Publications by authors named "Filip K Knop"

277 Publications

Glucagon Clearance is Preserved in Type 2 Diabetes.

Diabetes 2021 Oct 21. Epub 2021 Oct 21.

Center for Clinical Metabolic Research, Copenhagen University Hospital - Herlev and Gentofte, Hellerup, Denmark.

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 the hyperglucagonemia in type 2 diabetes and obesity. Individuals with type 2 diabetes and preserved kidney function (8 with and 8 without obesity) and matched control individuals (8 with and 8 without obesity) were recruited. Each participant underwent a 1-hour glucagon infusion (4 ng/kg/min), achieving steady-state plasma glucagon concentrations, followed by a 1-hour wash-out period. Plasma levels, the metabolic clearance rate (MCR), half-life (T½) 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 to the control group, while no significant differences between the groups were found in glucagon T½. Individuals with obesity had neither a significantly decreased MCR, T½, nor volume of distribution of glucagon. In our pharmacokinetic model, glucagon MCR associated positively with 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2337/db21-0024DOI Listing
October 2021

Associations of hypoglycemia, glycemic variability and risk of cardiac arrhythmias in insulin-treated patients with type 2 diabetes: a prospective, observational study.

Cardiovasc Diabetol 2021 12 24;20(1):241. Epub 2021 Dec 24.

Clinical Research, Steno Diabetes Center Copenhagen, University of Copenhagen, Borgmester Ib Juuls Vej 83, 2730, Herlev, Denmark.

Background: Insulin-treated patients with type 2 diabetes (T2D) are at risk of hypoglycemia, which is associated with an increased risk of cardiovascular disease and mortality. Using a long-term monitoring approach, we investigated the association between episodes of hypoglycemia, glycemic variability and cardiac arrhythmias in a real-life setting.

Methods: Insulin-treated patients with T2D (N = 21, [mean ± SD] age 66.8 ± 9.6 years, BMI 30.1 ± 4.5 kg/m, HbA1c 6.8 ± 0.4% [51.0 ± 4.8 mmol/mol]) were included for a one-year observational study. Patients were monitored with continuous glucose monitoring ([mean ± SD] 118 ± 6 days) and an implantable cardiac monitor (ICM) during the study period.

Results: Time spend in hypoglycemia was higher during nighttime than during daytime ([median and interquartile range] 0.7% [0.7-2.7] vs. 0.4% [0.2-0.8]). The ICMs detected 724 episodes of potentially clinically significant arrhythmias in 12 (57%) participants, with atrial fibrillation and pauses accounting for 99% of the episodes. No association between hypoglycemia and cardiac arrhythmia was found during daytime. During nighttime, subject-specific hourly incidence of cardiac arrhythmias tended to increase with the occurrence of hypoglycemia (incident rate ratio [IRR] 1.70 [95% CI 0.36-8.01]) but only slightly with increasing time in hypoglycemia (IRR 1.04 [95% CI 0.89-1.22] per 5 min). Subject-specific incidence of cardiac arrhythmias during nighttime increased with increasing glycemic variability as estimated by coefficient of variation whereas it decreased during daytime (IRR 1.33 [95% CI 1.05-1.67] and IRR 0.77 [95% CI 0.59-0.99] per 5% absolute increase, respectively).

Conclusions: Cardiac arrhythmias were common in insulin-treated patients with T2D and were associated with glycemic variability, whereas arrhythmias were not strongly associated with hypoglycemia.

Trial Registration: NCT03150030, ClinicalTrials.gov, registered May 11, 2017. https://clinicaltrials.gov/ct2/show/NCT03150030.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12933-021-01425-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8710000PMC
December 2021

The glucagon receptor antagonist LY2409021 has no effect on postprandial glucose in type 2 diabetes.

Eur J Endocrinol 2022 Jan 6;186(2):207-221. Epub 2022 Jan 6.

Clinical Research, Copenhagen University Hospital - Steno Diabetes Center Copenhagen, Herlev, Denmark.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1530/EJE-21-0865DOI Listing
January 2022

Editorial: Proglucagon-Derived Peptides.

Front Endocrinol (Lausanne) 2021 11;12:776871. Epub 2021 Nov 11.

School Biomedical Sciences, Ulster University, Coleraine, Northern Ireland, United Kingdom.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fendo.2021.776871DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8631785PMC
November 2021

Arginine-vasopressin mediates counter-regulatory glucagon release and is diminished in type 1 diabetes.

Elife 2021 11 17;10. Epub 2021 Nov 17.

Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom.

Insulin-induced hypoglycemia is a major treatment barrier in type-1 diabetes (T1D). Accordingly, it is important that we understand the mechanisms regulating the circulating levels of glucagon. Varying glucose over the range of concentrations that occur physiologically between the fed and fuel-deprived states (8 to 4 mM) has no significant effect on glucagon secretion in the perfused mouse pancreas or in isolated mouse islets (in vitro), and yet associates with dramatic increases in plasma glucagon. The identity of the systemic factor(s) that elevates circulating glucagon remains unknown. Here, we show that arginine-vasopressin (AVP), secreted from the posterior pituitary, stimulates glucagon secretion. Alpha-cells express high levels of the vasopressin 1b receptor (V1bR) gene (). Activation of AVP neurons in vivo increased circulating copeptin (the C-terminal segment of the AVP precursor peptide) and increased blood glucose; effects blocked by pharmacological antagonism of either the glucagon receptor or V1bR. AVP also mediates the stimulatory effects of hypoglycemia produced by exogenous insulin and 2-deoxy-D-glucose on glucagon secretion. We show that the A1/C1 neurons of the medulla oblongata drive AVP neuron activation in response to insulin-induced hypoglycemia. AVP injection increased cytoplasmic Ca in alpha-cells (implanted into the anterior chamber of the eye) and glucagon release. Hypoglycemia also increases circulating levels of AVP/copeptin in humans and this hormone stimulates glucagon secretion from human islets. In patients with T1D, hypoglycemia failed to increase both copeptin and glucagon. These findings suggest that AVP is a physiological systemic regulator of glucagon secretion and that this mechanism becomes impaired in T1D.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.7554/eLife.72919DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8654374PMC
November 2021

The altered serum lipidome and its diagnostic potential for Non-Alcoholic Fatty Liver (NAFL)-associated hepatocellular carcinoma.

