarises the current and possible future insulin treatment of type 2 diabetes. The type 2 diabetes treatment guidelines prioritise a person-centred approach with various options before insulin addressing cardiorenal protection. Long-acting daily insulin injections are warranted in severe hyperglycaemia or when glycaemic targets are not met. Insulin, when possible, should be combined with other agents to lower insulin dosage, weight gain and hypoglycaemia. Once-weekly insulin offers a promising treatment, reducing injection burden, enhancing treatment satisfaction, and lowering the risk of severe hypoglycaemia, potentially improving type 2 diabetes management.

Introduction & Objective: Pathogenic variants in HNF1A cause maturity-onset diabetes of the young type 3 (HNF1A-MODY, MODY3) which is associated with relative hyper-glucosuria that has been attributed to lower expression of sodium-glucose cotransporter 2 (SGLT2) in HNF1A knockout mice; questioning SGLT2 as a relevant treatment target in these individuals. Methods: In a randomized, double-blind, crossover study, persons with MODY3 and type 2 diabetes (T2D) underwent two three-step hyperglycemic clamps targeted at 10, 14, and 18 mmol/L (1h each) with and without acute SGLT2 inhibition (25 mg empagliflozin or placebo 2h before clamp). Results: Participants characteristics: MODY3 (N = 11, 5 men; age (mean, SD) 49 ± 15 years; BMI 24.5 ± 3.9 kg/m2; HbA1c 6.7 ± 0.7%; eGFR 109 ± 14 mL/min/1.73 m2); T2D (n = 10, 8 men; age 63 ± 7 years; BMI 26.4 ± 3.5 kg/m2; HbA1c 6.7 ± 0.6%; eGFR 93 ± 12 mL/min/1.73 m2). In both groups, SGLT2 inhibition had robust effects on urinary glucose excretion, urine volume, infused glucose, and plasma glucose AUC (data in table). No significant differences between groups in the effects of SGLT2 inhibition were observed. Conclusion: The similar effects of SGLT2 inhibition in persons with MODY3 and T2D observed here, point to SGLT2 inhibition as a relevant glucose-lowering treatment strategy in persons with MODY3 despite the potentially lower SGLT2 expression. Disclosure H. Maagensen: None. J.S. Jensen: None. S. Offersgaard Høyerup: None. A.B. Thuesen: None. J. Krogh: None. P. Rossing: Other Relationship; AstraZeneca, Bayer Inc., Boehringer-Ingelheim, Gilead Sciences, Inc., Novo Nordisk, Eli Lilly and Company, Novartis AG, Abbott Diagnostics. T. Hansen: None. F.K. Knop: Advisory Panel; AstraZeneca. Consultant; AstraZeneca. Speaker's Bureau; AstraZeneca. Advisory Panel; Boehringer-Ingelheim. Consultant; Boehringer-Ingelheim. Speaker's Bureau; Boehringer-Ingelheim. Advisory Panel; Eli Lilly and Company. Consultant; Eli Lilly and Company. Speaker's Bureau; Eli Lilly and Company. Stock/Shareholder; Eli Lilly and Company. Advisory Panel; Novo Nordisk A/S. Consultant; Novo Nordisk A/S. Employee; Novo Nordisk A/S. Research Support; Novo Nordisk A/S. Speaker's Bureau; Novo Nordisk A/S. Stock/Shareholder; Novo Nordisk A/S. Advisory Panel; Sanofi. Speaker's Bureau; Lundbeck. Advisory Panel; Zealand Pharma A/S. Consultant; Zealand Pharma A/S. Research Support; Zealand Pharma A/S. Speaker's Bureau; Zealand Pharma A/S. Stock/Shareholder; Zealand Pharma A/S. S. Haedersdal: None. T. Vilsbøll: Consultant; AstraZeneca. Advisory Panel; Boehringer-Ingelheim. Speaker's Bureau; Mundipharma. Advisory Panel; Novo Nordisk, Lilly Diabetes, Sanofi. Speaker's Bureau; Bayer Inc., Gilead Sciences, Inc. Advisory Panel; Sun Pharmaceutical Industries Ltd. Research Support; Lilly Diabetes.

