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Objective Colesevelam, a bile acid sequestrant approved for the treatment of hypercholesterolaemia, improves glycaemic control in type 2 diabetes. We hypothesised that single-dose colesevelam increases postprandial GLP-1 secretion, thus, reducing postprandial glucose excursions in individuals with type 2 diabetes. Further, we explored the effects of single-dose colesevelam on ultrasonography-assessed postprandial gallbladder motility, paracetamol absorption (proxy for gastric emptying), and circulating factors known to affect gallbladder motility. Methods In a randomised, double-blind, placebo-controlled crossover study, 12 individuals with type 2 diabetes (mean ± SD: age 61 ± 8.8 years; body mass index 29.8 ± 3.0 kg/m2) were subjected to 4 mixed meal tests on separate days; 2 with orally administered colesevelam (3.75 g) and 2 with placebo, with intravenous infusion of the GLP-1 receptor antagonist exendin(9-39)NH2 or saline. Results Single-dose colesevelam had no effect on postprandial concentrations of glucose (P = .786), C-peptide (P = .440), or GLP-1 (P = .729), and exendin(9-39)NH2 administration revealed no GLP-1-mediated effects of colesevelam. Colesevelam did not affect gallbladder emptying but abolished gallbladder refilling (P = .001), increased postprandial cholecystokinin (CCK) secretion (P = .010), and decreased postprandial serum concentrations of fibroblast growth factor 19 (FGF19) (P = .035) and bile acids (P = .043). Conclusion Single-dose colesevelam had no effect on postprandial GLP-1 responses or glucose tolerance but disrupted postprandial gallbladder refilling by increasing CCK secretion and reducing circulating concentrations of FGF19 and bile acids. These findings leave the antidiabetic actions of colesevelam unresolved but provide mechanistic insights into its effect on gallbladder motility., OBJECTIVE: Colesevelam, a bile acid sequestrant approved for the treatment of hypercholesterolaemia, improves glycaemic control in type 2 diabetes. We hypothesised that single-dose colesevelam increases postprandial GLP-1 secretion, thus, reducing postprandial glucose excursions in individuals with type 2 diabetes. Further, we explored the effects of single-dose colesevelam on ultrasonography-assessed postprandial gallbladder motility, paracetamol absorption (proxy for gastric emptying), and circulating factors known to affect gallbladder motility.METHODS: In a randomised, double-blind, placebo-controlled crossover study, 12 individuals with type 2 diabetes (mean ± SD: age 61 ± 8.8 years; body mass index 29.8 ± 3.0 kg/m2) were subjected to 4 mixed meal tests on separate days; 2 with orally administered colesevelam (3.75 g) and 2 with placebo, with intravenous infusion of the GLP-1 receptor antagonist exendin(9-39)NH2 or saline.RESULTS: Single-dose colesevelam had no effect on postprandial concentrations of glucose (P = .786), C-peptide (P = .440), or GLP-1 (P = .729), and exendin(9-39)NH2 administration revealed no GLP-1-mediated effects of colesevelam. Colesevelam did not affect gallbladder emptying but abolished gallbladder refilling (P = .001), increased postprandial cholecystokinin (CCK) secretion (P = .010), and decreased postprandial serum concentrations of fibroblast growth factor 19 (FGF19) (P = .035) and bile acids (P = .043).CONCLUSION: Single-dose colesevelam had no effect on postprandial GLP-1 responses or glucose tolerance but disrupted postprandial gallbladder refilling by increasing CCK secretion and reducing circulating concentrations of FGF19 and bile acids. These findings leave the antidiabetic actions of colesevelam unresolved but provide mechanistic insights into its effect on gallbladder motility.