EBioMedicine 2021 11 29;73:103661. Epub 2021 Oct 29.

Biotech Research and Innovation Centre, Department of Health and Medical Sciences, University of Copenhagen, Denmark. Electronic address:

Background: Non-alcoholic fatty liver disease (NAFLD) is affecting more people globally. Indeed, NAFLD is a spectrum of metabolic dysfunctions that can progress to hepatocellular carcinoma (NAFLD-HCC). This development can occur in a non-cirrhotic liver and thus, often lack clinical surveillance. The aim of this study was to develop non-invasive surveillance method for NAFLD-HCC.

Methods: Using comprehensive ultra-high-performance liquid chromatography mass-spectrometry, we investigated 1,295 metabolites in serum from 249 patients. Area under the receiver operating characteristic curve was calculated for all detected metabolites and used to establish their diagnostic potential. Logistic regression analysis was used to establish the diagnostic score.

Findings: We show that NAFLD-HCC is characterised by a complete rearrangement of the serum lipidome, which distinguishes NAFLD-HCC from non-cancerous individuals and other HCC patients. We used machine learning to build a diagnostic model for NAFLD-HCC. We quantified predictive metabolites and developed the NAFLD-HCC Diagnostic Score (NHDS), presenting superior diagnostic potential compared to alpha-fetoprotein (AFP). Patients' metabolic landscapes show a progressive depletion in unsaturated fatty acids and acylcarnitines during transformation. Upregulation of fatty acid transporters in NAFLD-HCC tumours contribute to fatty acid depletion in the serum.

Interpretation: NAFLD-HCC patients can be efficiently distinguished by serum metabolic alterations from the healthy population and from HCC patients related to other aetiologies (alcohol and viral hepatitis). Our model can be used for non-invasive surveillance of individuals with metabolic syndrome(s), allowing for early detection of NAFLD-HCC. Therefore, serum metabolomics may provide valuable insight to monitor patients at risk, including morbidly obese, diabetics, and NAFLD patients.

Funding: The funding sources for this study had no role in study design, data collection, data analyses, interpretation or writing of the report as it is presented herein.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ebiom.2021.103661DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8577325PMC
November 2021

Hemoglobin A1c and Fructosamine Evaluated in Patients with Type 2 Diabetes Receiving Peritoneal Dialysis Using Long-Term Continuous Glucose Monitoring.

Nephron 2021 Nov 3:1-7. Epub 2021 Nov 3.

Department of Nephrology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.

Introduction: Shortened erythrocyte life span and erythropoietin-stimulating agents may affect hemoglobin A1c (HbA1c) levels in patients receiving peritoneal dialysis (PD). We compared HbA1c with interstitial glucose measured by continuous glucose monitoring (CGM) in patients with type 2 diabetes receiving PD.

Methods: Fourteen days of CGM (Ipro2, Medtronic) were performed in 23 patients with type 2 diabetes receiving PD and in 23 controls with type 2 diabetes and an estimated glomerular filtration rate over 60 mL/min/1.73 m2. Patients were matched on gender and age (±5 years). HbA1c (mmol/mol), its derived estimate of mean plasma glucose (eMPGA1c) (mmol/L), and fructosamine (µmol/L) were measured at the end of the CGM period and compared with the mean sensor glucose (mmol/L) from CGM.

Results: In the PD group, mean sensor glucose was 0.98 (95% con-fidence interval (CI): 0.43-1.54) mmol/L higher than the eMPGA1c compared with the control group (p = 0.002) where glucose levels were nearly identical (-0.05 (95% CI: -0.35-0.25) mmol/L). A significant association was found between fructosamine and mean sensor glucose using linear regression with no difference between slopes (p = 0.89) or y-intercepts (p = 0.28).

Discussion/conclusion: HbA1c underestimates mean plasma glucose levels in patients with type 2 diabetes receiving PD. However, the clinical significance of this finding is undetermined. Fructosamine seems to more accurately reflect glycemic status. CGM or fructosamine could complement HbA1c to increase the accuracy of glycemic monitoring in the PD population.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1159/000519493DOI Listing
November 2021

Glucagon Clearance is Preserved in Type 2 Diabetes.

Diabetes 2021 Oct 26. Epub 2021 Oct 26.

Center for Clinical Metabolic Research, Copenhagen University Hospital - Herlev and Gentofte, Hellerup, Denmark,

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 the hyperglucagonemia in type 2 diabetes and obesity. Individuals with type 2 diabetes and preserved kidney function (8 with and 8 without obesity) and matched control individuals (8 with and 8 without obesity) were recruited. Each participant underwent a 1-hour glucagon infusion (4 ng/kg/min), achieving steady-state plasma glucagon concentrations, followed by a 1-hour wash-out period. Plasma levels, the metabolic clearance rate (MCR), half-life (T) 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 to the control group, while no significant differences between the groups were found in glucagon T Individuals with obesity had neither a significantly decreased MCR, T, nor volume of distribution of glucagon. In our pharmacokinetic model, glucagon MCR associated positively with 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2337/db21-0024DOI Listing
October 2021

Effects of short-acting exenatide added three times daily to insulin therapy on bone metabolism in type 1 diabetes.

