Effects of Exogenous GIP and GLP-2 on Bone Turnover in Individuals With Type 2 Diabetes.

CONTEXT: Individuals with type 2 diabetes (T2D) have an increased risk of bone fractures despite normal or increased bone mineral density. The underlying causes are not well understood but may include disturbances in the gut-bone axis, in which both glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-2 (GLP-2) are regulators of bone turnover. Thus, in healthy fasting participants, both exogenous GIP and GLP-2 acutely reduce bone resorption. OBJECTIVE: The objective of this study was to investigate the acute effects of subcutaneously administered GIP and GLP-2 on bone turnover in individuals with T2D. METHODS: We included 10 men with T2D. Participants met fasting in the morning on 3 separate test days and were injected subcutaneously with GIP, GLP-2, or placebo in a randomized crossover design. Blood samples were drawn at baseline and regularly after injections. Bone turnover was estimated by circulating levels of collagen type 1 C-terminal telopeptide (CTX), procollagen type 1 N-terminal propeptide (P1NP), sclerostin, and PTH. RESULTS: GIP and GLP-2 significantly reduced CTX to (mean ± SEM) 66 ± 7.8% and 74 ± 5.9% of baseline, respectively, compared with after placebo (P = .001). In addition, P1NP and sclerostin increased acutely after GIP whereas a decrease in P1NP was seen after GLP-2. PTH levels decreased to 67 ± 2.5% of baseline after GLP-2 and to only 86 ± 3.4% after GIP. CONCLUSION: Subcutaneous GIP and GLP-2 affect CTX and P1NP in individuals with T2D to the same extent as previously demonstrated in healthy individuals.

The effects of postprandial exercise and meal glycemic index on plasma glucose and glucoregulatory hormone responses after Roux-en-Y gastric bypass.

Postprandial hypoglycemia is a complication of Roux-en-Y gastric bypass (RYGB), but the effects of postprandial exercise and meal glycemic index (GI) on postprandial glucose and glucoregulatory hormone responses are unknown. Ten RYGB-operated and 10 age and weight-matched unoperated women completed four test days in random order ingesting mixed meals with high GI (HGI, GI = 93) or low GI (LGI, GI = 54), but matched on energy and macronutrient content. Ten minutes after meal completion, participants rested or cycled for 30 min at 70% of maximum oxygen uptake (V̇o2max). Blood was collected for 4 h. Postprandial exercise did not lower plasma nadir glucose in RYGB after HGI (HGI/rest 3.7 ± 0.5 vs. HGI/Ex 4.1 ± 0.4 mmol/L, P = 0.070). Replacing HGI with LGI meals raised glucose nadir in RYGB (LGI/rest 4.1 ± 0.5 mmol/L, P = 0.034) and reduced glucose excursions (Δpeak-nadir) but less so in RYGB (-14% [95% CI: -27; -1]) compared with controls (-33% [-51; -14]). Insulin responses mirrored glucose concentrations. Glucagon-like peptide 1 (GLP-1) responses were greater in RYGB versus controls, and higher with HGI versus LGI. Glucose-dependent insulinotropic polypeptide (GIP) responses were greater after HGI versus LGI in both groups. Postexercise glucagon responses were lower in RYGB than controls, and noradrenaline responses tended to be lower in RYGB, whereas adrenaline responses were similar between groups. In conclusion, moderate intensity cycling shortly after meal intake did not increase the risk of postprandial hypoglycemia after RYGB. The low GI meal increased nadir glucose and reduced glucose excursions compared with the high GI meal. RYGB participants had lower postexercise glucagon responses compared with controls.NEW & NOTEWORTHY We investigate the effect of moderate exercise after a high or a low glycemic index meal on nadir glucose and glucoregulatory hormones in gastric bypass-operated individuals and in matched unoperated controls. Cycling shortly after meal intake did not increase the risk of hypoglycemia in operated individuals. The low glycemic index meal increased glucose nadir and reduced excursions compared with the high glycemic index meal. Operated individuals had lower postexercise glucagon responses compared with controls.

The Importance of Endogenously Secreted GLP-1 and GIP for Postprandial Glucose Tolerance and ß-Cell Function After Roux-en-Y Gastric Bypass and Sleeve Gastrectomy Surgery.

