AIMS:Individuals with type 1 diabetes are at high risk of cardiovascular disease (CVD) and chronic kidney disease (CKD) even with optimal glycaemic control. The Steno 1 study will test a strategy of intensified care based on multifactorial intervention (MFI) including treatment with semaglutide, sotagliflozin and finerenone in high-risk individuals with type 1 diabetes. We hypothesize that this strategy will reduce major adverse cardiovascular endpoints (MACE), hospitalization for heart failure (HHF), progression of CKD and mortality. MATERIALS AND METHODS:The study is a prospective, cluster-randomized, open study with blinded endpoint evaluation. We will enrol 2000 high-risk individuals with type 1 diabetes of >10 years duration. All five Steno Diabetes Centres and 11 partner hospitals in Denmark will participate, with the addition of the Steno Diabetes Centres in Greenland and the Faroe Islands. Sites will be randomized either to receive guideline-recommended standard-of-care, or to receive the MFI. Eligible individuals with type 1 diabetes (≥40 years of age with presence of either CKD, CVD, HF, obesity or a >10% 5-year CVD risk determined by the Steno T1 Risk Engine) will be included. For the MFI group, the intervention will comprise more ambitious treatment targets for blood pressure and lipid levels, and in addition, participants will be allocated to semaglutide, sotagliflozin and/or finerenone based on phenotype. RESULTS AND CONCLUSIONS:The Steno 1 study will determine whether MFI is superior to standard care with respect to MACE, HHF progression of CKD, and mortality in individuals with type 1 diabetes and high risk of CVD.

An intravenous glucose-infusion of 0.3 g glucose per Kg body weight was administered over 1 min in nine healthy males with simultaneous blood sampling from the hepatic vein, femoral artery and a peripheral vein. Insulin secretion rates (ISR) were determined by the Eaton method and the ISEC method using C-peptide concentrations from arterial and peripheral venous blood. First phase (0-10 min), second phase (10-60 min), and total insulin secretion (0-60 min) were calculated as the incremental areas (iAUC) above baseline. The primary endpoint was first phase insulin response. The first phase insulin response in artery and venous blood did not differ with the Eaton method (p = 0.25), but was significantly greater with the ISEC method in arterial compared with venous blood (p < 0.05). The first phase insulin responses did not differ between methods in artery (p = 0.73) or venous blood (p = 0.73). The first phase responses of insulin and C-peptide were significant higher in the hepatic vein compared with those in the artery (p < 0.05) and peripheral vein (p < 0.05) but did not differ significantly between the artery compared with the peripheral vein for insulin (p = 0.09) or C-peptide (p = 0.26). Prehepatic insulin secretion rates did not differ between the Eaton and ISEC methods, but with the ISEC method the first phase insulin response was significantly greater in arterial compared with venous blood. The first phase insulin response differs when calculated from plasma insulin or C-peptide and depends on sample sites.

AIM:To test the effect of the glucagon-like peptide-1 receptor agonist, liraglutide, on residual beta-cell function in adults with newly diagnosed type 1 diabetes. MATERIALS AND METHODS:In a multicentre, double-blind, parallel-group trial, adults with newly diagnosed type 1 diabetes and stimulated C-peptide of more than 0.2 nmol/L were randomized (1:1) to 1.8-mg liraglutide (Victoza) or placebo once daily for 52 weeks with 6 weeks of follow-up with only insulin treatment. The primary endpoint was the between-group difference in C-peptide area under the curve (AUC) following a liquid mixed-meal test after 52 weeks of treatment. RESULTS:Sixty-eight individuals were randomized. After 52 weeks, the 4-hour AUC C-peptide response was maintained with liraglutide, but decreased with placebo (P = .002). Six weeks after end-of-treatment, C-peptide AUCs were similar for liraglutide and placebo. The average required total daily insulin dose decreased from 0.30 to 0.23 units/kg/day with liraglutide, but increased from 0.29 to 0.43 units/kg/day in the placebo group at week 52 (P < .001). Time without the need for insulin treatment was observed in 13 versus two patients and lasted for 22 weeks (from 3 to 52 weeks) versus 6 weeks (from 4 to 8 weeks) on average for liraglutide and placebo, respectively. Patients treated with liraglutide had fewer episodes of hypoglycaemia compared with placebo-treated patients. The adverse events with liraglutide were predominantly gastrointestinal and transient. CONCLUSIONS:Treatment with liraglutide improves residual beta-cell function and reduces the dose of insulin during the first year after diagnosis. Beta-cell function was similar at 6 weeks postliraglutide treatment.

