David P. Sonne

Postprandial gallbladder emptying in patients with type 2 diabetes: potential implications for bile-induced secretion of glucagon-like peptide 1

OBJECTIVE Recent preclinical work has suggested that postprandial flow of bile acids into the small intestine potentiates nutrient-induced glucagon-like peptide 1 (GLP1(GCG)) secretion via bile acid-induced activation of the G protein-coupled receptor TGR5 in intestinal L cells. The notion of bile-induced GLP1 secretion combined with the findings of reduced postprandial gallbladder emptying in patients with type 2 diabetes (T2DM) led us to speculate whether reduced postprandial GLP1 responses in some patients with T2DM arise as a consequence of diabetic gallbladder dysmotility. DESIGN AND METHODS In a randomised design, 15 patients with long-standing T2DM and 15 healthy age-, gender- and BMI-matched control subjects were studied during 75-g oral glucose tolerance test (OGTT) and three isocaloric (500 kcal) and isovolaemic (350 ml) liquid meals: i) 2.5 g fat, 107 g carbohydrate and 13 g protein; ii) 10 g fat, 93 g carbohydrate and 11 g protein; and iii) 40 g fat, 32 g carbohydrate and 3 g protein. Basal and postprandial plasma concentrations of glucose, insulin, C-peptide, glucagon, GLP1, glucose-dependent insulinotropic polypeptide (GIP), cholecystokinin and gastrin were measured. Furthermore, gallbladder emptying and gastric emptying were examined. RESULTS Gallbladder emptying increased with increasing meal fat content, but no intergroup differences were demonstrated. GIP and GLP1 responses were comparable among the groups with GIP levels being higher following high-fat meals, whereas GLP1 secretion was similar after both OGTT and meals. CONCLUSIONS In conclusion, patients with T2DM exhibited normal gallbladder emptying to meals with a wide range of fat content. Incretin responses were similar to that in controls, and an association with postprandial gallbladder contraction could not be demonstrated.

Bile Acid Sequestrants: Glucose-Lowering Mechanisms and Efficacy in Type 2 Diabetes

Bile acids are synthesized in the liver from cholesterol and have traditionally been recognized for their role in absorption of lipids and in cholesterol homeostasis. In recent years, however, bile acids have emerged as metabolic signaling molecules that are involved in the regulation of lipid and glucose metabolism, and possibly energy homeostasis, through activation of the bile acid receptors farnesoid X receptor (FXR) and TGR5. Bile acid sequestrants (BASs) constitute a class of drugs that bind bile acids in the intestine to form a nonabsorbable complex resulting in interruption of the enterohepatic circulation. This increases bile acid synthesis and consequently reduces serum low-density lipoprotein cholesterol. Also, BASs improve glycemic control in patients with type 2 diabetes. Despite a growing understanding of the impact of BASs on glucose metabolism, the mechanisms behind their glucose-lowering effect in patients with type 2 diabetes remain unclear. This article offers a review of the mechanisms behind the glucose-lowering effect of BASs, and the efficacy of BASs in the treatment of type 2 diabetes.

Effect of chenodeoxycholic acid and the bile acid sequestrant colesevelam on glucagon-like peptide-1 secretion.

To evaluate the effects of the primary human bile acid, chenodeoxycholic acid (CDCA), and the bile acid sequestrant (BAS) colesevelam, instilled into the stomach, on plasma levels of glucagon‐like peptide‐1 (GLP‐1), glucose‐dependent insulinotropic polypeptide, glucose, insulin, C‐peptide, glucagon, cholecystokinin and gastrin, as well as on gastric emptying, gallbladder volume, appetite and food intake.

