Glucagon-Like Peptide 1:A Predictor of Type 2 Diabetes?

Background. The incretin effect is impaired in patients with type 2 diabetes. Aim. To assess the relation between the incretin hormone GLP-1 and the prediabetic subtypes: impaired fasting glucose (IFG), impaired glucose tolerance (IGT), and the combined IFG/IGT to investigate whether a low GLP-1 response may be a predictor of prediabetes in adults. Method. 298 articles were found using a broad search phrase on the PubMed database and after the assessment of titles and abstracts 19 articles were included. Results and Discussion. Studies assessing i-IFG/IFG and i-IGT/IGT found both increased, unaltered, and reduced GLP-1 levels. Studies assessing IFG/IGT found unaltered or reduced GLP-1 levels. When assessing the five studies with the largest sample size, it clearly suggests a decreased GLP-1 response in IFG/IGT subjects. Several other factors (BMI, glucagon, age, and nonesterified fatty acids (NEFA)), including medications (metformin), may also influence the secretion of GLP-1. Conclusion. This review suggests that the GLP-1 response is a variable in prediabetes possibly due to a varying GLP-1-secreting profile during the development and progression of type 2 diabetes or difference in the measurement technique. Longitudinal prospective studies are needed to assess whether a reduced GLP-1 response is a predictor of diabetes

Patients with Long-QT Syndrome Caused by Impaired hERG -Encoded Kv11.1 Potassium Channel Have Exaggerated Endocrine Pancreatic and Incretin Function Associated with Reactive Hypoglycemia

Background: Loss-of-function mutations in hERG (encoding the Kv11.1 voltage-gated potassium channel) cause long-QT syndrome type 2 (LQT2) because of prolonged cardiac repolarization. However, Kv11.1 is also present in pancreatic and β cells and intestinal L and K cells, secreting glucagon, insulin, and the incretins glucagon-like peptide-1 (GLP-1) and GIP (glucose-dependent insulinotropic polypeptide), respectively. These hormones are crucial for glucose regulation, and long-QT syndrome may cause disturbed glucose regulation. We measured secretion of these hormones and cardiac repolarization in response to glucose ingestion in LQT2 patients with functional mutations in hERG and matched healthy participants, testing the hypothesis that LQT2 patients have increased incretin and β-cell function and decreased -cell function, and thus lower glucose levels. Methods: Eleven patients with LQT2 and 22 sex-, age-, and body mass index-matched control participants underwent a 6-hour 75-g oral glucose tolerance test with ECG recording and blood sampling for measurements of glucose, insulin, C-peptide, glucagon, GLP-1, and GIP. Results: In comparison with matched control participants, LQT2 patients had 56% to 78% increased serum insulin, serum C-peptide, plasma GLP-1, and plasma GIP responses (P=0.03-0.001) and decreased plasma glucose levels after glucose ingestion (P=0.02) with more symptoms of hypoglycemia (P=0.04). Sixty-three percent of LQT2 patients developed hypoglycemic plasma glucose levels (&lt;70 mg/dL) versus 36% control participants (P=0.16), and 18% patients developed serious hypoglycemia (&lt;50 mg/dL) versus none of the controls. LQT2 patients had defective glucagon responses to low glucose, P=0.008. β-Cell function (Insulin Secretion Sensitivity Index-2) was 2-fold higher in LQT2 patients than in controls (4398 [95% confidence interval, 2259-8562] versus 2156 [1961-3201], P=0.03). Pharmacological Kv11.1 blockade (dofetilide) in rats had similar effect, and small interfering RNA inhibition of hERG in β and L cells increased insulin and GLP-1 secretion up to 50%. Glucose ingestion caused cardiac repolarization disturbances with increased QTc intervals in both patients and controls, but with a 122% greater increase in QTcF interval in LQT2 patients (P=0.004). Conclusions: Besides a prolonged cardiac repolarization phase, LQT2 patients display increased GLP-1, GIP, and insulin secretion and defective glucagon secretion, causing decreased plasma glucose and thus increased risk of hypoglycemia. Furthermore, glucose ingestion increased QT interval and aggravated the cardiac repolarization disturbances in LQT2 patients.</p

Homozygous carriers of the G allele of rs4664447 of the glucagon gene (GCG) are characterised by decreased fasting and stimulated levels of insulin, glucagon and glucagon-like peptide (GLP)-1

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

Instrumentalization of eating improves weight loss maintenance in obesity

Aim: The purpose of this study was to identify psychosocial determinants for maintaining weight loss. Methods: 42 obese individuals who achieved a 12% weight loss before entering a 52-week weight maintenance program were interviewed qualitatively. Psychosocial factors related to weight loss maintenance were identified in two contrasting groups: weight reducers and weight regainers. Groups were defined by health-relevant weight maintenance (additional weight loss > 3% at week 52, n = 9 versus weight gain > 3%, at week 52, n = 20). Results: Weight reducers reported structured meal patterns (p = 0.008), no comfort eating (p = 0.016) and less psychosocial stress (p = 0.04) compared to weight regainers. The ability to instrumentalize eating behavior emerged as an important factor (p = 0.007). Nutritional knowledge, motivation or exercise level did not differ between groups (p > 0.05). Conclusions: Successful weight loss maintenance was associated with an interplay between behavioral, affective and contextual changes. ‘Instrumentalization of eating behavior' seems to be an important element in long-term weight maintenance

GLP-1 Receptor Agonist Treatment in Morbid Obesity and Type 2 Diabetes Due to Pathogenic Homozygous Melanocortin-4 Receptor Mutation: A Case Report