Background The indication for treatment of type 1 diabetes(T1D) with the sodium–glucose cotransporter 2 inhibitor (SGLT2i) dapagliflozin has been withdrawn in Europe likely because of concern for diabetic ketoacidosis (DKA). We calculated the incidence of DKA in people with T1D treated with SGLT2i in Denmark. Methods Clinical data from adults with T1D in Denmark were collected from nine outpatient clinics. Electronic health records made the search for DKA accurate. Results From a population of 10.500 we observed 134 people treated with SGLT2i over a total period of 222 patient-years. Of those 72% were female, mean age (SD) was 51.4 (13.6) years and median duration of treatment (median, IQR) with an SGLT2i were 12.0 (6.0–29.0) months. The incidence of DKA was zero%. Conclusion In 134 people with T1D treated with SGLT2i we found that none of the participants developed DKA during the treatment.

Non-invasive biomarkers of non-alcoholic fatty liver disease (NAFLD) supporting diagnosis and monitoring disease progression are urgently needed. The present study aimed to establish a bioinformatics pipeline capable of defining and validating NAFLD biomarker candidates based on paired hepatic global gene expression and plasma bioanalysis from individuals representing different stages of histologically confirmed NAFLD (no/mild, moderate, more advanced NAFLD). Liver secretome gene signatures were generated in a patient cohort of 26 severely obese individuals with the majority having no or mild fibrosis. To this end, global gene expression changes were compared between individuals with no/mild NAFLD and moderate/advanced NAFLD with subsequent filtering for candidate gene products with liver-selective expression and secretion. Four candidate genes, including LPA (lipoprotein A), IGFBP-1 (insulin-like growth factor-binding protein 1), SERPINF2 (serpin family F member 2) and MAT1A (methionine adenosyltransferase 1A), were differentially expressed in moderate/advanced NAFLD, which was confirmed in three independent RNA sequencing datasets from large, publicly available NAFLD studies. The corresponding gene products were quantified in plasma samples but could not discriminate among different grades of NAFLD based on NAFLD activity score. Conclusion: We demonstrate a novel approach based on the liver transcriptome allowing for identification of secreted hepatic gene products as potential circulating diagnostic biomarkers of NAFLD. Using this approach in larger NAFLD patient cohorts may yield potential circulating biomarkers for NAFLD severity.

Introduction: Postprandial hypoglycemia is a frequent and debilitating complication following Roux-en-Y gastric bypass (RYGB) without effective treatments. In a proof-of-concept study, we investigated the effects of dasiglucagon, a novel, stable glucagon analog, on postprandial hypoglycemia after RYGB. Methods: Ten RYGB-operated individuals with confirmed symptomatic postprandial hypoglycemia (plasma glucose concentration (PG) <3.5 mmol×L-1) completed a randomized crossover study consisting of three study days each including a standardized liquid mixed meal test (25 kJ per kg body mass; 50% carbohydrates, 35% fat and 15% protein). A subcutaneous injection of either placebo, 80 or 200 µg dasiglucagon (D80µg and D200µg) was administered after the postprandial PG peak, ten minutes before the projected time point where PG returned to fasting levels, using a subject-specific linear regression model. Blood sampling and assessment of hypoglycemic symptoms (Edinburgh Hypoglycemia Symptom Scale) were performed at fixed time intervals. Data were analyzed using linear mixed models and Tuckey’s corrections model for multiple comparisons. Results: Compared with placebo, treatment with both D80µg and D200µg significantly increased nadir PG (placebo: 3.0±0.2 mmol×L-1; D80µg: 3.9±0.3 mmol×L-1; D200µg: 4.5±0.2 mmol×L-1; P=0.002 and P=0.0002) and PG incremental area under the curve (iAUC70-240min) after drug administration (placebo: 752±19 mmol×L-1×min; D80µg: 917±22 mmol×L-1×min; D200µg: 992±28 mmol×L-1×min; P<0.0001 and P<0.0001). Moreover, both doses reduced time spent in hypoglycemia (<3.9 mmol×L-1) (placebo: 62.0±8 min; D80µg: 27.5±12 min; D200µg: 14.0±9 min; P=0.05 and P=0.003). There were no significant changes in hypoglycemic symptoms between the three study days. Conclusion: Administration of dasiglucagon effectively ameliorates postprandial hypoglycemia representing a promising new therapeutic option for management of postprandial hypoglycemia after RYGB. Disclosure C.K. Nielsen: None. C. Oehrstroem: None. U. Kielgast: None. D.L. Hansen: None. A. Lund: Speaker’s Bureau; Self; AstraZeneca, Novo Nordisk A/S, Sanofi. 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. 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.

