No effect of the turmeric root phenol curcumin on prednisolone-induced glucometabolic perturbations in men with overweight or obesity.

Objectives: Preclinically, curcumin has been shown to protect against glucocorticoid-induced insulin resistance. We evaluated the effect of curcumin administered with prednisolone in healthy overweight or obese men. Methods: In a double-blind, parallel-group trial, 24 overweight/obese non-diabetic men were randomised to one of three intervention groups (A) prednisolone placebo+curcumin placebo, (B) prednisolone (50 mg/day)+curcumin placebo or (C) prednisolone and curcumin (400 mg/day). Curcumin or curcumin placebo treatment started 1 day prior to 10-day prednisolone or prednisolone placebo treatment. The primary endpoint was change in prednisolone-induced insulin resistance assessed by homeostatic model assessment of insulin resistance (HOMA2-IR). Other endpoints included anthropometric measurements, magnetic resonance spectroscopy-assessed hepatic fat content, blood pressure, circulating metabolic markers and continuous glucose monitoring measures. Results: Baseline characteristics (mean ± s.d): age 44.2 ± 13.7 years, BMI 30.1 ± 3.5 kg/m2, HbAlc 33.3 ± 3.2 mmol/mol, HOMA2-IR 1.10 ± 0.45 and fasting plasma glucose 5.2 ± 0.4 mmol/L. Prednisolone significantly increased HOMA2-IR (estimated treatment difference 0.36 (95% CI 0.16; 0.57)). Co-treatment with curcumin had no effect on HOMA2-IR (estimated treatment difference 0.08 (95% CI -0.13; 0.39)). Prednisolone increased HbAlc, insulin, C-peptide, glucagon, blood pressure, mean interstitial glucose, time spent in hyperglycaemia and glucose variability, but no protective effect of curcumin on any of these measures was observed. Conclusions: In this double-blind, placebo-controlled parallel-group study involving 24 overweight or obese men randomised to one of three treatment arms, curcumin treatment had no protective effect on prednisolone-induced insulin resistance or other glucometabolic perturbations.

Effects of an exercise-based lifestyle intervention on systemic markers of oxidative stress and advanced glycation endproducts in persons with type 2 diabetes: Secondary analysis of a randomised clinical trial.

AIMS/HYPOTHESIS: This secondary analysis aimed to investigate the effects of a 12 months intensive exercise-based lifestyle intervention on systemic markers of oxidative stress in persons with type 2 diabetes. We hypothesized lifestyle intervention to be superior to standard care in decreasing levels of oxidative stress. METHODS: The study was based on the single-centre, assessor-blinded, randomised, controlled U-turn trial (ClinicalTrial.gov NCT02417012). Persons with type 2 diabetes ˂ 10 years, ˂ 3 glucose lowering medications, no use of insulin, BMI 25-40 kg/m2 and no severe diabetic complications were included. Participants were randomised (2:1) to either intensive exercise-based lifestyle intervention and standard (n = 64) or standard care alone (n = 34). Standard care included individual education in diabetes management, advice on a healthy lifestyle and regulation of medication by a blinded endocrinologist. The lifestyle intervention included five to six aerobic exercise sessions per week, combined with resistance training two to three times per week and an adjunct dietary intervention aiming at reduction of ∼500 kcal/day (month 0-4). The diet was isocaloric from months 5-12. The primary outcome of this secondary analysis was change in oxidative stress measured by 8-oxo-7,8-dihydroguanosine (8-oxoGuo) and secondarily in 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG), as markers of RNA and DNA oxidation, respectively, from baseline to 12-months follow-up. RESULTS: A total of 77 participants, 21 participants receiving standard care and 56 participants receiving the lifestyle intervention, were included in the analysis. Mean age at baseline was 54.1 years (SD 9.1), 41% were women and mean duration of type 2 diabetes was 5.0 years (SD 2.8). From baseline to follow-up the lifestyle group experienced a 7% decrease in 8-oxoGuo (-0.15 nmol/mmol creatinine [95% CI -0.27, -0.03]), whereas standard care conversely was associated with a 8.5% increase in 8-oxoGuo (0.19 nmol/mmol creatinine [95% CI 0.00, 0.40]). The between group difference in 8-oxoGuo was -0.35 nmol/mmol creatinine [95% CI -0.58, -0.12,], p = 0.003. No between group difference was observed in 8-oxodG. CONCLUSION/INTERPRETATION: A 12 months intensive exercise-based lifestyle intervention was associated with a decrease in RNA, but not DNA, oxidation in persons with type 2 diabetes.