Maturity-onset diabetes of the young (MODY) is a heterogeneous subset of monogenic diabetes characterized by early onset of diabetes, typically between the second and fifth decade of life. Pathogenic variants in HNF1A cause one of the most prevalent MODY types named HNF1A-MODY (or MODY3).1 Sulfonylureas (SU) are typically used as the primary treatment,2 while incretin-based treatments have also been shown to lower glucose levels.3, 4 In type 2 diabetes, sodium-glucose cotransporter 2 (SGLT2) inhibitors are effective glucose-lowering agents. However, the utility and safety of SGLT2 inhibitors in HNF1A-MODY are scarcely described.5-7 Here, we describe seven individuals with HNF1A-MODY treated with SGLT2 inhibitors as add-ons to SU, insulin and incretin-based therapies. At initiation of SGLT2 inhibitor, all persons (n = 7) were treated with SU (glimepiride) and incretin-based therapy, four persons were treated with insulin and one with metformin (Table 1). Estimated glomerular filtration rate (eGFR) was >90 mL/min/1.73 m2 for all but one individual with eGFR in the range of 45–60 mL/min/1.73 m2. The persons carried the following HNF1A variants: c.956-2A>G (n = 2), p.Glu332Ter, p.Leu12Phe, p.Pro379Ala, p.Pro379fs, p.Tyr218Cys (RefSeq NM_000545.5). All individuals started the SGLT2 inhibitor empagliflozin at a dose of 10 mg once daily. After 4 months, HbA1c had decreased in six individuals, BMI decreased in all participants, and three of four insulin-treated persons had discontinued insulin therapy (Table 1). After 1 year, the daily insulin dose was reduced from 15 units/day (four injections daily) to 2 units/day (one injection daily) in the remaining insulin-treated individual. After 1 year, HbA1c was markedly lower in three individuals (range −2.6%; −0.8% [−28; −9 mmol/mol]), including one person discontinuing insulin therapy), remained at baseline level (within 0.3% [3 mmol/mol]) in three participants (including two persons discontinuing insulin therapy) and was increased (1.1% [12 mmol/mol]) in the person with impaired kidney function in whom insulin dose was lowered. During the follow-up period (14 person-years), 11 adverse events were identified of which none were considered serious (death, life-threatening or leading to hospitalization) or led to permanent discontinuation of the SGLT2 inhibitor. Five adverse events were considered related to empagliflozin: balanitis (n = 1, single occasion), cystitis (three instances in two males, symptoms confirmed by either dipstick or urine culture) and mild polyuria (n = 1). Other adverse events considered not to be related to empagliflozin included non-specific dizziness (n = 2, single occasions, hypoglycaemia and volume-depletion were excluded as the cause), gastroenteritis (n = 2, no signs of volume depletion, not hospitalized) and flank/stomach pain (two instances in one individual, both leading to emergency department visit without hospitalization, considered urolithiasis). In conclusion, the use of an SGLT2 inhibitor was associated with glycaemic control that improved or remained stable despite discontinuation or reduction of insulin and decreased BMI. Further, no unexpected side effects were observed during the treatment with SGLT2 inhibitor. Data on the effects and use of SGLT2 inhibitor therapy in HNF1A-MODY are scarce. The cases presented here provide, to our knowledge, the largest data set on the efficacy and safety of long-term SGLT2 inhibitor therapy in HNF1A-MODY. HNF1A encodes the transcription factor hepatocyte nuclear factor 1-alpha (HNF1A), which is involved in the expression of glycolytic and mitochondrial enzymes in the β-cell.8 Pathogenic variants of HNF1A result in insulin secretion defects.8 HNF1A also regulates the expression of SGLT2 which encodes a glucose transporter that is responsible for the majority of glucose reuptake from the proximal tubules in the kidney.9 Individuals with HNF1A-MODY have a lower threshold for glucose excretion compared to individuals with type 1 diabetes and type 2 diabetes,9, 10 supporting the notion that SGLT2 expression is lower in individuals with HNF1A-MODY. Hypothetically, a reduced expression of SGLT2 in HNF1A-MODY may compromise the efficacy of SGLT2 inhibition in these individuals. However, a single dose of the SGLT2 inhibitor dapagliflozin has previously been shown to increase glucose excretion in persons with HNF1A-MODY5; supporting that SGLT2 inhibitors may induce glucosuria in HNF1A-MODY. HNF1A-MODY is characterised by insulin deficiency rather than insulin resistance,8 and (euglycemic) diabetic ketoacidosis, as observed in SGLT2 inhibitor-treated persons with type 1 diabetes, is a potential concern. Indeed, ketonemia has been associated with SGLT2-inhibitor monotherapy as reported in a woman with HNF1A-MODY.6 In the present cases, the SGLT2 inhibitor was used as adjunctive therapy together with insulin secretagogues. SGLT2 inhibitors are not associated with increased rates of hypoglycaemia except when used in combination with SU or insulin. In this case series, hypoglycaemia was not reported despite all persons being SU-treated during follow-up. Meanwhile, insulin exposure was low due to discontinuation or dose reduction. Down-titration of insulin and SU (if treated with high doses) could prevent hypoglycaemia. Initiation of SGLT2 inhibitor treatment in these seven persons with HNF1A-MODY was associated with clinically relevant reductions in HbA1c, body weight and insulin use and was well-tolerated. To further investigate the glucose-lowering effects of empagliflozin in person with HNF1A-MODY, we have initiated a randomized controlled, crossover trial (EUCT 2023-503760-17-00). None. T.V. has served on scientific advisory panels, been part of speaker's bureaus, served as a consultant to and/or received research support from Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, GSK, Mundipharma, Novo Nordisk, Roche, Sanofi, Sun Pharmaceuticals and Zealand Pharma. F.K.K. is employed by Novo Nordisk and has been on advisory panel of, consultant for, in the speaker's bureau of, owns shares in and/or has received research support from 89bio, AstraZeneca, Boehringer Ingelheim, Cytoki Pharma, Eli Lilly, Gubra, Novo Nordisk, Merck Sharp & Dohme, Sanofi, Structure Therapeutics, Zealand Pharma and Zucara; and is co-founder of and minority shareholder in Antag Therapeutics. S.H. has served as a consultant to Novo Nordisk. No other potential conflicts of interest relevant to this article were reported. The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.