Enhanced secretion of glucagon-like peptide 1 (GLP-1) seems to be essential for improved postprandial ß-cell function after Roux-en-Y gastric bypass (RYGB) but is less studied after sleeve gastrectomy (SG). Moreover, the role of the other major incretin hormone, glucose-dependent insulinotropic polypeptide (GIP), is relatively unexplored after bariatric surgery. We studied the effects of separate and combined GLP-1 receptor (GLP-1R) and GIP receptor (GIPR) blockade during mixed-meal tests in unoperated (CON), SG-operated, and RYGB-operated people with no history of diabetes. Postprandial GLP-1 concentrations were highest after RYGB but also higher after SG compared with CON. In contrast, postprandial GIP concentrations were lowest after RYGB. The effect of GLP-1R versus GIPR blockade differed between groups. GLP-1R blockade reduced ß-cell glucose sensitivity and increased or tended to increase postprandial glucose responses in the surgical groups but had no effect in CON. GIPR blockade reduced ß-cell glucose sensitivity and increased or tended to increase postprandial glucose responses in the CON and SG groups but had no effect in the RYGB group. Our results support that GIP is the most important incretin hormone in unoperated people, whereas GLP-1 and GIP are equally important after SG, and GLP-1 is the most important incretin hormone after RYGB.

Effect of Meal Texture on Postprandial Glucose Excursions and Gut Hormones After Roux-en-Y Gastric Bypass and Sleeve Gastrectomy.

Background and aims: The metabolic consequences after Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG) are often studied using a liquid mixed meal. However, liquid meals may not be representative of the patients' everyday diet. We therefore examined postprandial glucose and gut hormone responses using mixed meals differing only with respect to meal texture. Methods: Twelve RYGB-operated, 12 SG-operated, and 12 unoperated individuals (controls) were enrolled in the study. Participants were matched on age, sex, and body mass index. In randomized order, each participant underwent a liquid and a solid 4-h mixed meal test on separate days. The meals were isocaloric (309 kcal), and with identical macronutrient composition (47 E% carbohydrate, 18 E% protein, 32 E% fat, and 3 E% dietary fibers). The liquid meal was blended to create a smooth liquid texture while the other meal retained its solid components. Results: Postprandial glucose concentrations (peak and incremental area under curve, iAUC) did not differ between the two meal textures in any group. In the control group, peak C-peptide was higher after the liquid meal compared with the solid meal (p = 0.04), whereas iAUCs of C-peptide were similar between the two meals in all groups. Peak of glucagon-like peptide-1 (GLP-1) was higher after the liquid meal compared with the solid meal in RYGB- and SG-operated individuals (RYGB p = 0.02; SG p < 0.01), but iAUC of GLP-1 did not differ between meal textures within any group. Peak of glucose-dependent insulin tropic polypeptide (GIP) was higher after the liquid meal in the SG and control groups (SG p = 0.02; controls p < 0.01), but iAUCs of GIP were equal between meals. There were no differences in total AUC of ghrelin between the liquid and solid meals within any of the groups. Conclusion: A liquid and a solid meal with identical macronutrient composition result in similar postprandial glucose responses, both in operated and unoperated individuals. Small differences were observed for the postprandial peaks of C-peptide, GLP-1, and GIP concentrations. Overall, a liquid meal is suitable for evaluating glucose tolerance, ß-cell function, and gut hormones responses, both after RYGB and SG and in unoperated individuals. Clinical Trial Registration: [www.clinicaltrials.gov], identifier [NCT04082923].

Early effects of Roux-en-Y gastric bypass on dietary fatty acid absorption and metabolism in people with obesity and normal glucose tolerance.