Glucagon-like peptide-1 (GLP-1) stimulates insulin secretion in adults with type 1 diabetes and residual beta-cell function. This randomized, double-blind, placebo-controlled, 52-week trial evaluated the efficacy of liraglutide 1.8 mg QD added to insulin treatment in adults diagnosed with type 1 diabetes within 6 weeks prior to screening. At randomization, at end-of-treatment (week 52) and at follow-up (week 58), a 240-min. liquid mixed meal test (237 kcal Nestlé BOOST) was conducted to evaluate the C-peptide response. In total, 65 adults (age 18-40 years) with newly diagnosed type 1 diabetes, stimulated C-peptide ≥200 pmol/L and BMI >20 kg/m2 were randomized (1:1) to liraglutide or placebo added to insulin treatment. Baseline characteristics were similar between groups (mean±SD) age 27±5 years, fasting C-peptide 359±226 pM and diabetes duration 4.4±1.2 weeks. At end-of-treatment, liraglutide sustained stimulated C-peptide secretion and reduced insulin dose compared with placebo (Table). At 6 weeks post-treatment, stimulated C-peptide levels and total insulin dose did not differ between the groups. No difference was found between groups in HbA1c or BMI (Table). No events of severe hypoglycemia or ketoacidosis were reported. In conclusion, liraglutide preserved postprandial insulin secretion one year after diagnosis of type 1 diabetes. The effects had disappeared 6 weeks post-treatment. Disclosure T.F. Dejgaard: Consultant; Self; Novo Nordisk A/S. Research Support; Self; AstraZeneca, Novo Nordisk A/S. Speaker's Bureau; Self; Boehringer Ingelheim International GmbH. C.S. Frandsen: None. U. Kielgast: Advisory Panel; Self; Novo Nordisk A/S. Consultant; Self; Eli Lilly and Company, Sanofi. H.U. Andersen: Advisory Panel; Self; Abbott Laboratories, AstraZeneca, Novo Nordisk A/S. Speaker's Bureau; Self; Nordic Infucare. Stock/Shareholder; Self; Novo Nordisk Inc. B. Thorsteinsson: None. T. Krarup: None. J.J. Holst: Advisory Panel; Self; Novo Nordisk A/S. S. Madsbad: None. Funding Novo Nordisk

To estimate lifetime prevalence of diabetes-related upper limb and non-acquired skin manifestations in a representative type 1 diabetes (T1D) population and to identify associations between these conditions and quality of life. A questionnaire on these complications and measures of quality of life (World Health Organization–Five Well-Being Index [WHO-5]), depression, and diabetes-specific burden (Problem Areas in Diabetes [PAID] scale) was sent to all T1D patients in a Danish clinic (N = 583). The response rate was 68.6%. Lifetime prevalence of any upper limb soft tissue lesion was 72%; prevalence of any skin lesion was 10.5%. Frozen shoulder and vitiligo were most common upper limb and skin manifestation, at a prevalence of 53 and 9.1%, respectively. Compared to patients with no skin lesion, those with at least one skin lesion had more depression (19 vs. 33%; P < 0.01) and lower WHO-5 scores. Frozen shoulder was associated with lower WHO-5 scores (P < 0.001), more depression (29 vs. 14%; P < 0.001), and a higher PAID score (P < 0.01). A diagnosis of carpal tunnel syndrome was associated with lower WHO-5 scores (P < 0.001), a higher risk of depression (29 vs. 16%; P < 0.01), and a higher PAID score (P < 0.001). Upper limb soft tissue lesions and diabetes-specific non-acquired skin lesions are very common in patients with T1D and strongly associated with impaired life quality and increased risk of depression.