Diabetes Obes Metab 2022 Feb 18;24(2):221-227. Epub 2021 Oct 18.

Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark.

Aim: To evaluate the efficacy of the short-acting glucagon-like peptide-1 receptor agonist, exenatide, added to insulin therapy in type 1 diabetes on bone mineral density and bone turnover markers.

Materials And Methods: In a randomized, double-blinded, parallel-group trial, 108 individuals with type 1 diabetes aged 18 years or older on basal-bolus therapy with HbA1c 59-88 mmol/mol (7.5%-10.0%) and body mass index of more than 22.0 kg/m were randomized (1:1) to preprandial subcutaneous injection of 10 μg exenatide (Byetta) before breakfast, lunch, and dinner over 26 weeks as add-on treatment to insulin therapy.

Results: Exenatide elicited a body weight reduction of 4.4 kg compared with placebo, but no between-group differences in bone mineral density, as assessed by whole-body, hip, lumbar, and forearm dual-energy X-ray absorptiometry following 26 weeks of treatment, were observed. Fasting plasma levels of C-terminal telopeptides of type I collagen, a marker of bone resorption, and amino-terminal propeptide of type I procollagen, a marker of bone formation, were unchanged by exenatide compared with placebo after 26 weeks.

Conclusions: Despite an exenatide-induced body weight reduction, no changes in bone metabolism were observed with exenatide added to insulin therapy in type 1 diabetes after 26 weeks.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/dom.14568DOI Listing
February 2022

Weight gain on antipsychotics - A perfect storm of complex pathophysiology and psychopharmacology.

Acta Psychiatr Scand 2021 12 18;144(6):521-523. Epub 2021 Oct 18.

Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/acps.13376DOI Listing
December 2021

The Accuracy of Hemoglobin A1c and Fructosamine Evaluated by Long-Term Continuous Glucose Monitoring in Patients with Type 2 Diabetes Undergoing Hemodialysis.

Blood Purif 2021 Sep 28:1-9. Epub 2021 Sep 28.

Department of Nephrology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.

Introduction: The accuracy of hemoglobin A1c (HbA1c) as a glycemic marker in patients with type 2 diabetes (T2D) receiving hemodialysis (HD) remains unknown. To assess accuracy, we compared HbA1c and fructosamine levels with interstitial glucose measured by continuous glucose monitoring (CGM) in patients with T2D receiving HD.

Methods: Thirty patients in the HD group and 36 patients in the control group (T2D and an estimated glomerular filtration rate >60 mL/min/1.73 m2) completed the study period of 17 weeks. CGM (Ipro2®, Medtronic) was performed 5 times for periods of up to 7 days (with 4-week intervals) during a 16-week period. HbA1c (mmol/mol), the estimated mean plasma glucose from HbA1c (eMPGA1c [mmol/L]) and fructosamine (μmol/L) was measured at week 17 and compared with mean sensor glucose levels from CGM.

Findings: In the HD group, mean sensor glucose was 1.4 mmol/L (95% confidence interval [CI]: 1.0-1.8) higher than the eMPGA1c, whereas the difference for controls was 0.1 mmol/L (95% CI: -0.1-[0.4]; p < 0.001). Adjusted for mean sensor glucose, HbA1c was lower in the HD group (-7.3 mmol/mol, 95% CI: -10.0-[-4.7]) than in the control group (p < 0.001), with no difference detected for fructosamine (p = 0.64).

Discussion: HbA1c evaluated by CGM underestimates plasma glucose levels in patients receiving HD. The underestimation represents a clinical challenge in optimizing glycemic control in the HD population. Fructosamine is unaffected by the factors affecting HbA1c and appears to be more accurate for glycemic monitoring. CGM or fructosamine could thus complement HbA1c in obtaining more accurate glycemic control in this patient group.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1159/000519050DOI Listing
September 2021

Prevalence of non-alcoholic fatty liver disease in patients with chronic kidney disease: a case-control study.

Nephrol Dial Transplant 2021 Sep 10. Epub 2021 Sep 10.

Department of Nephrology, Copenhagen University Hospital-Rigshospitalet, Copenhagen, Denmark.

Background: Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease and represents a wide spectrum ranging from mild steatosis over non-alcoholic steatohepatitis with and without fibrosis to overt cirrhosis. Patients with NAFLD have a high risk of developing cardiovascular disease and chronic kidney disease (CKD). So far, there is scarce evidence of the prevalence of NAFLD among patients with CKD. We investigated the prevalence of moderate-to-severe hepatic steatosis graded according to the definition of NAFLD in a cohort of patients with CKD.

Methods: Hepatic liver fat content was evaluated by computed tomography (CT) scan in 291 patients from the Copenhagen Chronic Kidney Disease Cohort Study and in 866 age- and sex-matched individuals with normal kidney function from the Copenhagen General Population Study. Liver attenuation density <48 Hounsfield units was used as cut-off value for moderate-to-severe hepatic steatosis.

Results: The prevalence of moderate-to-severe hepatic steatosis was 7.9% and 10.7% (P = 0.177) among patients with CKD and controls, respectively. No association between liver fat content and CKD stage was found. In the pooled data set from both cohorts, adjusted odds ratios for moderate-to-severe hepatic steatosis among persons with diabetes, overweight and obesity amounted to 3.1 (95% confidence interval (CI) 1.6-5.9), 14.8 (95% CI 4.6-47.9) and 42.0 (95% CI 12.9-136.6), respectively.