INTRODUCTION: Roux-en-Y gastric bypass (RYGB) surgery markedly increases the rate of intestinal nutrient exposure after food intake, accelerates intestinal absorption of dietary glucose and protein, and alters the postprandial gut hormone response. However, our understanding of postprandial fat absorption and metabolism after RYGB is incomplete. METHODS: Stable palmitate tracers were administered intravenously (K-[2,2-2H2]palmitate) and orally with a mixed meal ([U-13C16]palmitate) to study fatty acid absorption and metabolism before and 3 months after RYGB in 10 participants with obesity and normal glucose tolerance. RESULTS: There was a tendency toward reduced fasting plasma nonesterified palmitate concentrations after RYGB, but neither fasting palmitate kinetics nor fasting triacylglycerol (TAG) concentrations changed compared with before surgery. Postprandial TAG concentrations were numerically, but nonsignificantly, reduced 3-4 h after meal intake after compared with before RYGB. However, the postprandial appearance of the oral palmitate tracer in the plasma TAG pool and overflow into the nonesterified palmitate pool were initially faster but overall reduced after RYGB by 50% (median, IQR: [47;64], P = 0.004) and 46% (median, IQR: [33;70], P = 0.041), respectively. The maximal postprandial suppression of plasma nonesterified palmitate concentrations was slightly greater but shorter lasting after RYGB ('time × visit' interaction: P < 0.001), without detectable effects of surgery on the rate of appearance and disappearance of plasma palmitate. CONCLUSION: RYGB resulted in an initially accelerated but overall ~50% reduced 4-h postprandial systemic appearance of dietary palmitate in participants with obesity and normal glucose tolerance. This is likely a result of faster but incomplete intestinal fat absorption combined with enhanced chylomicron-TAG clearance, but it needs further investigation in studies specifically designed to investigate these mechanisms.

Effect of 6 weeks of very low-volume high-intensity interval training on oral glucose-stimulated incretin hormone response.

Introduction: Decreased fasting and oral glucose-stimulated incretin hormone concentrations following moderate-intensity continuous endurance training interventions have been reported in glucose-tolerant people, however results are conflicting. The effect of more time-efficient, very low-volume, high-intensity interval training (HIT) on circulating incretin hormone levels has never been studied.Materials and methods: Ten sedentary and overweight-to-obese participants (4 women and 6 men; age 43 ± 6 years (mean ± SD); BMI 30.2 ± 3.2 kg∙m-2; HbA1c 35 ± 5.1 mmol∙mol-1 (5.3 ± 0.3%); VO2max 30 ± 5 ml∙min-1∙kg-1) from the Copenhagen cohort of the METAPREDICT trial underwent 6 weeks of supervised low-volume HIT (3 sessions per week: 7 × 1 min at ∼100% VO2max separated by 1 min of active recovery). We measured glucose, insulin, C-peptide, glucagon, GLP-1 and GIP concentrations during a frequently sampled 75 g oral glucose tolerance test as well as VO2max and body composition before and after the intervention.Results: Training compliance was 100%. Relative VO2max improved after the intervention (median 2.69 ml∙min-1∙kg-1, IQR [0.43; 3.14], p = 0.037) while there were no significant effects on body weight and composition. No significant effects on oral glucose-stimulated glucose and hormone responses or estimates of insulin sensitivity and ß-cell function were observed.Conclusion: Low-volume HIT improved aerobic fitness, but neither affected glucose tolerance nor oral glucose-stimulated incretin hormone responses in sedentary and overweight-to-obese people.Highlights Ten sedentary, overweight-to-obese, glucose-tolerant participants underwent 6 weeks of supervised, very low-volume HIT.Aerobic fitness improved.Fasting and oral glucose-stimulated incretin hormone concentrations were not affected.

Successful Use of a GLP-1 Receptor Agonist as Add-on Therapy to Sulfonylurea in the Treatment of KCNJ11 Neonatal Diabetes.

Sulfonylurea monotherapy is the standard treatment for patients with the most common form of permanent neonatal diabetes, KCNJ11 neonatal diabetes, but it is not always sufficient. For the first time, we present a case of successful use of a GLP-1 receptor agonist as add-on therapy in the treatment of a patient with KCNJ11 neonatal diabetes and insufficient effect of sulfonylurea monotherapy. Good glycaemic control was maintained with a HbA1c level of 48 mmol/mol (6.5%) at the end of 26 months' follow-up. LEARNING POINTS: Genetic testing is important in patients with neonatal diabetes.Sulfonylurea is the standard treatment for patients with the most common mutation (KCNJ11).We present the novel use of a GLP-1 receptor agonist as effective add-on therapy in a patient with KCNJ11 neonatal diabetes and insufficient effect of sulfonylurea monotherapy.

The role of GLP-1 in postprandial glucose metabolism after bariatric surgery: a narrative review of human GLP-1 receptor antagonist studies.

The Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG) bariatric procedures lead to remission or improvement of type 2 diabetes. A weight loss-independent augmentation of postprandial insulin secretion contributes to the improvement in glycemic control after RYGB and is associated with a ∼10-fold increase in plasma concentrations of the incretin hormone glucagon-like peptide-1 (GLP-1). However, the physiologic importance of the markedly increased postprandial GLP-1 secretion after RYGB has been much debated. The effect of GLP-1 receptor blockade after RYGB has been investigated in 12 studies. The studies indicate a shift toward a more prominent role for GLP-1 in postprandial ß-cell function after RYGB. The effect of GLP-1 receptor antagonism on glucose tolerance after RYGB is more complex and is associated with important methodological challenges. The postprandial GLP-1 response is less enhanced after SG compared with RYGB. However, the effect of GLP-1 receptor blockade after SG has been examined in 1 study only and needs further investigation.

Sex and age differences among tramadol users in three Nordic countries.

INTRODUCTION: The aim of this study was to examine the prevalence and characteristics of tramadol users in Denmark, Norway and Sweden. METHODS: Data from the national prescription databases comprising the entire population of Denmark, Norway and Sweden between 2007 and 2015 were used to assess prescription medicine use and sold amount (in defined daily doses (DDDs)) of tramadol, other opioids and non-steroidal anti-inflammatory drugs. RESULTS: From 2007 to 2015 the prevalence of tramadol users increased in Denmark from 45 to 52 per 1,000 residents, and in Norway from 20 to 41 per 1,000 residents. In Sweden, the prevalence decreased from 36 to 17 per 1,000 residents. In comparison, the prevalence of other opioid users decreased in Denmark and Norway, but increased in Sweden. During the study period, there were more female than male tramadol users in all three countries, and the prevalence of tramadol users tended to increase with age. The average tramadol DDD per treated patient remained fairly constant in Norway, while it increased in Denmark and Sweden. In Denmark and Norway, women received a higher DDD than men. The amount of sold tramadol and other opioids combined per 1,000 residents was highest in Denmark. CONCLUSIONS: From 2007 to 2015, the prescription patterns of tramadol and other opioids differed between the three countries. Tramadol was generally used more frequently by women. Women received higher DDD then men in Norway and Denmark, but not in Sweden. The prevalence of tramadol users tended to increase with age in all countries. FUNDING: none. TRIAL REGISTRATION: not relevant.

High-intensity interval training changes mitochondrial respiratory capacity differently in adipose tissue and skeletal muscle.

The effect of high-intensity training (HIT) on mitochondrial ADP sensitivity and respiratory capacity was investigated in human skeletal muscle and subcutaneous adipose tissue (SAT). Twelve men and women underwent 6 weeks of HIT (7 × 1 min at app. 100% of maximal oxygen uptake (VO2max )). Mitochondrial respiration was measured in permeabilized muscle fibers and in abdominal SAT. Mitochondrial ADP sensitivity was determined using Michaelis Menten enzyme kinetics. VO2max , body composition and citrate synthase (CS) activity (skeletal muscle) and mtDNA (SAT) were measured before and after training. VO2max increased from 2.6 ± 0.2 to 2.8 ± 0.2 L O2 /min (P = 0.011) accompanied by a decreased mitochondrial ADP sensitivity in skeletal muscle (Km : 0.14 ± 0.02 to 0.29 ± 0.03 mmol/L ADP (P = 0.002)), with no changes in SAT (Km : 0.12 ± 0.02 to 0.16 ± 0.05 mmol/L ADP; P = 0.186), following training. Mitochondrial respiratory capacity increased in skeletal muscle from 57 ± 4 to 67 ± 4 pmol O2 ·mg-1 ·sec-1 (P < 0.001), but decreased with training in SAT from 1.3 ± 0.1 to 1.0 ± 0.1 pmol O2 ·mg-1 ·sec-1 (P < 0.001). CS activity increased (P = 0.027) and mtDNA was unchanged following training. Intrinsic mitochondrial respiratory capacity was unchanged in skeletal muscle, but increased in SAT after HIT. In summary, our results demonstrate that mitochondrial adaptations to HIT in skeletal muscle are comparable to adaptations to endurance training, with an increased mitochondrial respiratory capacity and CS activity. However, mitochondria in SAT adapts differently compared to skeletal muscle mitochondria, where mitochondrial respiratory capacity decreased and mtDNA remained unchanged after HIT.