Context Subclinical thyroid dysfunction is a marker for atrial fibrillation (AF) and stroke risk.Objective This study explored the effects of AF screening according to thyroid-stimulating hormone (TSH) levels.Methods An AF screening trial (the LOOP study) was analyzed post hoc according to baseline TSH. The primary outcome was stroke or systemic embolism (SE). Secondary outcomes included major bleeding, all-cause death, and the combination of stroke, SE, and cardiovascular death.Results TSH measurements were available in 6003 of 6004 trial participants, 1500 randomized to implantable loop recorder (ILR) screening for AF and anticoagulation upon detection vs 4503 to usual care; mean age was 74.7 +/- 4.1 years and 2836 (47%) were women. AF detection was approximately triple for ILR vs usual care across TSH tertiles (adjusted P interaction = 0.44). In the first tertile, screening was associated with decreased risk of the primary outcome (hazard ratio [HR] 0.52, 95% CI 0.30-0.90; P = .02) and stroke, SE, or cardiovascular death (HR 0.54, 95% CI 0.34-0.84; P = .006) compared with usual care, while no effect was observed among participants with higher TSH (adjusted P interaction .03 and .01, respectively). There was no effect on other outcomes. Analyses of continuous TSH or excluding those with abnormal TSH or thyroid medication showed similar results.Conclusion AF screening and subsequent treatment was associated with decreased stroke risk among participants with low TSH, though the yield of screening was similar across TSH levels. TSH may be useful as a marker to indicate benefit from AF screening vs overdiagnosis and overtreatment. These findings should be considered exploratory and warrant further study.

