Kinetics of insulin and C-peptide and estimation of prehepatic insulin secretion rates after intravenous glucose stimulation using arterial versus venous blood sampling in healthy males.

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.

Postprandial hypoglycaemia after Roux-en-Y gastric bypass and the effects of acarbose, sitagliptin, verapamil, liraglutide and pasireotide.

AIM: To investigate the effects of acarbose, sitagliptin, verapamil, liraglutide and pasireotide on post-bariatric hypoglycaemia (PBH) after Roux-en-Y gastric bypass. MATERIALS AND METHODS: In a randomized crossover study, 11 women who had undergone Roux-en-Y gastric bypass and had documented hypoglycaemia were each evaluated during a baseline period without treatment and during five treatment periods with the following interventions: acarbose 50 mg for 1 week, sitagliptin 100 mg for 1 week, verapamil 120 mg for 1 week, liraglutide 1.2 mg for 3 weeks and pasireotide 300 µg as a single dose. Treatment effects were evaluated by a mixed-meal tolerance test (MMTT) and, for all treatment periods except pasireotide, by 6 days of continuous glucose monitoring (CGM). RESULTS: Treatment with acarbose and treatment with pasireotide both significantly lifted nadir glucose levels (mean ± SEM 3.9 ± 0.2 and 7.9 ± 0.4 vs 3.4 ± 0.2; P < .03) and reduced time in hypoglycaemia during the MMTTs. Acarbose reduced peak glucose levels and time in hyperglycaemia, whereas pasireotide greatly increased both variables. Acarbose and pasireotide reduced insulin and C-peptide levels, and pasireotide also diminished glucagon-like peptide-1 levels. Sitagliptin lowered nadir glucose values, while verapamil and liraglutide had no effect on hypoglycaemia. During the CGM periods, the treatments had no impact on hypoglycaemia, whereas acarbose and liraglutide reduced hyperglycaemia and glycaemic variability. CONCLUSIONS: In an experimental setting, treatment with acarbose and pasireotide reduced PBH. Acarbose appears to have an overall glucose-stabilizing effect, whereas pasireotide leads to increased and sustained hyperglycaemia.

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

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.

A liver secretome gene signature-based approach for determining circulating biomarkers of NAFLD severity.

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.

Real life evaluation of sodium-glucose cotransporter 2 inhibition in type 1 diabetes and the risk of diabetic ketoacidosis.

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.

Counterregulatory responses to postprandial hypoglycemia after Roux-en-Y gastric bypass.

BACKGROUND: Postbariatric hypoglycemia (PBH) is a potentially serious complication after Roux-en-Y gastric bypass (RYGB), and impaired counterregulatory hormone responses have been suggested to contribute to the condition. OBJECTIVES: We evaluated counterregulatory responses during postprandial hypoglycemia in individuals with PBH who underwent RYGB. SETTING: University hospital. METHODS: Eleven women with documented PBH who had RYGB underwent a baseline liquid mixed meal test (MMT) followed by 5 MMTs preceded by treatment with (1) acarbose 50 mg, (2) sitagliptin 100 mg, (3) verapamil 120 mg, (4) liraglutide 1.2 mg, and (5) pasireotide 300 µg. Blood was collected at fixed time intervals. Plasma and serum were analyzed for glucose, insulin, glucagon, epinephrine, norepinephrine, pancreatic polypeptide (PP), and cortisol. RESULTS: During the baseline MMT, participants had nadir blood glucose concentrations of 3.3 ± .2 mmol/L. At the time of nadir glucose, there was a small but significant increase in plasma glucagon. Plasma epinephrine concentrations were not increased at nadir glucose but were significantly elevated by the end of the MMT. There were no changes in norepinephrine, PP, and cortisol concentrations in response to hypoglycemia. After treatment with sitagliptin, 8 individuals had glucose nadirs <3.2 mmol/L (versus 4 individuals at baseline), and significant increases in glucagon, PP, and cortisol responses were observed. CONCLUSIONS: In response to postprandial hypoglycemia, individuals with PBH who underwent RYGB only had minor increases in counterregulatory hormones, while larger hormone responses occurred when glucose levels were lowered during treatment with sitagliptin. The glycemic threshold for counterregulatory activation could be altered in individuals with PBH, possibly explained by recurrent hypoglycemia.

Evidence for Relationship Between Early Dumping and Postprandial Hypoglycemia After Roux-en-Y Gastric Bypass.