Postprandial gut hormone responses and glucose metabolism in cholecystectomized patients

Preclinical studies suggest that gallbladder emptying, via bile acid-induced activation of the G protein-coupled receptor TGR5 in intestinal L cells, may play a significant role in the secretion of the incretin hormone glucagon-like peptide-1 (GLP-1) and, hence, postprandial glucose homeostasis. We examined the secretion of gut hormones in cholecystectomized subjects to test the hypothesis that gallbladder emptying potentiates postprandial release of GLP-1. Ten cholecystectomized subjects and 10 healthy, age-, gender-, and body mass index-matched control subjects received a standardized fat-rich liquid meal (2,200 kJ). Basal and postprandial plasma concentrations of glucose, insulin, C-peptide, glucagon, GLP-1, glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-2 (GLP-2), cholecystokinin (CCK), and gastrin were measured. Furthermore, gastric emptying and duodenal and serum bile acids were measured. We found similar basal glucose concentrations in the two groups, whereas cholecystectomized subjects had elevated postprandial glucose excursions. Cholecystectomized subjects had reduced postprandial concentrations of duodenal bile acids, but preserved postprandial plasma GLP-1 responses, compared with control subjects. Also, cholecystectomized patients exhibited augmented fasting glucagon. Basal plasma CCK concentrations were lower and peak concentrations were higher in cholecystectomized patients. The concentrations of GIP, GLP-2, and gastrin were similar in the two groups. In conclusion, cholecystectomized subjects had preserved postprandial GLP-1 responses in spite of decreased duodenal bile delivery, suggesting that gallbladder emptying is not a prerequisite for GLP-1 release. Cholecystectomized patients demonstrated a slight deterioration of postprandial glycemic control, probably because of metabolic changes unrelated to incretin secretion.

Clinical relevance of the bile acid receptor TGR5 in metabolism

The bile acid receptor TGR5 (also known as GPBAR1) is a promising target for the development of pharmacological interventions in metabolic diseases, including type 2 diabetes, obesity, and non-alcoholic steatohepatitis. TGR5 is expressed in many metabolically active tissues, but complex enterohepatic bile acid cycling limits the exposure of some of these tissues to the receptor ligand. Profound interspecies differences in the biology of bile acids and their receptors in different cells and tissues exist. Data from preclinical studies show promising effects of targeting TGR5 on outcomes such as weight loss, glucose metabolism, energy expenditure, and suppression of inflammation. However, clinical studies are scarce. We give a summary of key concepts in bile acid metabolism; outline different downstream effects of TGR5 activation; and review available data on TGR5 activation, with a focus on the translation of preclinical studies into clinically applicable findings. Studies in rodents suggest an important role for Tgr5 in Glp-1 secretion, insulin sensitivity, and energy expenditure. However, evidence of effects on these processes from human studies is less convincing. Ultimately, safe and selective human TGR5 agonists are needed to test the therapeutic potential of TGR5.

Involvement of glucagon-like peptide-1 in the glucose-lowering effect of metformin.

Metformin is an oral antihyperglycaemic drug used in the first‐line treatment of type 2 diabetes. Metformins classic and most well‐known blood glucose‐lowering mechanisms include reduction of hepatic gluconeogenesis and increased peripheral insulin sensitivity. Interestingly, intravenously administered metformin is ineffective and recently, metformin was shown to increase plasma concentrations of the glucose‐lowering gut incretin hormone glucagon‐like peptide‐1 (GLP‐1), which may contribute to metformins glucose‐lowering effect in patients with type 2 diabetes. The mechanisms behind metformin‐induced increments in GLP‐1 levels remain unknown, but it has been hypothesized that metformin stimulates GLP‐1 secretion directly and/or indirectly and that metformin prolongs the half‐life of GLP‐1. Also, it has been suggested that metformin may potentiate the glucose‐lowering effects of GLP‐1 by increasing target tissue sensitivity to GLP‐1. The present article critically reviews the possible mechanisms by which metformin may affect GLP‐1 levels and sensitivity and discusses whether such alterations may constitute important and clinically relevant glucose‐lowering actions of metformin.