Previous studies highlight the potential for sodium-glucose cotransporter type 2 (SGLT2) inhibitors (SGLT2i) to exert cardioprotective effects in heart failure by increasing plasma ketones and shifting myocardial fuel utilization toward ketone oxidation. However, SGLT2i have multiple in vivo effects and the differential impact of SGLT2i treatment and ketone supplementation on cardiac metabolism remains unclear. Here, using gas chromatography-mass spectrometry (GC-MS) and liquid chromatography-tandem mass spectrometry (LC-MS/MS) methodology combined with infusions of [13C6]glucose or [13C4]βOHB, we demonstrate that acute SGLT2 inhibition with dapagliflozin shifts relative rates of myocardial mitochondrial metabolism toward ketone oxidation, decreasing pyruvate oxidation with little effect on fatty acid oxidation in awake rats. Shifts in myocardial ketone oxidation persisted when plasma glucose levels were maintained. In contrast, acute βOHB infusion similarly augmented ketone oxidation, but markedly reduced fatty acid oxidation and did not alter glucose uptake or pyruvate oxidation. After inducing heart failure, dapagliflozin increased relative rates of ketone and fatty acid oxidation, but decreased pyruvate oxidation. Dapagliflozin increased mitochondrial redox and reduced myocardial oxidative stress in heart failure, which was associated with improvements in left ventricular ejection fraction after 3 weeks of treatment. Thus, SGLT2i have pleiotropic effects on systemic and heart metabolism, which are distinct from ketone supplementation and may contribute to the long-term cardioprotective benefits of SGLT2i.

Insulin and glucagon exert opposing effects on glucose metabolism and, consequently, pancreatic islet β-cells and α-cells are considered functional antagonists. The intra-islet hypothesis has previously dominated the understanding of glucagon secretion, stating that insulin acts to inhibit the release of glucagon. By contrast, glucagon is a potent stimulator of insulin secretion and has been used to test β-cell function. Over the past decade, α-cells have received increasing attention due to their ability to stimulate insulin secretion from neighbouring β-cells, and α-cell–β-cell crosstalk has proven central for glucose homeostasis in vivo. Glucagon is not only the counter-regulatory hormone to insulin in glucose metabolism but also glucagon secretion is more susceptible to changes in the plasma concentration of certain amino acids than to changes in plasma concentrations of glucose. Thus, the actions of glucagon also include a central role in amino acid turnover and hepatic fat oxidation. This Review provides insights into glucagon secretion, with a focus on the local paracrine actions on glucagon and the importance of α-cell–β-cell crosstalk. We focus on dysregulated glucagon secretion in obesity, non-alcoholic fatty liver disease and type 2 diabetes mellitus. Lastly, the future potential of targeting hyperglucagonaemia and applying dual and triple receptor agonists with glucagon receptor-activating properties in combination with incretin hormone receptor agonism is discussed.

Fibroblast growth factor 21 (FGF21) is a liver-secreted peptide hormone reportedly improving metabolic homeostasis, partly via reduced hunger for sugar, fat, protein and alcohol. Exogenous glucagon has been shown to increase circulating FGF21 levels, but the role of endogenous glucagon for the control of FGF21 secretion remains unknown. To elucidate the relationship between endogenous glucagon and FGF21 in humans, we investigated the effect of chronic pancreatic glucagon depletion and acute glucagon receptor antagonism, respectively, on FGF21 levels. Nine totally pancreatectomized subjects (7 men, 2 women, age 61.3 ± 10.3 years, BMI 22.6 ± 4.8 kg/m2) and 9 matched control subjects (6 men, 3 women, age 65.9 ± 8.8 years, BMI 23.9 ± 2.7 kg/m2) underwent two randomized, double-blinded test days 24 hours after single-dose oral administration of either the glucagon receptor antagonist LY2409021 (300 mg) or placebo. FGF21 levels were measured both in the fasting state and in response to an oral glucose tolerance test (OGTT). The pancreatectomized patients exhibited significantly increased mean fasting FGF21 levels compared to the control subjects (493 ± 429 vs 108 ± 58 pg/mL, P=0.02). In the control subjects, administration of LY2409021 significantly increased mean fasting levels of FGF21 (216 ± 117 vs 108 ± 58 pg/mL, P=0.004) whereas fasting FGF21 levels in the pancreatectomized patients were unaffected by LY2409021. In both groups, FGF21 levels increased in response to the OGTT, with no significant treatment effect of LY2409021. Our results suggest that both chronic glucagon depletion and acute antagonism of the glucagon receptor mediate an increase in FGF21 levels in humans, pointing to direct or indirect effects of glucagon as important regulators of FGF21 secretion. Disclosure M.F.G.Grøndahl: Speaker's Bureau; Novo Nordisk A/S. T.Vilsbøll: Consultant; AstraZeneca, Boehringer Ingelheim Inc., Gilead Sciences, Inc., Eli Lilly and Company, Mundipharma, Merck & Co., Inc., Novo Nordisk A/S, Sanofi, Sun Pharmaceutical Industries Ltd., Bristol-Myers Squibb Company. F.K.Knop: Advisory Panel; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk, Sanofi, Consultant; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk, Sanofi, Research Support; Novo Nordisk, Zealand Pharma A/S, Speaker's Bureau; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk, Sanofi, Lundbeck. C.T.Juel: None. A.Lund: Speaker's Bureau; Novo Nordisk. S.Haedersdal: Consultant; Novo Nordisk. M.M.Andersen: None. J.S.Svenningsen: None. M.Gillum: None. B.Hartmann: Stock/Shareholder; Bainan Biotech. J.J.Holst: Advisory Panel; Novo Nordisk A/S, Eli Lilly and Company, Board Member; Bainan Biotech, Antag Therapeutics, Consultant; Alphasights, Eli Lilly and Company, ShouTi Pharma Inc., Zealand Pharma A/S, Other Relationship; Novo Nordisk, Novo Nordisk Pharma, Mayo Clinic, Boehringer-Ingelheim, Scohia Pharma Inc., Research Support; ARLA, European Union, Novo Nordisk Foundation. Funding Aase and Ejnar Danielsen's Foundation; Novo Nordisk Foundation (LY2409021); Eli Lilly and Company