Skeletal muscle adaptations to exercise are not influenced by metformin treatment in humans: secondary analyses of 2 randomized, clinical trials.

Metformin and exercise both improve glycemic control, but in vitro studies have indicated that an interaction between metformin and exercise occurs in skeletal muscle, suggesting a blunting effect of metformin on exercise training adaptations. Two studies (a double-blind, parallel-group, randomized clinical trial conducted in 29 glucose-intolerant individuals and a double-blind, cross-over trial conducted in 15 healthy lean males) were included in this paper. In both studies, the effect of acute exercise ± metformin treatment on different skeletal muscle variables, previously suggested to be involved in a pharmaco-physiological interaction between metformin and exercise, was assessed. Furthermore, in the parallel-group trial, the effect of 12 weeks of exercise training was assessed. Skeletal muscle biopsies were obtained before and after acute exercise and 12 weeks of exercise training, and mitochondrial respiration, oxidative stress and AMPK activation was determined. Metformin did not significantly affect the effects of acute exercise or exercise training on mitochondrial respiration, oxidative stress or AMPK activation, indicating that the response to acute exercise and exercise training adaptations in skeletal muscle is not affected by metformin treatment. Further studies are needed to investigate whether an interaction between metformin and exercise is present in other tissues, e.g., the gut. Trial registration: ClinicalTrials.gov (NCT03316690 and NCT02951260). Novelty: Metformin does not affect exercise-induced alterations in mitochondrial respiratory capacity in human skeletal muscle. Metformin does not affect exercise-induced alterations in systemic levels of oxidative stress nor emission of reactive oxygen species from human skeletal muscle. Metformin does not affect exercise-induced AMPK activation in human skeletal muscle.

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

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 A1c (HbA1c ) 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; HbA1c 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 HbA1c 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 HbA1c and body weight comparable with the effects observed in clinical studies with fewer persons in our cohort receiving maximum dose of semaglutide.

The interaction between metformin and physical activity on postprandial glucose and glucose kinetics: a randomised, clinical trial.

AIMS/HYPOTHESIS: The aim of this parallel-group, double-blinded (study personnel and participants), randomised clinical trial was to assess the interaction between metformin and exercise training on postprandial glucose in glucose-intolerant individuals. METHODS: Glucose-intolerant (2 h OGTT glucose of 7.8-11.0 mmol/l and/or HbA1c of 39-47 mmol/mol [5.7-6.5%] or glucose-lowering-medication naive type 2 diabetes), overweight/obese (BMI 25-42 kg/m2) individuals were randomly allocated to a placebo study group (PLA, n = 15) or a metformin study group (MET, n = 14), and underwent 3 experimental days: BASELINE (before randomisation), MEDICATION (after 3 weeks of metformin [2 g/day] or placebo treatment) and TRAINING (after 12 weeks of exercise training in combination with metformin/placebo treatment). Training consisted of supervised bicycle interval sessions with a mean intensity of 64% of Wattmax for 45 min, 4 times/week. The primary outcome was postprandial glucose (mean glucose concentration) during a mixed meal tolerance test (MMTT), which was assessed on each experimental day. For within-group differences, a group × time interaction was assessed using two-way repeated measures ANOVA. Between-group changes of the outcomes at different timepoints were compared using unpaired two-tailed Student's t tests. RESULTS: Postprandial glucose improved from BASELINE to TRAINING in both the PLA group and the MET group (∆PLA: -0.7 [95% CI -1.4, 0.0] mmol/l, p = 0.05 and ∆MET: -0.7 [-1.5, -0.0] mmol/l, p = 0.03), with no between-group difference (p = 0.92). In PLA, the entire reduction was seen from MEDICATION to TRAINING (-0.8 [-1.3, -0.1] mmol/l, p = 0.01). Conversely, in MET, the entire reduction was observed from BASELINE to MEDICATION (-0.9 [-1.6, -0.2] mmol/l, p = 0.01). The reductions in mean glucose concentration during the MMTT from BASELINE to TRAINING were dependent on differential time effects: in the PLA group, a decrease was observed at timepoint (t) = 120 min (p = 0.009), whereas in the MET group, a reduction occurred at t = 30 min (p < 0.001). V̇O2peak increased 15% (4.6 [3.3, 5.9] ml kg-1 min-1, p < 0.0001) from MEDICATION to TRAINING and body weight decreased (-4.0 [-5.2, -2.7] kg, p < 0.0001) from BASELINE to TRAINING, with no between-group differences (p = 0.7 and p = 0.5, respectively). CONCLUSIONS/INTERPRETATION: Metformin plus exercise training was not superior to exercise training alone in improving postprandial glucose. The differential time effects during the MMTT suggest an interaction between the two modalities. FUNDING: The Beckett foundation, A.P Møller Foundation, DDA, the Research Foundation of Rigshospitalet and Trygfonden. TRIAL REGISTRATION: ClinicalTrials.gov (NCT03316690). Graphical abstract.