Introduction: Hypoglycemia is a severe complication after Roux-en-Y gastric bypass (RYGB), with no effective treatment options. We investigated the glucose stabilizing effects of five therapeutic agents in RYGB operated subjects with hypoglycemia. Methods: In a randomized crossovers study, 11 RYGB operated subjects with documented hypoglycemia (blood glucose <70.2 mg/dL) underwent six separate meal tolerance tests (Fresubin Energy Drink) preceded by either: no treatment (NT), acarbose 50 mg (A), sitagliptin 100 mg for 1 week (S), verapamil 120 mg for 1 week (V), liraglutide 1.2 mg for 3 weeks (L) or pasireotide 300 µg (P). Blood samples were drawn at fixed time intervals from -20 to 180 minutes. Hormonal responses were calculated as the incremental area under the curve (iAUC), and the glucose response was further specified as the area above (+iAUC) and below (-iAUC) baseline values. Data were analyzed by use of linear mixed models. Results: Treatment with A and P significantly reduced -iAUCglucose (NT: 106±14 mmolxL-1xmin (mean±SEM) A: 63±14 mmolxL-1xmin, p=0.02; P: 0±0 mmolxL-1xmin, p<0.0001). Additionally A reduced +iAUCglucose, whereas P increased this area (NT: 182±18 mmolxL-1xmin; A: 78±18 mmolxL-1xmin, p=0.0008; P: 1,144±62 mmolxL-1xmin, p<0.0001). Time spent in hypoglycemia decreased with both A and P (NT: 48±12 min; A: 5±3 min, p=0.02; P: 0±0 min, p<0.0001), whereas time in hyperglycemia (>140.4 mg/dL) decreased with A but increased with P (NT: 29±4 min; A: 5±5 min, p=0.0017; P: 159±6 min, p<0.0001). Treatment with A and P both reduced iAUCinsulin (NT: 534±8 nmolxL-1xmin; A: 22±3 nmolxL-1xmin, p=0.0009; P: 14±2 nmolxL-1xmin, p<0.0001). Treatment with S, V and L did not have a significant impact on any of the measurements. Conclusion: Acarbose reduced both hypoglycemia and hyperglycemia, whereas pasireotide resolved hypoglycemia, but at the cost of increased hyperglycemia. Both acarbose and pasireotide can be considered in the treatment of hypoglycemia after RYGB. Disclosure C. øhrstrôm: None. U. Kielgast: None. 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. D. Worm: None. D.L. Hansen: None.

BACKGROUND:Roux-en-Y gastric bypass (RYGB) causes extensive changes in gastrointestinal anatomy and leads to reduced appetite and large weight loss, which partly is due to an exaggerated release of anorexigenic gut hormones.METHODS:To examine whether the altered passage of foods through the gastrointestinal tract after RYGB could be responsible for the changes in gut hormone release, we studied gastrointestinal motility with a scintigraphic technique as well as the secretion of the gut hormones glucagon-like peptide (GLP)-1 and peptide YY3-36 (PYY3-36 ) in 17 patients>1 year after RYGB and in nine healthy control subjects.KEY RESULTS:At meal completion, a smaller fraction of liquid and solid radiolabeled marker was retained in the pouch of RYGB patients than in the stomach of control subjects (P = 0.002 and P < 0.001, respectively). Accordingly, pouch emptying in patients was faster than gastric emptying in control subjects (P < 0.001 and P = 0.004, respectively liquid and solid markers). For the solid marker, small intestinal transit was slower in patients than control subjects (P = 0.034). Colonic transit rate did not differ between the groups. GLP-1 and PYY3-36 secretion was increased in patients compared to control subjects and fast pouch emptying of the liquid marker was associated with high gut hormone secretion.CONCLUSIONS & INFERENCES:After RYGB, the bulk of foods pass without hindrance into the small intestine, while the small intestinal transit is prolonged. The rapid exposure of the gut epithelium contributes to the exaggerated release of GLP-1 and PYY3-36 after RYGB.