Fibroblast growth factor 21 (FGF21) is a liver-secreted peptide hormone reportedly improving metabolic homeostasis, partly via reduced hunger for sugar, fat, protein and alcohol. Exogenous glucagon has been shown to increase circulating FGF21 levels, but the role of endogenous glucagon for the control of FGF21 secretion remains unknown. To elucidate the relationship between endogenous glucagon and FGF21 in humans, we investigated the effect of chronic pancreatic glucagon depletion and acute glucagon receptor antagonism, respectively, on FGF21 levels. Nine totally pancreatectomized subjects (7 men, 2 women, age 61.3 ± 10.3 years, BMI 22.6 ± 4.8 kg/m2) and 9 matched control subjects (6 men, 3 women, age 65.9 ± 8.8 years, BMI 23.9 ± 2.7 kg/m2) underwent two randomized, double-blinded test days 24 hours after single-dose oral administration of either the glucagon receptor antagonist LY2409021 (300 mg) or placebo. FGF21 levels were measured both in the fasting state and in response to an oral glucose tolerance test (OGTT). The pancreatectomized patients exhibited significantly increased mean fasting FGF21 levels compared to the control subjects (493 ± 429 vs 108 ± 58 pg/mL, P=0.02). In the control subjects, administration of LY2409021 significantly increased mean fasting levels of FGF21 (216 ± 117 vs 108 ± 58 pg/mL, P=0.004) whereas fasting FGF21 levels in the pancreatectomized patients were unaffected by LY2409021. In both groups, FGF21 levels increased in response to the OGTT, with no significant treatment effect of LY2409021. Our results suggest that both chronic glucagon depletion and acute antagonism of the glucagon receptor mediate an increase in FGF21 levels in humans, pointing to direct or indirect effects of glucagon as important regulators of FGF21 secretion. Disclosure M.F.G.Grøndahl: Speaker's Bureau; Novo Nordisk A/S. T.Vilsbøll: Consultant; AstraZeneca, Boehringer Ingelheim Inc., Gilead Sciences, Inc., Eli Lilly and Company, Mundipharma, Merck & Co., Inc., Novo Nordisk A/S, Sanofi, Sun Pharmaceutical Industries Ltd., Bristol-Myers Squibb Company. F.K.Knop: Advisory Panel; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk, Sanofi, Consultant; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk, Sanofi, Research Support; Novo Nordisk, Zealand Pharma A/S, Speaker's Bureau; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk, Sanofi, Lundbeck. C.T.Juel: None. A.Lund: Speaker's Bureau; Novo Nordisk. S.Haedersdal: Consultant; Novo Nordisk. M.M.Andersen: None. J.S.Svenningsen: None. M.Gillum: None. B.Hartmann: Stock/Shareholder; Bainan Biotech. J.J.Holst: Advisory Panel; Novo Nordisk A/S, Eli Lilly and Company, Board Member; Bainan Biotech, Antag Therapeutics, Consultant; Alphasights, Eli Lilly and Company, ShouTi Pharma Inc., Zealand Pharma A/S, Other Relationship; Novo Nordisk, Novo Nordisk Pharma, Mayo Clinic, Boehringer-Ingelheim, Scohia Pharma Inc., Research Support; ARLA, European Union, Novo Nordisk Foundation. Funding Aase and Ejnar Danielsen's Foundation; Novo Nordisk Foundation (LY2409021); Eli Lilly and Company