No detectable effect of a type 2 diabetes-associated TCF7L2 genotype on the incretin effect.

The T allele of TCF7L2 rs7903146 is a common genetic variant associated with type 2 diabetes (T2D), possibly by modulation of incretin action. In this study, we evaluated the effect of the TCF7L2 rs7903146 T allele on the incretin effect and other glucometabolic parameters in normal glucose tolerant individuals (NGT) and participants with T2D. The rs7903146 variant was genotyped in cohorts of 61 NGT individuals (23 were heterozygous (CT) or homozygous (TT) T allele carriers) and 43 participants with T2D (20 with CT/TT). Participants were previously examined by an oral glucose tolerance test (OGTT) and a subsequent isoglycemic intravenous glucose infusion (IIGI). The incretin effect was assessed by quantification of the difference in integrated beta cell secretory responses during the OGTT and IIGI. Glucose and hormonal levels were measured during experimental days, and from these, indices of beta cell function and insulin sensitivity were calculated. No genotype-specific differences in the incretin effect were observed in the NGT group (P = 0.70) or the T2D group (P = 0.68). NGT T allele carriers displayed diminished glucose-dependent insulinotropic polypeptide response during OGTT (P = 0.01) while T allele carriers with T2D were characterized by lower C-peptide AUC after OGTT (P = 0.04) and elevated glucose AUC after OGTT (P = 0.04). In conclusion, our findings do not exclude that this specific TCF7L2 variant increases the risk of developing T2D via diminished incretin effect, but genotype-related defects were not detectable in these cohorts.

Effects of an intensive lifestyle intervention on the underlying mechanisms of improved glycaemic control in individuals with type 2 diabetes: a secondary analysis of a randomised clinical trial.

AIMS/HYPOTHESIS: The aim was to investigate whether an intensive lifestyle intervention, with high volumes of exercise, improves beta cell function and to explore the role of low-grade inflammation and body weight. METHODS: This was a randomised, assessor-blinded, controlled trial. Ninety-eight individuals with type 2 diabetes (duration <10 years), BMI of 25-40 kg/m2, no use of insulin and taking fewer than three glucose-lowering medications were randomised (2:1) to either the standard care plus intensive lifestyle group or the standard care alone group. Standard care consisted of individual guidance on disease management, lifestyle advice and blinded regulation of medication following a pre-specified algorithm. The intensive lifestyle intervention consisted of aerobic exercise sessions that took place 5-6 times per week, combined with resistance exercise sessions 2-3 times per week, with a concomitant dietary intervention aiming for a BMI of 25 kg/m2. In this secondary analysis beta cell function was assessed from the 2 h OGTT-derived disposition index, which is defined as the product of the Matsuda and the insulinogenic indices. RESULTS: At baseline, individuals were 54.8 years (SD 8.9), 47% women, type 2 diabetes duration 5 years (IQR 3-8) and HbA1c was 49.3 mmol/mol (SD 9.2); 6.7% (SD 0.8). The intensive lifestyle group showed 40% greater improvement in the disposition index compared with the standard care group (ratio of geometric mean change [RGM] 1.40 [95% CI 1.01, 1.94]) from baseline to 12 months' follow-up. Plasma concentration of IL-1 receptor antagonist (IL-1ra) decreased 30% more in the intensive lifestyle group compared with the standard care group (RGM 0.70 [95% CI 0.58, 0.85]). Statistical single mediation analysis estimated that the intervention effect on the change in IL-1ra and the change in body weight explained to a similar extent (59%) the variance in the intervention effect on the disposition index. CONCLUSIONS/INTERPRETATION: Our findings show that incorporating an intensive lifestyle intervention, with high volumes of exercise, in individuals with type 2 diabetes has the potential to improve beta cell function, associated with a decrease in low-grade inflammation and/or body weight. TRIAL REGISTRATION: ClinicalTrials.gov NCT02417012 Graphical abstract.

Dose-Response Effects of Exercise on Glucose-Lowering Medications for Type 2 Diabetes: A Secondary Analysis of a Randomized Clinical Trial.