Conclusions: In a cohort of 291 patients with CKD, kidney function was not associated with the prevalence of moderate-to-severe hepatic steatosis as assessed by CT scan.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/ndt/gfab266DOI Listing
September 2021

Glucose-dependent insulinotropic polypeptide induces lipolysis during stable basal insulin substitution and hyperglycaemia in men with type 1 diabetes: A randomized, double-blind, placebo-controlled, crossover clinical trial.

Diabetes Obes Metab 2022 Jan 20;24(1):142-147. Epub 2021 Sep 20.

Centre for Clinical Metabolic Research, Copenhagen University Hospital - Herlev and Gentofte, Hellerup, Denmark.

Glucose-dependent insulinotropic polypeptide (GIP) plays an important role in the glucose and lipid metabolism. We investigated the effects of exogenous GIP on lipid metabolism during time of stable insulin levels. Ten male patients with type 1 diabetes without endogenous insulin secretion (C-peptide-negative, mean [±SD] age 26 ± 4years, body mass index 24 [±2] kg/m , glycated haemoglobin 56 [±8] mmol/mol or 7.3 [±0.8]%) were studied in a randomized, double-blind, placebo-controlled, crossover study with continuous intravenous infusions of GIP (4 pmol/kg/min) or placebo (saline), during two separate 90-minute hyperglycaemic (12 mmol/L) clamps with basal insulin substitution (0.1-0.2 mU/kg/min). Plasma glycerol concentrations increased from baseline during GIP infusion and decreased during placebo infusion (baseline-subtracted area under the curve [bsAUC] 703 ± 407 vs. -262 ± 240 μmol/L × min, respectively; P < 0.001). Free fatty acids (FFAs) increased during GIP infusions (bsAUC 5505 ± 2170 μEq/L × min) and remained unchanged during placebo infusion (bsAUC -74 ± 2363 μEq/L × min), resulting in a significant difference between GIP and placebo infusions (P < 0.001). Plasma concentrations of glucose, insulin, glucagon-like peptide-1 and glucagon were similar during GIP and placebo infusions. GIP increased plasma glycerol and FFAs in patients with type 1 diabetes during hyperglycaemia and stable basal insulin levels. This supports a direct lipolytic effect of GIP at high glucose and low levels of plasma insulin.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/dom.14545DOI Listing
January 2022

Systemic Corticosteroids and the Risk of Venous Thromboembolism in Patients with Severe COPD: A Nationwide Study of 30,473 Outpatients.

Biomedicines 2021 Jul 23;9(8). Epub 2021 Jul 23.

Section of Respiratory Medicine, Herlev-Gentofte Hospital, 2900 Hellerup, Denmark.

Due to frequent exacerbations, many patients with chronic obstructive pulmonary disease (COPD) are exposed to oral corticosteroids (OCS), which may be thrombogenic. We evaluated the risk of hospitalisation with venous thromboembolism (VTE) and death in patients with acute exacerbation of COPD (AECOPD) treated with long and short OCS regimens. In this nationwide cohort study of 30,473 COPD outpatients treated for AECOPD, we compared the risk of VTE hospitalisation and all-cause mortality within 6 months in OCS dose of >250 mg vs. ≤250 mg. A multivariable Cox proportional hazard regression was used to estimate the risk. The incidence of VTE hospitalisations was 0.23%. A long OCS treatment course was associated with an increased risk of VTE compared to a short course (hazard ratio (HR) 1.69, [95% confidence interval (CI) 1.05 to 2.72], < 0.031). A higher risk of all-cause mortality was seen in the group of COPD patients treated with a long OCS course (HR 1.71, [95% CI 1.63 to 1.79], < 0.0001). The risk of reported VTE hospitalisation was higher among AECOPD patients treated with long courses of OCS, but the absolute risk was low, suggesting under-reporting of the condition.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/biomedicines9080874DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8389624PMC
July 2021

Treatment of type 2 diabetes in children: what are the specific considerations?

Expert Opin Pharmacother 2021 Nov 21;22(16):2127-2141. Epub 2021 Aug 21.

Center for Clinical Metabolic Research, Copenhagen University Hospital - Herlev and Gentofte, Hellerup, Denmark.

: The number of individuals under 18 years of age with type 2 diabetes is increasing at an alarming rate worldwide. These patients are often characterized by obesity and they often experience a more rapid disease progression than adults with type 2 diabetes. Thus, focus on prevention and management of complications and comorbidities is imperative. With emphasis on weight loss and optimal glycemic control, treatment includes lifestyle changes and pharmacotherapy, which in this patient group is limited to metformin, liraglutide and insulin. In selected cases, bariatric surgery is indicated.: This perspective article provides an overview of the literature covering pathophysiology, diagnosis, characteristics and treatment of pediatric type 2 diabetes, and outlines the gaps in our knowledge where further research is needed. The paper draws on both mechanistic studies, large scale intervention trials, epidemiological studies and international consensus statements.: Type 2 diabetes in pediatric patients is an increasing health care problem, and the current treatment strategies do not successfully meet the many challenges and obstacles in this patient group. Treatments must be early, intensive, multifaceted and durable. Also, prevention of obesity and type 2 diabetes in at-risk children should be addressed and prioritized on all levels.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/14656566.2021.1954160DOI Listing
November 2021

The effect of 6-day subcutaneous glucose-dependent insulinotropic polypeptide infusion on time in glycaemic range in patients with type 1 diabetes: a randomised, double-blind, placebo-controlled crossover trial.

Diabetologia 2021 Nov 17;64(11):2425-2431. Epub 2021 Aug 17.

Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark.