Objective Type 2 diabetes (T2D) pathophysiology includes fasting and postprandial hyperglucagonemia, which has been linked to hyperglycemia via increased endogenous glucose production (EGP). We used a glucagon receptor antagonist (LY2409021) and stable isotope tracer infusions to investigate the consequences of hyperglucagonemia in T2D. Design A double-blinded, randomized, placebo-controlled crossover study was conducted. Methods Ten patients with T2D and ten matched non-diabetic controls underwent two liquid mixed meal tests preceded by single-dose administration of LY2409021 (100 mg) or placebo. Double-tracer technique was used to quantify EGP. Antagonist selectivity toward related incretin receptors was determined in vitro . Results Compared to placebo, LY2409021 lowered the fasting plasma glucose (FPG) from 9.1 to 7.1 mmol/L in patients and from 5.6 to 5.0 mmol/L in controls (both P < 0.001) by mechanisms involving reduction of EGP. Postprandial plasma glucose excursions (baseline-subtracted area under the curve) were unaffected by LY2409021 in patients and increased in controls compared to placebo. Glucagon concentrations more than doubled during glucagon receptor antagonism. The antagonist interfered with both glucagon-like peptide 1 and glucose-dependent insulinotropic polypeptide receptors, complicating the interpretation of the postprandial data. Conclusions LY2409021 lowered FPG concentrations but did not improve postprandial glucose tolerance after a meal in patients with T2D and controls. The metabolic consequences of postprandial hyperglucagonemia are difficult to evaluate using LY2409021 because of its antagonizing effects on the incretin receptors.

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 and 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 2 isoglycaemic i.v. glucose infusions, succeeding (~10 h) 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 area under the curve 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.

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. Disclosure 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.

Recent clinical outcome studies demonstrate that SGLT2 inhibitors (i) significantly reduce major adverse cardiovascular events and heart failure in patients with and without type 2 diabetes; however, the mechanisms by which SGLT2i exert their cardiovascular benefits remain unclear. Here, we aimed to elucidate the acute effects of SGLT2i (dapagliflozin, dapa) on cardiac mitochondrial substrate oxidation. Using LC-MS/MS methodology combined with an infusion of [13C6]glucose and [13C4]βOHB, we assessed the ratio of cardiac mitochondrial pyruvate (VPDH) and βOHB (VβOHB) oxidation rates to rates of mitochondrial citrate synthase flux (VCS) in awake male Sprague Dawley (SD) rats. Metabolic studies were performed 4-6 h after oral dapa (1.5 mg/kg) or vehicle treatment in control rats and after induction of heart failure induced by permanent ligation of the left anterior descending coronary artery. Acute dapa treatment led to marked glycosuria with a 15% reduction in fasting plasma glucose concentrations and 50% increase in whole-body βOHB turnover and plasma βOHB concentrations (all P Conclusion: Collectively, these studies demonstrate that dapa shifts both the normal and failing heart to increased mitochondrial ketone oxidation, which may be mediated by increased hepatic ketogenesis and βOHB availability. Disclosure L. Goedeke: None. X. Zhang: None. R. J. Perry: None. G. Cline: None. L. H. Young: None. G. I. Shulman: Consultant; Self; 89bio, Inc., BridgeBio, Ionis Pharmaceuticals, Maze Therapeutics, Novo Nordisk, Other Relationship; Self; AstraZeneca, Esperion Therapeutics, Inc, Generian Pharmaceuticals, Inc., Gilead Sciences, Inc., iMetabolic Biopharma Corporation, Janssen Research & Development, LLC, Merck & Co., Inc., The Liver Company. J. Lee: None. Y. Ma: None. X. Hu: None. J. Zhang: n/a. J. Dong: None. K. D. Galsgaard: None. N. Guerrera: None. S. Haedersdal: None. Funding National Institutes of Health (R01DK113984, R01DK045735, K99HL150234); AstraZeneca