OBJECTIVE: To investigate whether a dose-response relationship exists between volume of exercise and discontinuation of glucose-lowering medication treatment in patients with type 2 diabetes. PATIENTS AND METHODS: Secondary analyses of a randomized controlled exercise-based lifestyle intervention trial (April 29, 2015 to August 17, 2016). Patients with non-insulin-dependent type 2 diabetes were randomly assigned to an intensive lifestyle intervention (U-TURN) or standard-care group. Both groups received lifestyle advice and objective target-driven medical regulation. Additionally, the U-TURN group received supervised exercise and individualized dietary counseling. Of the 98 randomly assigned participants, 92 were included in the analysis (U-TURN, n=61, standard care, n=31). Participants in the U-TURN group were stratified into tertiles based on accumulated volumes of exercise completed during the 1-year intervention. RESULTS: Median exercise levels of 178 (interquartile range [IQR], 121-213; lower tertile), 296 (IQR, 261-310; intermediate tertile), and 380 minutes per week (IQR, 355-446; upper tertile) were associated with higher odds of discontinuing treatment with glucose-lowering medication, with corresponding odds ratios of 12.1 (95% CI, 1.2-119; number needed to treat: 4), 30.2 (95% CI, 2.9-318.5; 3), and 34.4 (95% CI, 4.1-290.1; 2), respectively, when comparing with standard care. Cardiovascular risk factors such as glycated hemoglobin A1c levels, fitness, 2-hour glucose levels, and triglyceride levels were improved significantly in the intermediate and upper tertiles, but not the lower tertile, compared with the standard-care group. CONCLUSION: Exercise volume is associated with discontinuation of glucose-lowering medication treatment in a dose-dependent manner, as are important cardiovascular risk factors in well-treated participants with type 2 diabetes and disease duration less than 10 years. Further studies are needed to support these findings. STUDY REGISTRATION: ClinicalTrials.gov registration (NCT02417012).

Type 2 diabetes remission 1 year after an intensive lifestyle intervention: A secondary analysis of a randomized clinical trial.

AIM: To investigate whether an intensive lifestyle intervention induces partial or complete type 2 diabetes (T2D) remission. MATERIALS AND METHODS: In a secondary analysis of a randomized, assessor-blinded, single-centre trial, people with non-insulin-dependent T2D (duration <10 years), were randomly assigned (2:1, stratified by sex, from April 2015 to August 2016) to a lifestyle intervention group (n = 64) or a standard care group (n = 34). The primary outcome was partial or complete T2D remission, defined as non-diabetic glycaemia with no glucose-lowering medication at the outcome assessments at both 12 and 24 months from baseline. All participants received standard care, with standardized, blinded, target-driven medical therapy during the initial 12 months. The lifestyle intervention included 5- to 6-weekly aerobic and combined aerobic and strength training sessions (30-60 minutes) and individual dietary plans aiming for body mass index ≤25 kg/m2 . No intervention was provided during the 12-month follow-up period. RESULTS: Of the 98 randomized participants, 93 completed follow-up (mean [SD] age 54.6 [8.9] years; 46 women [43%], mean [SD] baseline glycated haemoglobin 49.3 [9.3] mmol/mol). At follow-up, 23% of participants (n = 14) in the intervention and 7% (n = 2) in the standard care group met the criteria for any T2D remission (odds ratio [OR] 4.4, 95% confidence interval [CI] 0.8-21.4]; P = 0.08). Assuming participants lost to follow-up (n = 5) had relapsed, the OR for T2D remission was 4.4 (95% CI 1.0-19.8; P = 0.048). CONCLUSIONS: The statistically nonsignificant threefold increased remission rate of T2D in the lifestyle intervention group calls for further large-scale studies to understand how to implement sustainable lifestyle interventions among people with T2D.

Determinants of Fasting Hyperglucagonemia in Patients with Type 2 Diabetes and Nondiabetic Control Subjects.