AIM: Bile acid sequestrants are cholesterol-lowering drugs, which also improve glycaemic control in people with type 2 diabetes. The mechanism behind the glucose-lowering effect is unknown but has been proposed to be mediated by increased glucagon-like peptide-1 (GLP-1) secretion. Here, we investigated the glucose-lowering effects of sevelamer including any contribution from GLP-1 in people with type 2 diabetes.MATERIALS AND METHODS: In a randomized, double-blind, placebo-controlled, crossover study, 15 people with type 2 diabetes on metformin monotherapy underwent two 17-day treatment periods with the bile acid sequestrant sevelamer and placebo, respectively, in a randomized order and with an interposed wash-out period of minimum 6 weeks. On days 15 and 17 of each treatment period, participants underwent experimental days with 4-h liquid meal tests and application of concomitant infusion of exendin(9-39)NH 2 or saline. RESULTS: Compared with placebo, sevelamer improved insulin sensitivity (assessed by homeostatic model assessment of insulin resistance) and beta-cell sensitivity to glucose and lowered fasting and postprandial plasma glucose concentrations. In both treatment periods, exendin(9-39)NH 2 increased postprandial glucose excursions compared with saline but without absolute or relative difference between the two treatment periods. In contrast, exendin(9-39)NH 2 abolished the sevelamer-induced improvement in beta-cell glucose sensitivity. CONCLUSIONS: The bile acid sequestrant sevelamer improved insulin sensitivity and beta-cell sensitivity to glucose, but using the GLP-1 receptor antagonist exendin(9-39)NH 2 we were not able to detect a GLP-1-mediated glucose-lowering effect of sevelamer in individuals with type 2 diabetes. Nevertheless, the sevelamer-induced improvement of beta-cell sensitivity to glucose was shown to be GLP-1-dependent.

Context: In individuals with hypothyroidism and overweight, levothyroxine substitution therapy is often expected to cause weight loss due to its effect on resting energy expenditure. However, despite levothyroxine-induced enhancement of resting energy expenditure, fat mass loss is rarely seen after levothyroxine substitution therapy. The mechanism behind this conundrum is unknown. Aim: The aim of the study was to assess the effect of levothyroxine therapy on hunger sensations and ad libitum food intake in individuals with hypothyroidism. Design and setting: Prospective cohort study of 18 newly diagnosed hypothyroid women (thyroid-stimulating hormone (TSH) >10 mU/L). Participants were investigated at diagnosis, after normalization of TSH (<4.0 mU/L), and after 6 months of successful treatment. Eighteen age and body mass index-matched healthy controls were also included. Intervention: Hypothyroid individuals were treated with levothyroxine according to European Thyroid Association guidelines. Main outcomes: Changes in hunger sensation were assessed using visual analog scales (cm) before and during a standardized mixed meal test, and food intake was measured during a subsequent ad libitum meal (g). Results: After 6 months of levothyroxine therapy, mean resting energy expenditure was increased by 144 kcal/day (10%) (P < 0.001). Weight loss was comprised of 0.8 kg fat-free mass while fat mass remained unchanged. Fasting hunger sensation increased from a mean of 4.5 (s.d. 2.2) cm to 5.5 (s.d. 2.2) cm (P = 0.047). The numerical increase in ad libitum meal intake did not reach statistical significance. Conclusion: Our data suggest that levothyroxine-induced hunger may be a culprit in the lack of fat mass loss from levothyroxine therapy.

AIM: Liraglutide treatment is associated with gallbladder-related disorders and has been shown to delay postprandial gallbladder refilling. The gut hormones cholecystokinin (CCK), fibroblast growth factor 19 (FGF19) and glucagon-like peptide 2 (GLP-2), are known to regulate gallbladder motility and may be implicated in gallbladder-related disorders associated with liraglutide treatment.MATERIALS AND METHODS: In a double-blind, 12-week trial, 52 participants [50% male, age 47.6 ± 10.0 years, body mass index 32.6 ± 3.4 kg/m 2 (mean ± standard deviation)] with obesity were randomized 1:1 to once-daily subcutaneous liraglutide (escalated from 0.6 mg to 3.0 mg once-daily) or placebo. During liquid meal tests performed at baseline, after the first dose and following 12 weeks of treatment, we evaluated postprandial gallbladder dynamics and plasma responses of CCK, FGF19 and GLP-2. RESULTS: Liraglutide reduced postprandial FGF19 after the first dose [area under the curve (AUC) 0-240 min 24.8 vs. 48.0 min × ng/ml, treatment ratio (TR) (95% confidence interval) 0.52 (0.39; 0.69)] and following 12 weeks of treatment [AUC 0-240 min 33.7 vs. 48.5 ng/ml × min, TR 0.69 (0.52; 0.93)]. Liraglutide also reduced postprandial GLP-2 responses (AUC 0-240 min 3650 vs. 4894 min × pmol/L, TR 0.75 (0.62; 0.90)] following the first dose as well as after 12 weeks [AUC 0-240 min 3760 vs. 4882 min × pmol/L, TR 0.77 (0.60; 0.99)]. Liraglutide increased postprandial responses of CCK after the first dose [AUC 0-240 min 762 vs. 670 min × pmol/L; TR 1.14 (0.97; 1.33)] and following 12 weeks of treatment [AUC 0-240 min 873 vs. 628 min × pmol/L; TR 1.39 (1.12; 1.73)]. CONCLUSION: Compared with placebo, treatment with liraglutide decreased postprandial FGF19 and GLP-2 concentrations and increased postprandial CCK concentrations, which may explain the delayed postprandial gallbladder refilling observed in individuals with obesity treated with liraglutide.