Aims/hypothesis: Type 1 diabetes is characterised by reduced glucagon response to hypoglycaemia, increasing the risk of insulin treatment-associated hypoglycaemia known to hamper glycaemic control. We previously reported a glucagonotropic effect of exogenous glucose-dependent insulinotropic polypeptide (GIP) during insulin-induced hypoglycaemia in individuals with type 1 diabetes. Here we investigate the effect of a 6-day s.c. GIP infusion on time in glycaemic range as assessed by continuous glucose monitoring (CGM) in individuals with type 1 diabetes.

Methods: In a randomised, placebo-controlled, double-blind crossover study, time in glycaemic range (assessed by double-blinded CGM) was evaluated in 20 men with type 1 diabetes (18-75 years, stable insulin treatment ≥3 months, diabetes duration 2-15 years, fasting plasma C-peptide below 200 pmol/l, BMI 20-27 kg/m, HbA <69 mmol/mol [8.5%]) during two × 6 days of continuous s.c. GIP (6 pmol kg min) and placebo (saline [154 mmol/l NaCl]) infusion, respectively, with an interposed 7-day washout period. The primary outcome was glycaemic time below range, time in range and time above range.

Results: There were no significant differences in time below range (<3.9 mmol/l, p = 0.53) or above range (>10 mmol/l, p = 0.32) during night-time or daytime, in mean glucose, or in hypoglycaemic events as assessed by CGM. GIP altered neither self-reported hypoglycaemia nor safety measures. Compared with placebo, GIP significantly increased time in tight range (3.9-7.8 mmol/l) during daytime (06:00-23:59 hours) by [mean ± SEM] 11.2 ± 5.1% [95% CI 0.41, 21.9] (p = 0.02).

Conclusions/interpretation: Six-day s.c. GIP infusion in men with type 1 diabetes did not procure convincing effect on overall time in range, but increased time in tight glycaemic range during daytime by ~2 h per day.

Trial Registration: ClinicalTrials.gov NCT03734718.

Funding: The study was funded by grants from The Leona M. and Harry B. Helmsley Charitable Trust and Aase og Ejnar Danielsens Fond.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00125-021-05547-8DOI Listing
November 2021

Neurotensin secretion after Roux-en-Y gastric bypass, sleeve gastrectomy, and truncal vagotomy with pyloroplasty.

Neurogastroenterol Motil 2022 01 11;34(1):e14210. Epub 2021 Aug 11.

Department of Endocrinology, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark.

Objective: Neurotensin (NT) is released from enteroendocrine cells and lowers food intake in rodents. We evaluated postprandial NT secretion in humans after surgeries associated with accelerated small intestinal nutrient delivery, and after Roux-en-Y gastric bypass (RYGB) when glucagon-like peptide-1 (GLP-1) signalling and dipeptidyl peptidase 4 (DPP-4) were inhibited, and during pharmacological treatments influencing entero-pancreatic functions.

Methods: We measured NT concentrations in plasma from meal studies: (I) after truncal vagotomy with pyloroplasty (TVP), cardia resection +TVP (CTVP), and matched controls (n = 10); (II) after RYGB, sleeve gastrectomy (SG), and in matched controls (n = 12); (III) after RYGB (n = 11) with antagonism of GLP-1 signalling using exendin(9-39) and DPP-4 inhibition using sitagliptin; (IV) after RYGB (n = 11) during a run-in period and subsequent treatment with, sitagliptin, liraglutide (GLP-1 receptor agonist), verapamil (calcium antagonist), acarbose (alpha glucosidase inhibitor), and pasireotide (somatostatin analogue), respectively.

Results: (I) NT secretion was similar after TVP/CTVP (p = 0.9), but increased vs. controls (p < 0.0001). (II) NT secretion was increased after RYGB vs. SG and controls (p < 0.0001). NT responses were similar in SG and controls (p = 0.3), but early postprandial NT concentrations were higher after SG (p < 0.05). (III) Exendin (9-39) and sitagliptin did not change NT responses vs placebo (p > 0.2), but responses were lower during sitagliptin vs. exendin(9-39) (p = 0.03). (IV) Pasireotide suppressed NT secretion (p = 0.004). Sitagliptin tended to lower NT secretion (p = 0.08). Liraglutide, verapamil, and acarbose had no effect (p > 0.9).

Conclusion: Neurotensin secretion is increased after surgeries associated with accelerated gastric emptying and lowered by pasireotide.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/nmo.14210DOI Listing
January 2022

MECHANISMS IN ENDOCRINOLOGY: The physiology of neuronostatin.

Eur J Endocrinol 2021 Sep 1;185(4):R93-R101. Epub 2021 Sep 1.

Center for Clinical Metabolic Research, Department of Medicine, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark.

In 2008, the first evidence of a new hormone called neuronostatin was published. The hormone was discovered using a bioinformatic method and found to originate from the same preprohormone as somatostatin. This small peptide hormone of 13 amino acids and a C-terminal amidation was soon found to exert pleiotropic physiological effects. In animal studies, neuronostatin has been shown to reduce food intake and delay gastric emptying and gastrointestinal transit. Furthermore, neuronostatin has been shown to affect glucose metabolism by increasing glucagon secretion during situations when glucose concentrations are low. Additionally, neuronostatin has been shown to affect neural tissue and cardiomyocytes by suppressing cardiac contractility. The effects of neuronostatin have not yet been delineated in humans, but if the effects found in animal studies translate to humans it could position neuronostatin as a promising target in the treatment of obesity, hypertension and diabetes. In this review, we describe the discovery of neuronostatin and the current understanding of its physiological role and potential therapeutic applicability.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1530/EJE-21-0347DOI Listing
September 2021

Once-weekly subcutaneous semaglutide treatment for persons with type 2 diabetes: Real-world data from a diabetes out-patient clinic.