BACKGROUND: Fasting hyperglucagonemia can be detrimental to glucose metabolism in patients with type 2 diabetes (T2D) and may contribute to metabolic disturbances in obese and/or prediabetic subjects. However, the mechanisms underlying fasting hyperglucagonemia remain elusive. METHODS: We evaluated the interrelationship between fasting hyperglucagonemia and demographic and biochemical parameters in 106 patients with T2D (31% female, age: 57 ± 9 years [mean ± standard deviation; body mass index (BMI): 30.1 ± 4.4 kg/m2; fasting plasma glucose (FPG): 9.61 ± 2.39 mM; hemoglobin A1c (HbA1c): 57.1 ± 13.1 mmol/mol] and 163 nondiabetic control subjects (29% female; age: 45 ± 17 years; BMI: 25.8 ± 4.1 kg/m2; FPG: 5.2 ± 0.4 mM; and HbA1c: 35.4 ± 3.8 mmol/mol). Multiple linear regression analysis was applied using a stepwise approach with fasting plasma glucagon as dependent parameter and BMI, waist-to-hip ratio (WHR), blood pressure, hemoglobin A1c, FPG, and insulin concentrations as independent parameters. RESULTS: Fasting plasma glucagon concentrations were significantly higher among patients with T2D (13.5 ± 6.3 vs. 8.5 ± 3.8 mM, P < 0.001) together with HbA1c (P < 0.001), FPG (P < 0.001), and insulin (84.9 ± 56.4 vs. 57.7 ± 35.3 mM, P < 0.001). When adjusted for T2D, HbA1c and insulin were significantly positive determinants for fasting plasma glucagon concentrations. Furthermore, WHR comprised a significant positive determinant. CONCLUSIONS: We confirm that fasting plasma glucagon concentrations are abnormally high in patients with T2D, and show that fasting plasma glucagon concentrations are influenced by WHR (in addition to glycemic control and fasting plasma insulin concentrations), which may point to visceral fat deposition as an important determinant of increased fasting plasma glucagon concentrations.

Why prescribe exercise as therapy in type 2 diabetes? We have a pill for that!

The majority of T2D cases are preventable through a healthy lifestyle, leaving little room for questions that lifestyle should be the first line of defence in the fight against the development of T2D. However, when it comes to the clinical care of T2D, the potential efficacy of lifestyle is much less clear-cut, both in terms of impacting the pathological metabolic biomarkers of the disease, and long-term complications. A healthy diet, high leisure-time physical activity, and exercise are considered to be cornerstones albeit adjunct to drug therapy in the management of T2D. The prescription and effective implementation of structured exercise and other lifestyle interventions in the treatment of T2D have not been routinely used. In this article, we critically appraise and debate our reflections as to why exercise and physical activity may not have reached the status of a viable and effective treatment in the clinical care of T2D to the same extent as pharmaceutical drugs. We argue that the reason why exercise therapy is not utilized to a satisfactory degree is multifaceted and primarily relates to a "vicious cycle" with lack of proven efficacy on T2D complications and a lack of proven effectiveness on risk factors in the primary care of T2D. Furthermore, there is a lack of experimental research establishing the optimal dose of exercise. This precludes widespread and sustained implementation of physical activity and exercise in the clinical treatment of T2D will not succeed.

Head-to-head comparison of intensive lifestyle intervention (U-TURN) versus conventional multifactorial care in patients with type 2 diabetes: protocol and rationale for an assessor-blinded, parallel group and randomised trial.

INTRODUCTION: Current pharmacological therapies in patients with type 2 diabetes (T2D) are challenged by lack of sustainability and borderline firm evidence of real long-term health benefits. Accordingly, lifestyle intervention remains the corner stone in the management of T2D. However, there is a lack of knowledge regarding the optimal intervention programmes in T2D ensuring both compliance as well as long-term health outcomes. Our objective is to assess the effects of an intensive lifestyle intervention (the U-TURN intervention) on glycaemic control in patients with T2D. Our hypothesis is that intensive lifestyle changes are equally effective as standard diabetes care, including pharmacological treatment in maintaining glycaemic control (ie, glycated haemoglobin (HbA1c)) in patients with T2D. Furthermore, we expect that intensive lifestyle changes will decrease the need for antidiabetic medications. METHODS AND ANALYSIS: The study is an assessor-blinded, parallel group and a 1-year randomised trial. The primary outcome is change in glycaemic control (HbA1c), with the key secondary outcome being reductions in antidiabetic medication. Participants will be patients with T2D (T2D duration <10 years) without complications who are randomised into an intensive lifestyle intervention (U-TURN) or a standard care intervention in a 2:1 fashion. Both groups will be exposed to the same standardised, blinded, target-driven pharmacological treatment and can thus maintain, increase, reduce or discontinue the pharmacological treatment. The decision is based on the standardised algorithm. The U-TURN intervention consists of increased training and basal physical activity level, and an antidiabetic diet including an intended weight loss. The standard care group as well as the U-TURN group is offered individual diabetes management counselling on top of the pharmacological treatment. ETHICS AND DISSEMINATION: This study has been approved by the Scientific Ethical Committee at the Capital Region of Denmark (H-1-2014-114). Positive, negative or inconclusive findings will be disseminated in peer-reviewed journals, at national and international conferences. TRIAL REGISTRATION NUMBER: NCT02417012.