Aim: Postprandial secretion of the appetite-inhibiting hormones, glucagon-like peptide-1 (GLP-1), and peptide YY are reduced with obesity. It is unclear if the reduced secretion persists following weight loss (WL), if other appetite-inhibiting hormones are also reduced, and if so whether reduced secretion results from intrinsic changes in the gut. Methods: To address whether WL may restore secretion of GLP-1 and other appetite-inhibiting hormones, we performed a gut perfusion study of the small intestine in diet-induced obese (DIO) rats after WL. A 20% weight loss (means ± SEM (g): 916 ± 53 vs. 703 ± 35, p < 0.01, n = 7) was induced by calorie restriction, and maintained stable for ≥7 days prior to gut perfusion to allow for complete renewal of enteroendocrine cells. Age-matched DIO rats were used as comparator. Several gut hormones were analyzed from the venous effluent, and gene expression was performed on gut tissue along the entire length of the intestine. Results: Secretion of cholecystokinin, gastrin, glucose-dependent insulinotropic peptide, GLP-1, neurotensin, and somatostatin was not affected by WL during basal conditions (p ≥ 0.25) or in response to macronutrients and bile acids (p ≥ 0.14). Glucose absorption was indistinguishable following WL. The expression of genes encoding the studied peptides, macronutrient transporters (glucose, fructose, and di-/tripeptides) and bile acid receptors did also not differ between DIO and WL groups. Conclusions: These data suggest that the attenuated postprandial responses of GLP-1, as well as reduced responses of other appetite-inhibiting gut hormones, in people living with obesity may persist after weight loss and may contribute to their susceptibility for weight regain.

To better understand the physiological basis of obesity in women, we investigated whether obesity or menstrual cycle phase affects laboratory test-meal size or meal-stimulated plasma cholecystokinin (CCK) concentration. Women with healthy weight (body mass index [BMI] of 18.5-24.9 kg/m(2), N = 16) or obesity (BMI 30-39.9 kg/m(2), N = 20) were tested once in the late-follicular or peri-ovulatory phase (LF/PO) and once in the mid-luteal phase (ML). Meals of ham sandwiches were offered and blood was sampled. Menstrual cycle phases were verified with participants' reports of menses and measurements of progesterone and luteinizing hormone (LH) concentrations. Women with obesity ate significantly larger meals than women with healthy weight, (mean, 711 [95% CI, 402-1013] kJ, P = 0.001, during the LF/PO and 426 [105-734] kJ, P = 0.027, larger during the ML). Women with healthy weight ate smaller meals during LF/PO than ML (decrease, 510 [192-821 kJ], P = 0.008), but women with obesity did not (decrease, 226 [-87-542] kJ, P = 0.15). CCK concentrations 18 to 30 minutes after meal onset were lower in women with obesity than in women with healthy weight during LF/PO (3.6 [3.1-4.1] vs 6.1 [4.5-7.7] pmol/L; P = 0.004), but not during ML, with a significant interaction effect (1.8 [1.2-2.4] pmol/L, P = 0.048). Women with obesity consumed larger meals than women with healthy weight but displayed reduced meal-stimulated plasma CCK concentrations. These data are consistent with the hypothesis that a defect in CCK secretion compromises satiation in obese women and contributes to the development or maintenance of obesity.