To identify factors contributing to the variation in weight loss after Roux-en-Y gastric bypass (RYGB). Cross-sectional study of patients with good (excess body mass index lost (EBL) >60%) and poor weight loss response (EBL <50%) >12 months after RYGB and a lean control group matched for age and gender. Sixteen patients with good weight loss response, 17 patients with poor weight loss response, and eight control subjects were included in the study. Participants underwent dual energy X-ray absorptiometry scan, indirect calorimetry and a 9 h multiple-meal test with measurements of glucose, insulin, total bile acids (TBA), glucagon-like peptide (GLP)-1, peptide YY3–36 (PYY), cholecystokinin (CCK), ghrelin, neurotensin and pancreatic polypeptide (PP) as well as assessment of early dumping and appetite. Suppression of hunger was more pronounced in the good than the poor responders in response to the multiple-meal test (P=0.006). In addition, the good responders had a larger release of GLP-1 (P=0.009) and a greater suppression of ghrelin (P=0.037) during the test, whereas the postprandial secretion of CCK was highest in the poor responders (P=0.005). PYY, neurotensin, PP and TBA release did not differ between the RYGB-operated groups. Compared with control subjects, patients had exaggerated release of GLP-1 (P<0.001), PYY (P=0.008), CCK (P=0.010) and neurotensin (P<0.001). Early dumping was comparable in the good and poor responders, but more pronounced than in controlled subjects. Differences in resting energy expenditure between the three groups were entirely explained by differences in body composition. Favorable meal-induced changes in hunger and gut hormone release in patients with good compared with poor weight loss response support the role of gut hormones in the weight loss after RYGB.

Background Roux-en-Y gastric bypass (RYGB) surgery causes profound changes in secretion of gastrointestinal hormones and glucose metabolism. We present a detailed analysis of the early hormone changes after RYGB in response to three different oral test meals designed to provide this information without causing side effects (such as dumping). Methods We examined eight obese non-diabetic patients before and within 2 weeks after RYGB. On separate days, oral glucose tolerance tests (25 or 50 g glucose dissolved in 200 mL of water) and a liquid mixed meal test (200 mL 300 kcal) were performed. We measured fasting and postprandial glucose, insulin, C-peptide, glucagon, total and intact glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-2 (GLP-2), peptide YY 3-36 (PYY), cholecystokinin (CCK), total and active ghrelin, gastrin, somatostatin, pancreatic polypeptide (PP), amylin, leptin, free fatty acids (FFA), and registered postprandial dumping. Insulin sensitivity was measured by homeostasis model assessment of insulin resistance. Results Fasting glucose, insulin, ghrelin, and PYY were significantly decreased and FFA was elevated postoperatively. Insulin sensitivity increased after surgery. The postprandial response increased for C-peptide, GLP-1, GLP-2, PYY, CCK, and glucagon (in response to the mixed meal) and decreased for total and active ghrelin, leptin, and gastrin, but were unchanged for GIP, amylin, PP, and somatostatin after surgery. Dumping symptoms did not differ before and after the operation or between the tests. Conclusions Within 2 weeks after RYGB, we found an increase in insulin secretion and insulin sensitivity. Responses of appetite-regulating intestinal hormones changed dramatically, all in the direction of reducing hunger.