The 2-monoacylglycerol moiety of dietary fat appears to be responsible for the fat-induced release of GLP-1 in humans.

BACKGROUND: Dietary triglycerides can, after digestion, stimulate the intestinal release of incretin hormones through activation of G protein-coupled receptor (GPR) 119 by 2-monoacylglycerol and by the activation of fatty acid receptors for long- and short-chain fatty acids. Medium-chain fatty acids do not stimulate the release of intestinal hormones. OBJECTIVE: To dissect the mechanism of fat-induced glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) release in humans, we compared the effects of tributyrin (containing short-chain fatty acids; i.e., butyric acid), olive oil [containing long-chain fatty acids; e.g., oleic acid plus 2-oleoyl glycerol (2-OG)], and 1,3-dioctanoyl-2-oleoyl glycerol (C8-dietary oil), which is digested to form medium-chain fatty acids : i.e., octanoic acid : and 2-OG. DESIGN: In a randomized, single-blinded crossover study, 12 healthy white men [mean age: 24 y; BMI (in kg/m(2)): 22] were given the following 4 meals on 4 different days: 200 g carrots + 6.53 g tributyrin, 200 g carrots + 13.15 g C8-dietary oil, 200 g carrots + 19 g olive oil, or 200 g carrots. All of the lipids totaled 0.0216 mol. Main outcome measures were incremental areas under the curve for total GLP-1, GIP, and cholecystokinin (CCK) in plasma. RESULTS: C8-dietary oil and olive oil showed the same GLP-1 response [583 ± 101 and 538 ± 71 (pmol/L) × 120 min; P = 0.733], whereas the GIP response was higher for olive oil than for C8-dietary oil [3293 ± 404 and 1674 ± 270 (pmol/L) × 120 min; P = 0.002]. Tributyrin and carrots alone resulted in no increase in any of the measured hormones. Peptide YY (PYY) and neurotensin responses resembled those of GLP-1. Only olive oil stimulated CCK release. CONCLUSIONS: Under our study conditions, 2-OG and GPR119 activation can fully explain the olive oil-induced secretion of GLP-1, PYY, and neurotensin. In contrast, both oleic acid and 2-OG contributed to the GIP response. Dietary butyrate did not stimulate gut hormone secretion. Olive oil-derived oleic acid seems to be fully responsible for olive oil-induced CCK secretion. This trial was registered at clinicaltrials.gov as NCT02264951.

Impaired incretin-induced amplification of insulin secretion after glucose homeostatic dysregulation in healthy subjects.

OBJECTIVE: The insulinotropic effect of the incretin hormones, glucose-dependent insulinotropic polypeptide (GIP), and glucagon-like peptide-1 (GLP-1) is impaired in patients with type 2 diabetes. It remains unclear whether this impairment is a primary pathophysiological trait or a consequence of developing diabetes. Therefore, we aimed to investigate the insulinotropic effect of GIP and GLP-1 compared with placebo before and after 12 d of glucose homeostatic dysregulation in healthy subjects. RESEARCH DESIGN AND METHODS: The insulinotropic effect was measured using hyperglycemic clamps and infusion of physiological doses of GIP, GLP-1, or saline in 10 healthy Caucasian males before and after intervention using a high-calorie diet, sedentary lifestyle, and administration of prednisolone (37.5 mg once daily) for 12 d. RESULTS: The intervention resulted in increased insulin resistance according to the homeostatic model assessment (1.2 ± 0.2 vs. 2.6 ± 0.5, P = 0.01), and glucose tolerance deteriorated as assessed by the area under curve for plasma glucose during a 75-g oral glucose tolerance test (730 ± 30 vs. 846 ± 57 mm for 2 h, P = 0.021). The subjects compensated for the change in insulin resistance by significantly increasing their postintervention insulin responses during saline infusion by 2.9 ± 0.5-fold (P = 0.001) but were unable to do so in response to incretin hormones (which caused insignificant increases of only 1.78 ± 0.3 and 1.38 ± 0.3-fold, P value not significant). CONCLUSIONS: These data show that impairment of the insulinotropic effect of both GIP and GLP-1 can be induced in healthy male subjects without risk factors for type 2 diabetes, indicating that the reduced insulinotropic effect of the incretin hormones observed in type 2 diabetes most likely is a consequence of insulin resistance and glucose intolerance rather than a primary event causing the disease.

Electroretinography in healthy subjects in relation to systemic glucocorticoid intake.