Diabet Med 2021 Oct 4;38(10):e14655. Epub 2021 Aug 4.

Steno Diabetes Center Copenhagen, Gentofte, Denmark.

Aims: The once-weekly administered glucagon-like peptide 1 (GLP-1) receptor agonist (GLP-1RA) semaglutide, has, in clinical trials, demonstrated significant reductions in glycated haemoglobin A (HbA ) and body weight in persons with type 2 diabetes. We evaluated the real-world clinical effects of semaglutide once weekly in a hospital-based diabetes out-patient clinic.

Methods: This retrospective observational cohort study included persons with type 2 diabetes (n = 119) on a broad range of antidiabetic medicine: GLP-1RA naïve persons (n = 37) and GLP-1RA-experienced persons (n = 82). Person characteristics at inclusion: age [median (quartiles)]: 65 (57, 72) years; body weight 99 (86, 118) kg; body mass index (BMI) 33 (29, 38) kg/m²; HbA 61 (54, 69) mmol/mol/(7.7 (7.1, 8.5) %). Data were collected at baseline and after 3, 6 and 12 months of semaglutide treatment. Data were analysed using a general linear mixed model for repeated measurements.

Results: After 12 months, the reductions in HbA were (mean [95% confidence interval]: GLP-1RA naïve: -12.8 [-17.0, -8.5] mmol/mol/ -1.2 [-1.6, -0.8]% (p < 0.01) and GLP-1RA experienced: -6.4 [-9.0, -3.8] mmol/mol/ -0.6 [-0.8, -0.4]% (p < 0.01), respectively. Body weight reductions in GLP-1RA naïve: -5 [-6.9, -3.1] kg (p < 0.01) and GLP-1RA experienced: -3.2 [-4.4, -2.0] kg (p < 0.01), respectively. Seventy-five percent received 1 mg QW semaglutide.

Conclusion: We observed effects of semaglutide once weekly on HbA and body weight comparable with the effects observed in clinical studies with fewer persons in our cohort receiving maximum dose of semaglutide.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/dme.14655DOI Listing
October 2021

Acute hypoglycemia and risk of cardiac arrhythmias in insulin-treated type 2 diabetes and controls.

Eur J Endocrinol 2021 Jul 21;185(2):343-353. Epub 2021 Jul 21.

Steno Diabetes Center Copenhagen, Gentofte Hospital, Hellerup, Denmark.

Objective: Hypoglycemia is associated with an increased risk of cardiovascular disease including cardiac arrhythmias. We investigated the effect of hypoglycemia in the setting of acute glycemic fluctuations on cardiac rhythm and cardiac repolarization in insulin-treated patients with type 2 diabetes compared with matched controls without diabetes.

Design: A non-randomized, mechanistic intervention study.

Methods: Insulin-treated patients with type 2 diabetes (n = 21, age (mean ± s.d.): 62.8 ± 6.5 years, BMI: 29.0 ± 4.2 kg/m2, HbA1c: 6.8 ± 0.5% (51.0 ± 5.4 mmol/mol)) and matched controls (n = 21, age: 62.2 ± 8.3 years, BMI 29.2 ± 3.5 kg/m2, HbA1c: 5.3 ± 0.3% (34.3 ± 3.3 mmol/mol)) underwent a sequential hyperglycemic and hypoglycemic clamp with three steady-states of plasma glucose: (i) fasting plasma glucose, (ii) hyperglycemia (fasting plasma glucose +10 mmol/L) and (iii) hyperinsulinemic hypoglycemia (plasma glucose < 3.0 mmol/L). Participants underwent continuous ECG monitoring and blood samples for counterregulatory hormones and plasma potassium were obtained.

Results: Both groups experienced progressively increasing heart rate corrected QT (Fridericia's formula) interval prolongations during hypoglycemia ((∆mean (95% CI): 31 ms (16, 45) and 39 ms (24, 53) in the group of patients with type 2 diabetes and controls, respectively) with similar increases from baseline at the end of the hypoglycemic phase (P = 0.43). The incidence of ventricular premature beats increased significantly in both groups during hypoglycemia (P = 0.033 and P < 0.0001, respectively). One patient with type 2 diabetes developed atrial fibrillation during recovery from hypoglycemia.

Conclusions: In insulin-treated patients with type 2 diabetes and controls without diabetes, hypoglycemia causes clinically significant and similar increases in cardiac repolarization that might increase vulnerability for serious cardiac arrhythmias and sudden cardiac death.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1530/EJE-21-0232DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8345897PMC
July 2021

Azithromycin and hydroxychloroquine in hospitalised patients with confirmed COVID-19: a randomised double-blinded placebo-controlled trial.

Eur Respir J 2022 01 6;59(1). Epub 2022 Jan 6.

Dept of Cardiology, Gentofte University Hospital, Hellerup, Denmark.

Background: Combining the antibiotic azithromycin and hydroxychloroquine induces airway immunomodulatory effects, with the latter also having antiviral properties. This may improve outcomes in patients hospitalised for coronavirus disease 2019 (COVID-19).

Methods: Placebo-controlled double-blind randomised multicentre trial. Patients aged ≥18 years, admitted to hospital for ≤48 h (not intensive care) with a positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) reverse transcription PCR test were recruited. The intervention was 500 mg daily azithromycin for 3 days followed by 250 mg daily azithromycin for 12 days combined with 200 mg twice-daily hydroxychloroquine for all 15 days. The control group received placebo/placebo. The primary outcome was days alive and discharged from hospital within 14 days (DAOH14).