Glucagon secretion plays an essential role in the regulation of hepatic glucose production, and elevated fasting and postprandial plasma glucagon concentrations in patients with type 2 diabetes (T2DM) contribute to their hyperglycaemia. The reason for the hyperglucagonaemia is unclear, but recent studies have shown lack of suppression after oral but preserved suppression after isoglycaemic intravenous glucose, pointing to factors from the gut. Gastrointestinal hormones that are secreted in response to oral glucose include glucagon-like peptide-1 (GLP-1) that strongly inhibits glucagon secretion, and GLP-2 and GIP, both of which stimulate secretion. When the three hormones are given together on top of isoglycaemic intravenous glucose, glucagon suppression is delayed in a manner similar to that observed after oral glucose. Studies with the GLP-1 receptor antagonist, exendin 9-39, suggest that endogenous GLP-1 plays an important role in regulation of glucagon secretion during fasting as well as postprandially. The mechanisms whereby GLP-1 regulates glucagon secretion are debated, but studies in isolated perfused rat pancreas point to an important role for a paracrine regulation by somatostatin from neighbouring D cells. Clinical studies of the antidiabetic effect of GLP-1 in T2DM suggest that the inhibition of glucagon secretion is as important as the stimulation of insulin secretion.

Incretin-based therapies, such as the injectable glucagon-like peptide-1 (GLP-1) receptor agonists and orally administered dipeptidyl peptidase-4 (DPP-4) inhibitors, have recently been introduced into clinical practice. At present, the GLP-1 receptor agonists need to be administered once or twice daily. Several once-weekly GLP-1 receptor agonists are in phase 3 development. This review examines the efficacy, safety and perspective for the future of the once-weekly GLP-1 receptor agonists: exenatide once weekly, taspoglutide, albiglutide, LY2189265 and CJC-1134-PC, and compared them to the currently available agonists, exenatide BID and liraglutide QD. A greater reduction in haemoglobin A1c (HbA1c) and fasting plasma glucose was found with the once-weekly GLP-1 receptor agonists compared with exenatide BID, while the effect on postprandial hyperglycaemia was modest with the once-weekly GLP-1 receptor agonist. The reduction in HbA1c was in most studies greater compared to oral antidiabetic drugs and insulin glargine. The reduction in weight did not differ between the short- and long-acting agonists. The gastrointestinal side effects were less with the once-weekly agonists compared with exenatide BID, except for taspoglutide. Antibodies seem to be most frequent with exenatide once weekly, while hypersensitivity has been described in few patients treated with taspoglutide. Injection site reactions differ among the long-acting GLP-1 receptor agonists and are observed more frequently than with exenatide BID and liraglutide. In humans, no signal has been found indicating an association between the once-weekly agonists and C-cell cancer. The cardiovascular safety, durability of glucose control and effect on weight will emerge from several ongoing major long-term trials. The once-weekly GLP-1 receptor analogues are promising candidates for the treatment of type 2 diabetes, although their efficacy may not be superior to once-daily analogue liraglutide.

OBJECTIVE To investigate the effect of exogenous as well as endogenous glucagon-like peptide 1 (GLP-1) on postprandial glucose excursions and to characterize the secretion of incretin hormones in type 1 diabetic patients with and without residual β-cell function. RESEARCH DESIGN AND METHODS Eight type 1 diabetic patients with (T1D+), eight without (T1D−) residual β-cell function, and eight healthy matched control subjects were studied during a mixed meal with concomitant infusion of GLP-1 (1.2 pmol/kg/min), saline, or exendin 9-39 (300 pmol/kg/min). Before the meal, half dose of usual fast-acting insulin was injected. Plasma glucose (PG), glucagon, C-peptide, total GLP-1, intact glucose-dependent insulinotropic polypeptide (GIP), free fatty acids, triglycerides, and gastric emptying rate (GE) by plasma acetaminophen were measured. RESULTS Incretin responses did not differ between patients and control subjects. Infusion of GLP-1 decreased peak PG by 45% in both groups of type 1 diabetic patients. In T1D+ patients, postprandial PG decreased below fasting levels and was indistinguishable from control subjects infused with saline. In T1D− patients, postprandial PG remained at fasting levels. GLP-1 infusion reduced GE and glucagon levels in all groups and increased fasting C-peptide in T1D+ patients and control subjects. Blocking endogenous GLP-1 receptor action increased endogenous GLP-1 secretion in all groups and increased postprandial glucose, glucagon, and GE in T1D+ and T1D− patients. The insulinogenic index (the ratio of insulin to glucose) decreased in T1D+ patients during blockade of endogenous GLP-1 receptor action. CONCLUSIONS Type 1 diabetic patients have normal incretin responses to meals. In type 1 diabetic patients, exogenous GLP-1 decreases peak postprandial glucose by 45% regardless of residual β-cell function. Endogenous GLP-1 regulates postprandial glucose excursions by modulating glucagon levels, GE, and β-cell responsiveness to glucose. Long-term effects of GLP-1 in type 1 diabetic patients should be investigated in future clinical trials.