This study examined electroretinographic function in healthy subjects before and after prednisolone intake. To separate the effect of prednisolone on the retina from the potentially confounding hyperglycemia-inducing effect of prednisolone, electroretinography was made while fasting and at a pre-specified level of clamped hyperglycemia. The study included 10 eyes in 10 healthy lean men aged 25 ± 3 years (mean ± SD). The subjects were examined before and after oral intake of prednisolone 37.5 mg/day for 9.1 ± 1.4 days. The diabetogenic potential of prednisolone was reinforced by the intake of a high-caloric diet and by the reduction of physical activity. Full-field electroretinography (ffERG) demonstrated no significant change (P < 0.05) in amplitudes or implicit times in relation to prednisolone intake, neither at fasting glycemia levels, which were 4.9 ± 0.2 mM before and 5.0 ± 0.3 mM (P = 0.467) after the intervention, nor at 10 mM clamped hyperglycemia. Specifically, the fasting b-wave amplitude of the combined rod-cone response was 432 ± 84 mV before and 463 ± 71 mV (P = 0.13) after prednisolone intake. Furthermore, the ffERG could not be shown to be influenced by the doubling of glycemia from fasting to clamped hyperglycemia, neither before, nor after prednisolone (P > 0.05). The stability of ffERG performance in the face of shifting glycemia levels, which differs from what has been found in diabetes, was not influenced by the mild diabetogenic effect of the intervention on insulin resistance (P = 0.011) and post-prandial glycemia (P = 0.023). We conclude that prednisolone had no detectable effect on the ffERG in healthy lean men in this study. Retinal function may be less sensitive to changes in glycemia in healthy subjects than in people with diabetes, a characteristic that was unchanged by a short course of prednisolone.

2-Oleoyl glycerol is a GPR119 agonist and signals GLP-1 release in humans.

OBJECTIVE: Dietary fat is thought to stimulate release of incretin hormones via activation of fatty acid receptors in the intestine. However, dietary fat (triacylglycerol) is digested to 2-monoacylglycerol and fatty acids. Activation of G protein-coupled receptor 119 (GPR119) stimulates glucagon-like peptide-1 (GLP-1) release from the intestinal L-cells. We aimed to investigate if 2-oleoyl glycerol (2OG) can activate GPR119 in vitro and stimulate GLP-1 secretion in vivo. RESEARCH DESIGN AND METHODS: Agonist activity for various lipids was tested on transiently expressed human GPR119 in COS-7 cells. The effect of a jejunal bolus of 2 g 2OG on plasma levels of GLP-1 was evaluated in eight healthy human volunteers. The effect of 2OG was compared to an equimolar amount of oleic acid, a degradation product from 2OG, and the vehicle, glycerol. Digestion of 5 ml olive oil with pancreatic lipase will result in formation of approximately 2 g 2OG and 3.2 g oleic acid. RESULTS: 2OG and other 2-monoacylglycerols increased intracellular concentrations of cAMP in GPR119-expressing COS-7 cells (2OG EC(50) = 2.5 µm). Administration of 2OG to humans significantly increased plasma GLP-1 (0-25 min) when compared to the two controls, oleic acid and vehicle. Plasma levels of glucose-dependent insulinotropic polypeptide also increased. CONCLUSION: 2OG and other 2-monoacylglycerols formed during fat digestion can activate GPR119 and cause incretin release from the human intestine. This mechanism is likely to contribute to the known stimulatory effect of dietary fat on incretin secretion, and it indicates that GPR119 is a fat sensor.

Gastric emptying of orally administered glucose solutions and incretin hormone responses are unaffected by laparoscopic adjustable gastric banding.

BACKGROUND: Laparoscopic adjustable gastric banding (LAGB) provides weight loss in obese individuals and is associated with improved glucose homeostasis and resolution of type 2 diabetes. However, in most available reports, potentially inappropriate methodology has been applied when measuring the impact of LAGB on glucose intolerance. In order to clarify the applicability of the diagnostic 75 g-oral glucose tolerance test (OGTT) to measure the effect of LAGB on glucose metabolism, we investigated the effect of LAGB on gastric emptying for liquids as well as pancreatic and incretin hormone responses. METHODS: Eight obese patients (three with normal glucose tolerance, three with impaired glucose tolerance, and two with type 2 diabetes; age 47.5 ± 1.1 years (mean±SEM); body mass index 44 ± 1 kg/m²; HbA(1)c 6.2 ± 0.4%) underwent a 75 g-oral glucose tolerance test with 1 g acetaminophen before and ~6 weeks after LAGB. RESULTS: A small weight reduction was seen after LAGB (125 ± 8 vs. 121 ± 8 kg, P = 0.014). No differences in determinants of gastric emptying were observed before and after LAGB (area under the serum acetaminophen curve 10.1 ± 0.6 vs. 9.8 ± 0.5 mM x 4 h, P = 0.8; peak acetaminophen concentration 62 ± 3 vs. 61 ± 3 µM, P = 0.8; acetaminophen peak time 98 ± 6 vs. 100 ± 6 min, P = 0.9). No differences in plasma glucose, insulin, C-peptide, glucagon, glucose-dependent insulinotropic polypeptide, or glucagon-like peptide-1 responses to the OGTT were observed before as compared to after LAGB. CONCLUSIONS: OGTT can be used to evaluate glucose tolerance in obese patients before and after LAGB without bias from changes in gastric emptying. LAGB has no direct impact on incretin hormone secretion.