Results: After randomisation of 117 patients, at the first planned interim analysis, the data and safety monitoring board recommended stopping enrolment due to futility, based on pre-specified criteria. Consequently, the trial was terminated on 1 February 2021. 61 patients received the combined intervention and 56 patients received placebo. In the intervention group, patients had a median (interquartile range) 9.0 (3-11) DAOH14 9.0 (7-10) DAOH14 in the placebo group (p=0.90). The primary safety outcome, death from all causes on day 30, occurred for one patient in the intervention group two patients receiving placebo (p=0.52), and readmittance or death within 30 days occurred for nine patients in the intervention group six patients receiving placebo (p=0.57).

Conclusions: The combination of azithromycin and hydroxychloroquine did not improve survival or length of hospitalisation in patients with COVID-19.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1183/13993003.00752-2021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8186006PMC
January 2022

Expression of Cholecystokinin and its Receptors in the Intestinal Tract of Type 2 Diabetes Patients and Healthy Controls.

J Clin Endocrinol Metab 2021 07;106(8):2164-2170

Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark.

Background: Cholecystokinin (CCK) is a gut hormone originally known for its effects on gallbladder contraction and release of digestive enzymes. CCK, however, also mediates satiety and stimulate insulin secretion. Knowledge of the distribution of CCK-producing enteroendocrine cells (I cells) in humans is sparse. The general notion, based on animal data, is that I cells are present mainly in the proximal small intestine. We examined the occurrence of I cells (immunohistochemically) and the expression of CCK messenger RNA (mRNA) as well as CCK1 and CCK2 receptor mRNA along the intestines in healthy individuals and patients with type 2 diabetes.

Methods: Mucosal biopsies collected with 30-cm intervals in the small intestine and from seven anatomical locations in the large intestine (using double-balloon enteroscopy) from 12 patients with type 2 diabetes and 12 gender-, age-, and body mass index-matched healthy individuals were analyzed using mRNA sequencing and immunohistochemical staining.

Results: We observed a gradual decrease in CCK mRNA expression and density of CCK-immunoreactive cells from duodenum to ileum. Very few CCK-immunoreactive cells and nearly undetectable CCK mRNA expression were found in the large intestine. No significant differences were seen between the groups. Expression of CCK receptors was observed in the duodenum of both groups.

Conclusions: Both density of CCK cells and expression of CCK mRNA decreased through the small intestine in both groups with low levels in the large intestine. Patients with type 2 diabetes did not have altered density of CCK cells or expression of CCK mRNA in intestinal mucosa.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1210/clinem/dgab367DOI Listing
July 2021

Pancreatic polypeptide: A potential biomarker of glucose-dependent insulinotropic polypeptide receptor activation in vivo.

Diabet Med 2021 Aug 17;38(8):e14592. Epub 2021 May 17.

Center for Clinical Metabolic Research, Gentofte Hospital, Hellerup, Denmark.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/dme.14592DOI Listing
August 2021

Metabolic effects of 1-week binge drinking and fast food intake during Roskilde Festival in young healthy male adults.

Eur J Endocrinol 2021 May 21;185(1):23-32. Epub 2021 May 21.

Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark.

Aims/hypothesis: Metabolic effects of intermittent unhealthy lifestyle in young adults are poorly studied. We investigated the gluco-metabolic and hepatic effects of participation in Roskilde Festival (1 week of binge drinking and junk food consumption) in young, healthy males.

Methods: Fourteen festival participants (FP) were studied before, during and after 1 week's participation in Roskilde Festival. Fourteen matched controls (CTRL) who did not participate in Roskilde Festival or change their lifestyle in other ways were investigated along a similar timeline.

Results: The FP group consumed more alcohol compared to their standard living conditions (2.0 ± 3.9 vs 16.3 ± 8.3 units/day, P < 0.001). CTRLs did not change their alcohol consumption. AUC for glucose during OGTT did not change in either group. C-peptide responses increased in the FP group (206 ± 24 vs 236 ± 17 min × nmol/L, P = 0.052) and the Matsuda index of insulin sensitivity decreased (6.2 ± 2.4 vs 4.7 ± 1.4, P = 0.054). AUC for glucagon during oral glucose tolerance test (OGTT) increased in the FP group (1037 ± 90 vs 1562 ± 195 min × pmol/L, P = 0.003) together with fasting fibroblast growth factor 21 (FGF21) (62 ± 30 vs 132 ± 72 pmol/L, P < 0.001), growth differentiation factor 15 (GDF5) (276 ± 78 vs 330 ± 83 pg/mL, P = 0.009) and aspartate aminotransferase (AST) levels (37.6 ± 6.8 vs 42.4 ± 11 U/L, P = 0.043). Four participants (29%) developed ultrasound-detectable steatosis and a mean strain elastography-assessed liver stiffness increased (P = 0.026) in the FP group.

Conclusions/interpretation: Participation in Roskilde Festival did not affect oral glucose tolerance but was associated with a reduction in insulin sensitivity, increases in glucagon, FGF21, GDF15 and AST and lead to increased liver stiffness and, in 29% of the participants, ultrasound-detectable hepatic steatosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1530/EJE-21-0122DOI Listing
May 2021

Effects of endogenous GIP in patients with type 2 diabetes.

Eur J Endocrinol 2021 May 21;185(1):33-45. Epub 2021 May 21.

Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark.

Objective: The insulinotropic effect of exogenous, intravenously infused glucose-dependent insulinotropic polypeptide (GIP) is impaired in patients with type 2 diabetes. We evaluated the effects of endogenous GIP in relation to glucose and bone metabolism in patients with type 2 diabetes using a selective GIP receptor antagonist and hypothesized that the effects of endogenous GIP were preserved.

Design: A randomized, double-blinded, placebo-controlled, crossover study.