This article reports on results from a 4-week randomized, open-label efficacy trial on the effects of treatment with liraglutide, a once-daily human GLP-1 receptor analog, on insulin dose and glycemic control in patients with type 1 diabetes mellitus with and without residual β-cell function [NCT00993720; Kielgast U et al. Diabetes Care 2011].

The glucagon gene (GCG) encodes several hormones important for energy metabolism: glucagon, oxyntomodulin and glucagon-like peptide (GLP)-1 and -2. Variants in GCG may associate with type 2 diabetes, obesity and/or related metabolic traits.

OBJECTIVE To investigate the effect of 4 weeks of treatment with liraglutide on insulin dose and glycemic control in type 1 diabetic patients with and without residual β-cell function. RESEARCH DESIGN AND METHODS Ten type 1 diabetic patients with residual β-cell function (C-peptide positive) and 19 without (C-peptide negative) were studied. All C-peptide–positive patients were treated with liraglutide plus insulin, whereas C-peptide–negative patients were randomly assigned to liraglutide plus insulin or insulin monotherapy. Continuous glucose monitoring with identical food intake and physical activity was performed before (week 0) and during (week 4) treatment. Differences in insulin dose; HbA1c; time spent with blood glucose <3.9, >10, and 3.9–9.9 mmol/L; and body weight were evaluated. RESULTS Insulin dose decreased from 0.50 ± 0.06 to 0.31 ± 0.08 units/kg per day (P < 0.001) in C-peptide–positive patients and from 0.72 ± 0.08 to 0.59 ± 0.06 units/kg per day (P < 0.01) in C-peptide–negative patients treated with liraglutide but did not change with insulin monotherapy. HbA1c decreased in both liraglutide-treated groups. The percent reduction in daily insulin dose was positively correlated with β-cell function at baseline, and two patients discontinued insulin treatment. In C-peptide–positive patients, time spent with blood glucose <3.9 mmol/L decreased from 3.0 to 1.0 h (P = 0.03). A total of 18 of 19 patients treated with liraglutide lost weight during treatment (mean [range] −2.3 ± 0.3 kg [−0.5 to −5.1]; P < 0.001). Transient gastrointestinal adverse effects occurred in almost all patients treated with liraglutide. CONCLUSIONS Treatment with liraglutide in type 1 diabetic patients reduces insulin dose with improved or unaltered glycemic control.

CONTEXT The mechanism by which glucagon-like peptide-1 (GLP-1) suppresses glucagon secretion is uncertain, and it is not determined whether endogenous insulin is a necessary factor for this effect. OBJECTIVE To characterize the alpha- and beta-cell responses to GLP-1 in type 1 diabetic patients without residual beta-cell function. METHODS Nine type 1 diabetic patients, classified as C-peptide negative by a glucagon test, were clamped at plasma glucose of 20 mmol/liter for 90 min with arginine infusion at time 45 min and concomitant infusion of GLP-1 (1.2 pmol/kg x min) or saline. RESULTS Infusion with GLP-1 increased C-peptide concentration just above the detection limit of 33 pmol/liter in one patient, but C-peptide remained immeasurable in all other patients. In the eight remaining patients, total area under the curve of glucagon was significantly decreased with GLP-1 compared with saline: 485 +/- 72 vs. 760 +/- 97 pmol/liter x min (P < 0.001). In addition, GLP-1 decreased the arginine-stimulated glucagon release (incremental AUC of 103 +/- 21 and 137 +/- 16 pmol/liter x min, with GLP-1 and saline, respectively, P < 0.05). CONCLUSIONS In type 1 diabetic patients without endogenous insulin secretion, GLP-1 decreases the glucagon secretion as well as the arginine-induced glucagon response during hyperglycemia. GLP-1 induced endogenous insulin secretion in one of nine type 1 diabetic patients previously classified as being without endogenous insulin secretion.