Increased postprandial GIP and glucagon responses, but unaltered GLP-1 response after intervention with steroid hormone, relative physical inactivity, and high-calorie diet in healthy subjects.

OBJECTIVE: Increased postprandial glucose-dependent insulinotropic polypeptide (GIP) and glucagon responses and reduced postprandial glucagon-like peptide-1 (GLP-1) responses have been observed in some patients with type 2 diabetes mellitus. The causality of these pathophysiological traits is unknown. We aimed to determine the impact of insulin resistance and reduced glucose tolerance on postprandial GIP, GLP-1, and glucagon responses in healthy subjects. RESEARCH DESIGN AND METHODS: A 4-h 2200 KJ-liquid meal test was performed in 10 healthy Caucasian males without family history of diabetes [age, 24 ± 3 yr (mean ± sd); body mass index, 24 ± 2 kg/m(2); fasting plasma glucose, 4.9 ± 0.3 mm; hemoglobin A(1)c, 5.4 ± 0.1%] before and after intervention using high-calorie diet, relative physical inactivity, and administration of prednisolone (37.5 mg/d) for 12 d. RESULTS: The intervention resulted in insulin resistance according to the homeostatic model assessment [1.1 ± 0.3 vs. 2.3 (mean ± SEM) ± 1.3; P = 0.02] and increased postprandial glucose excursions [area under curve (AUC), 51 ± 28 vs. 161 ± 32 mm · 4 h; P = 0.045], fasting plasma insulin (36 ± 3 vs. 61 ± 6 pm; P = 0.02), and postprandial insulin responses (AUC, 22 ± 6 vs. 43 ± 13 nm · 4 h; P = 0.03). This disruption of glucose homeostasis had no impact on postprandial GLP-1 responses (AUC, 1.5 ± 0.7 vs. 2.0 ± 0.5 nm · 4 h; P = 0.56), but resulted in exaggerated postprandial GIP (6.2 ± 1.0 vs. 10.0 ± 1.3 nm · 4 h; P = 0.003) and glucagon responses (1.6 ± 1.5 vs. 2.4 ± 3.2; P = 0.007). CONCLUSIONS: These data suggest that increased postprandial GIP and glucagon responses may occur as a consequence of insulin resistance and/or reduced glucose tolerance. Our data suggest that acute disruption of glucose homeostasis does not result in reduced postprandial GLP-1 responses as observed in some individuals with type 2 diabetes mellitus.

Incretin mimetics: a novel therapeutic option for patients with type 2 diabetes - a review.

Type 2 diabetes mellitus is a metabolic disease associated with low quality of life and early death. The goal in diabetes treatment is to prevent these outcomes by tight glycemic control and minimizing vascular risk factors. So far, even intensified combination regimen with the traditional antidiabetes agents have failed to obtain these goals. Incretin mimetics are a new class of antidiabetes drugs which involve modulation of the incretin system. They bind to and activate glucagon-like peptide-1 (GLP-1) receptors on pancreatic beta-cells following which insulin secretion and synthesis are initiated. Since the compounds have no insulinotropic activity at lower glucose concentrations the risk of hypoglycemia - a well-known shortcoming of existing antidiabetes treatments - is low. Additionally, incretin mimetics have been shown to be associated with beneficial effects on cardiovascular risk factors such as weight loss, decrease in blood pressure and changes in lipid profile. Current clinical data on the two available incretin mimetics, exenatide and liraglutide, are evaluated in this review, focusing on pharmacology, efficacy, safety and tolerability. The review is built on a systematic PubMed and Medline search for publications with the key words GLP-1 receptor agonist, exenatide, liraglutide and type 2 diabetes mellitus up to January 2009.