Methods: Ten patients with overweight/obesity and type 2 diabetes (mean±s.d.; HbA1c 52 ± 11 mmol/mol; BMI 32.5 ± 4.8 kg/m2) were included. We infused a selective GIP receptor antagonist, GIP(3-30)NH2 (1200 pmol/kg/min), or placebo (saline) during two separate, 230-min, standardized, liquid mixed meal tests followed by a meal ad libitum. Subcutaneous adipose tissue biopsies were analyzed.

Results: Compared with placebo, GIP(3-30)NH2 reduced postprandial insulin secretion (Δbaseline-subtracted area under the curve (bsAUC)C-peptide% ± s.e.m.; -14 ± 6%, P = 0.021) and peak glucagon (Δ% ± s.e.m.; -11 ± 6%, P = 0.046) but had no effect on plasma glucose (P = 0.692). Suppression of bone resorption (assessed by circulating carboxy-terminal collagen crosslinks (CTX)) was impaired during GIP(3-30)NH2 infusion compared with placebo (ΔbsAUCCTX; ±s.e.m.; -4.9 ± 2 ng/mL × min, P = 0.005) corresponding to a ~50% reduction. Compared with placebo, GIP(3-30)NH2 did not affect plasma lipids, meal consumption ad libitum or adipose tissue triglyceride content.

Conclusions: Using a selective GIP receptor antagonist during a meal, we show that endogenous GIP increases postprandial insulin secretion with little effect on postprandial glycaemia but is important for postprandial bone homeostasis in patients with type 2 diabetes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1530/EJE-21-0135DOI Listing
May 2021

INPP4B protects from metabolic syndrome and associated disorders.

Commun Biol 2021 03 26;4(1):416. Epub 2021 Mar 26.

Department of Human and Molecular Genetics, Herbert Wertheim College of Medicine, Florida International University, Miami, FL, USA.

A high fat diet and obesity have been linked to the development of metabolic dysfunction and the promotion of multiple cancers. The causative cellular signals are multifactorial and not yet completely understood. In this report, we show that Inositol Polyphosphate-4-Phosphatase Type II B (INPP4B) signaling protects mice from diet-induced metabolic dysfunction. INPP4B suppresses AKT and PKC signaling in the liver thereby improving insulin sensitivity. INPP4B loss results in the proteolytic cleavage and activation of a key regulator in de novo lipogenesis and lipid storage, SREBP1. In mice fed with the high fat diet, SREBP1 increases expression and activity of PPARG and other lipogenic pathways, leading to obesity and non-alcoholic fatty liver disease (NAFLD). Inpp4b male mice have reduced energy expenditure and respiratory exchange ratio leading to increased adiposity and insulin resistance. When treated with high fat diet, Inpp4b males develop type II diabetes and inflammation of adipose tissue and prostate. In turn, inflammation drives the development of high-grade prostatic intraepithelial neoplasia (PIN). Thus, INPP4B plays a crucial role in maintenance of overall metabolic health and protects from prostate neoplasms associated with metabolic dysfunction.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s42003-021-01940-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7998001PMC
March 2021

Prototype of an evidence-based tool to aid individualized treatment for type 2 diabetes.

Diabetes Obes Metab 2021 07 4;23(7):1666-1671. Epub 2021 May 4.

AdventHealth Translational Research Institute, Orlando, Florida, USA.

Data-driven tools are needed to inform individualized treatment decisions for people with type 2 diabetes (T2D). To show how treatment might be individualized, an interactive outline tool was developed to predict treatment outcomes. Individualized predictions were generated for change in HbA1c and body weight after initiation of newer antidiabetes drugs recommended by current guidelines. These predictions were based on data from randomized controlled trials of glucose-lowering drugs. The data included patient demographics and clinical characteristics (sex, age, body mass index, weight, diabetes duration, HbA1c level, current diabetes treatment and renal function). Predicted outcomes were determined using prespecified statistical models from original trial protocols and estimated coefficients for selected baseline characteristics. This prototype illustrates how evidence-based individualized treatment might be facilitated in the clinic for people with T2D. Further and ongoing development is required to improve the tool's prognostic value, including the addition of disease co-morbidities and patient-orientated outcomes. Patient engagement and data-sharing by sponsors of clinical trials, as well as real-world evidence, are needed to provide reliable predicted outcomes to inform shared patient-physician decision-making.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/dom.14381DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8251774PMC
July 2021

Glucagonostatic Potency of GLP-1 in Patients With Type 2 Diabetes, Patients With Type 1 Diabetes, and Healthy Control Subjects.

Diabetes 2021 06 15;70(6):1347-1356. Epub 2021 Mar 15.

Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2337/db20-0998DOI Listing
June 2021

An overview of obesity mechanisms in humans: Endocrine regulation of food intake, eating behaviour and common determinants of body weight.

Diabetes Obes Metab 2021 02;23 Suppl 1:17-35

Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark.

Obesity is one of the biggest health challenges of the 21st century, already affecting close to 700 million people worldwide, debilitating and shortening lives and costing billions of pounds in healthcare costs and loss of workability. Body weight homeostasis relies on complex biological mechanisms and the development of obesity occurs on a background of genetic susceptibility and an environment promoting increased caloric intake and reduced physical activity. The pathophysiology of common obesity links neuro-endocrine and metabolic disturbances with behavioural changes, genetics, epigenetics and cultural habits. Also, specific causes of obesity exist, including monogenetic diseases and iatrogenic causes. In this review, we provide an overview of obesity mechanisms in humans with a focus on energy homeostasis, endocrine regulation of food intake and eating behavior, as well as the most common specific causes of obesity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/dom.14270DOI Listing
February 2021
-->