BACKGROUND: Early dumping and post-bariatric hypoglycemia (PBH) are often addressed as two separate postprandial complications after Roux-en-Y gastric bypass (RYGB). The aim of the study was to evaluate the occurrence of early dumping in RYGB-operated individuals with PBH with and without treatment intervention. METHODS: Eleven RYGB-operated women with documented PBH each underwent a baseline liquid mixed meal test (MMT) followed by five MMTs preceded by treatment with: acarbose 50 mg for 1 week, sitagliptin 100 mg for 1 week, verapamil 120 mg for 1 week, liraglutide 1.2 mg for 3 weeks, and pasireotide 300 µg as a single dose. Repetitive venous blood sampling and continuous electrocardiogram recordings were performed at fasting and during a 3-h postprandial period. RESULTS: During the baseline MMT, there was a significant increase in HR (from 65 ± 2 to 90 ± 4 bpm, p < 0.0001) within 30 min after meal intake, while hypoglycemia occurred in the later postprandial period. The HR increase was accompanied by significant increases in serum albumin, plasma norepinephrine, blood glucose, serum insulin, and plasma GLP-1 concentrations. The postprandial HR changes were positively correlated with the changes in insulin and GLP-1 concentrations. Treatment with acarbose and pasireotide both reduced HR, plasma norepinephrine, and serum insulin, and pasireotide also decreased plasma GLP-1. CONCLUSIONS: RYGB-operated individuals with PBH also have large early postprandial HR increases, hemoconcentration, and sympathetic activation, consistent with early dumping. Moreover, hormone excursions associated with PBH appear to be related to measures of early dumping, suggesting a causal relationship between early dumping and PBH. TRIAL REGISTRATION: NCT02527993.

A Low Dose of Pasireotide Prevents Hypoglycemia in Roux-en-Y Gastric Bypass-Operated Individuals.

Post-bariatric hypoglycemia (PBH) can be a serious complication after Roux-en-Y gastric bypass (RYGB), and treatment with somatostatin analogs has been suggested. We investigated the acute effects of three different doses of pasireotide (75 µg, 150 µg, and 300 µg) on the postprandial glucose metabolism in five RYGB-operated individuals with PBH using a mixed meal test. All three doses prevented hypoglycemia but were associated with a notable increase in postprandial hyperglycemia. Moreover, all doses greatly diminished insulin, C-peptide, and glucagon-like peptide-1 responses. Considering its strong hyperglycemic potential, we suggest that pasireotide should be administered carefully in RYGB-operated individuals with PBH, and if necessary, a 75 µg dose seems sufficient to prevent hypoglycemia.

Quality of Life is Markedly Impaired by Rheumatological and Skin Manifestations in Patients with Type 1 Diabetes: A Questionnaire Survey.

INTRODUCTION: 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. METHODS: 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). RESULTS: 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). CONCLUSION: 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.

Four weeks of treatment with liraglutide reduces insulin dose without loss of glycemic control in type 1 diabetic patients with and without residual beta-cell function.

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 ß-cell function. RESEARCH DESIGN AND METHODS: Ten type 1 diabetic patients with residual ß-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 ß-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.

Antidiabetic actions of endogenous and exogenous GLP-1 in type 1 diabetic patients with and without residual ß-cell function.

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 ß-cell function. RESEARCH DESIGN AND METHODS: Eight type 1 diabetic patients with (T1D+), eight without (T1D-) residual ß-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 ß-cell function. Endogenous GLP-1 regulates postprandial glucose excursions by modulating glucagon levels, GE, and ß-cell responsiveness to glucose. Long-term effects of GLP-1 in type 1 diabetic patients should be investigated in future clinical trials.

Effect of glucagon-like peptide-1 on alpha- and beta-cell function in C-peptide-negative type 1 diabetic patients.

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.

Treatment of type 1 diabetic patients with glucagon-like peptide-1 (GLP-1) and GLP-1R agonists.

GLP-1 (glucagon-like peptide-1) is a peptide hormone secreted from endocrine cells in the intestinal mucosa in response to meals. The major effects of GLP-1 are to increase glucose-induced insulin secretion and reduce glucagon release, but GLP-1 also inhibits gastric emptying rate and reduces appetite and bodyweight in obese subjects. In vivo studies using animal models of type 2 diabetes and in vitro studies using human islet cells have suggested that GLP-1 or GLP-1 analogues are also able to increase beta-cell mass, but in animal models of type 1 diabetes, there is much less evidence for a beta-cell preserving effect. This review summarizes the present knowledge of GLP-1 and its analogues regarding its role as a possible treatment in patients with type 1 diabetes. The studies that address the effect of GLP-1 and GLP-1 analogues on beta-cell mass in both type 2 and type 1 diabetes, as well as the potential of GLP-1 as an adjuvant therapy in islet cell transplantation, will be reviewed. Suggestions for future studies of GLP-1 treatment in type 1 diabetes may include early treatment in order to preserve beta-cell mass and prolong the remission period, but should also take a potential insulin sparing effect and changes in the risk of hypoglycemia into account.

[Peripartum cardiomyopathy in an obese pregnant woman]. / Peripartum kardiomyopati hos overvaegtig gravid.

Peripartum cardiomyopathy (PPCM) is a rare, but life-threatening cardiac disorder which complicates pregnancy. However, the classical symptoms of heart failure can be masked - especially in obese women. Here, we present a case report of PPCM complicated with vitamin-D deficiency in a severely obese woman.