Individuals with obesity due to pathogenic heterozygous melanocortin 4 receptor (MC4R) mutations can betreated efficiently with the glucagon-like peptide-1 receptor agonist (GLP-1 RA) liraglutide. Here, we reportthe effect of 16 weeks of liraglutide 3 mg/day treatment in a woman with morbid obesity and type 2 diabetes(T2D) due to homozygous pathogenic MC4R mutation. The body weight loss was 9.7 kg, similar to weight lossin heterozygous MC4R mutation carriers and common obesity. In addition, the treatment led to clinically relevant decreases in fasting glucose, triglycerides, systolic blood pressure, and normalization of glucose tolerance. We conclude that liraglutide reduces body weight and blood glucose levels in hetero- and homozygousMC4R mutation carriers. This serves as proof-of-concept that MC4Rs are not required for the body weightand glucose lowering effects of GLP-1 RAs and that liraglutide may be used as part of the treatment of obesityand T2D due to MC4R mutations

Protocol for a randomised controlled trial of the combined effects of the GLP-1 receptor agonist liraglutide and exercise on maintenance of weight loss and health after a very low-calorie diet

Introduction The success rate of weight loss maintenance is limited. Therefore, the purpose of this study is to investigate the maintenance of weight loss and immunometabolic health outcomes after diet-induced weight loss followed by 1-year treatment with a glucagon-like peptide-1 receptor agonist (liraglutide), physical exercise or the combination of both treatments as compared with placebo in individuals with obesity.Methods and analysis This is an investigator-initiated, randomised, placebo-controlled, parallel group trial. We will enrol expectedly 200 women and men (age 18–65 years) with obesity (body mass index 32–43 kg/m2) to adhere to a very low-calorie diet (800 kcal/day) for 8 weeks in order to lose at least 5% of body weight. Subsequently, participants will be randomised in a 1:1:1:1 ratio to one of four study groups for 52 weeks: (1) placebo, (2) exercise 150 min/week+placebo, (3) liraglutide 3.0 mg/day and (4) exercise 150 min/week+liraglutide 3.0 mg/day. The primary endpoint is change in body weight from randomisation to end-of-treatment.Ethics and dissemination The trial has been approved by the ethical committee of the Capital Region of Denmark and the Danish Medicines Agency. The trial will be conducted in agreement with the Declaration of Helsinki and monitored to follow the guidelines for good clinical practice. Results will be submitted for publication in international peer-reviewed scientific journals.Trial registration number 2015-005585-3

Role of fasting duration and weekday in incretin and glucose regulation

Fasting duration has been associated with lower fasting blood glucose levels, but higher 2-h post-load levels, and research has indicated an adverse effect of ‘weekend behavior’ on human metabolism. We investigated associations of fasting duration and weekday of examination with glucose, insulin, glucagon and incretin responses to an oral glucose tolerance test (OGTT). This cross-sectional study is based on data from the ADDITION-PRO study, where 2082 individuals attended a health examination including an OGTT. Linear regression analysis was applied to study the associations of overnight fasting duration and day of the week with glucose, insulin, glucagon, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) responses to an OGTT. We found that a 1 h longer fasting duration was associated with 1.7% (95% CI: 0.8,2.5) higher 2-h glucose levels, as well as a 3.0% (95% CI: 1.3,4.7) higher GIP and 2.3% (95% CI: 0.3,4.4) higher GLP-1 response. Fasting insulin levels were 20.6% (95% CI: 11.2,30.7) higher on Mondays compared to the other weekdays, with similar fasting glucose levels (1.7%, 95% CI: 0.0,3.4). In this study, longer overnight fasting duration was associated with a worsening of glucose tolerance and increased incretin response to oral glucose. We found higher fasting insulin levels on Mondays compared to the other days of the week, potentially indicating a worsened glucose regulation after the weekend.</p

Habitual activity associates with lower fasting and greater glucose-induced GLP-1 response in men

Rationale: The hormone glucagon-like peptide-1 (GLP-1) decreases blood glucose and appetite. Greater physical activity (PA) is associated with lower incidence of type 2 diabetes. While acute exercise may increase glucose-induced response of GLP-1, it is unknown how habitual PA affects GLP-1 secretion. We hypothesised that habitual PA associates with greater glucose-induced GLP-1 responses in overweight individuals. Methods: Cross-sectional analysis of habitual PA levels and GLP-1 concentrations in 1326 individuals (mean (s.d.) age 66 (7) years, BMI 27.1 (4.5) kg/m2) from the ADDITION-PRO cohort. Fasting and oral glucose-stimulated GLP-1 responses were measured using validated radioimmunoassay. PA was measured using 7-day combined accelerometry and heart rate monitoring. From this, energy expenditure (PAEE; kJ/kg/day) and fractions of time spent in activity intensities (h/day) were calculated. Cardiorespiratory fitness (CRF; mL O2/kg/min) was calculated using step tests. Age-, BMI-and insulin sensitivity-adjusted associations between PA and GLP-1, stratified by sex, were evaluated by linear regression analysis. Results: In 703 men, fasting GLP-1 concentrations were 20% lower (95% CI: −33; −3%, P = 0.02) for every hour of moderate-intensity PA performed. Higher CRF and PAEE were associated with 1–2% lower fasting GLP-1 (P = 0.01). For every hour of moderate-intensity PA, the glucose-stimulated GLP-1 response was 16% greater at peak 30 min (1; 33%, PrAUC0-30 = 0.04) and 20% greater at full response (3; 40%, PrAUC0-120 = 0.02). No associations were found in women who performed PA 22 min/day vs 32 min/day for men. Conclusion: Moderate-intensity PA is associated with lower fasting and greater glucose-induced GLP-1 responses in overweight men, possibly contributing to improved glucose and appetite regulation with increased habitual PA.</p