Bile acid sequestrants for glycemic control in patients with type 2 diabetes: A systematic review with meta-analysis of randomized controlled trials

AIM To evaluate the effects of bile acid sequestrants (BASs) versus placebo, no intervention or active comparators on glycemic control in type 2 diabetes. METHODS Data were retrieved and a systematic review with meta-analyses was performed. We evaluated bias control and subgroup and sensitivity analyses were performed to evaluate heterogeneity and bias. RESULTS We included 17 trials with a total of 2950 patients randomized to BASs (colesevelam or colestimide) versus placebo, no intervention, statins or sitagliptin. Random-effects meta-analysis showed that patients randomized to BASs had a lower hemoglobin A1c at the end of treatment compared with the control group (mean difference-0.55%; 95% confidence interval-0.64 to -0.46). Analysis of trials with low risk of bias in all domains confirmed the findings. Data on adverse events were limited. There were no differences between trials stratified by the control group and no evidence of publication bias or small study effects. CONCLUSIONS Our analyses found that BAS treatment improves glycemic control. The size of the effect was clinically relevant and despite limited safety data, our findings support the inclusion of BASs in current diabetes management algorithms for type 2 diabetes.

Cholecystokinin-Induced Gallbladder Emptying and Metformin Elicit Additive Glucagon-Like Peptide-1 Responses.

CONTEXT Bile acids have been suggested to mediate glucagon-like peptide-1 (GLP-1) secretion. Metformin, too, has been shown to increase GLP-1 levels. The effect of gallbladder emptying, metformin, or a combination has, however, never been studied. OBJECTIVE We hypothesized that cholecystokinin (CCK)-8-induced gallbladder emptying stimulates human GLP-1 secretion and that metformin would potentiate this effect. DESIGN A double-blinded, randomized study. SETTING The study was conducted at a specialized research unit. PARTICIPANTS Ten healthy male subjects with no family history of diabetes (age, 22 [range, 20-32] years; body mass index, 21.7 [19.3-24.2] kg/m(2); fasting plasma glucose, 4.9 [4.7-5.3] mm; and glycosylated hemoglobin A1c, 5.1 [4.4-5.8] %). INTERVENTION On 4 separate days, the subjects received metformin or placebo and a concomitant 60-minute intravenous infusion of saline or CCK. Blood was sampled for 4 hours, and gallbladder volume was measured by ultrasound. MAIN OUTCOME MEASURES Plasma levels of GLP-1. RESULTS CCK-induced gallbladder emptying and metformin alone (no observed effect on gallbladder emptying) both elicited significant and additive GLP-1 responses. Metformin alone or combined with gallbladder emptying elicited a significant peptide YY response. CCK-induced gallbladder emptying resulted in a short-lasting glucose-dependent insulinotropic polypeptide response independent of metformin. No effects were seen on plasma glucose, insulin, C-peptide, or gastrin. CONCLUSIONS CCK-induced gallbladder emptying in healthy subjects elicits significant GLP-1 secretion, which can be potentiated by metformin.

Effect of bile acid sequestrants on glycaemic control: protocol for a systematic review with meta-analysis of randomised controlled trials

Introduction In addition to the lipid-lowering effect of bile acid sequestrants (BASs), they also lower blood glucose and, therefore, could be beneficial in the treatment of patients with type 2 diabetes mellitus (T2DM). Three oral BASs are approved by the US Food and Drug Administration (FDA) for the treatment of hypercholesterolaemia: colestipol, cholestyramine and colesevelam. The BAS colestimide/colestilan is used in Japan. Colesevelam was recently approved by the FDA for the treatment of T2DM. We plan to provide a systematic review with meta-analysis of the glucose-lowering effect of BASs with the aim to evaluate their potential as glucose-lowering agents in patients with T2DM. Methods and analysis In accordance with the preferred reporting items for systematic reviews and meta-analyses statement, a systematic review with meta-analysis of randomised clinical trials of BASs (vs placebo, oral antidiabetes drugs or insulin), reporting measures of glycaemic control in adult patients with T2DM, will be performed. Change in glycated haemoglobin constitutes the primary endpoint, and secondary endpoints include changes in fasting plasma glucose, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, total cholesterol, triglycerides, body weight and body mass index and adverse events. Electronic searches will be performed in The Cochrane Library, MEDLINE and EMBASE, along with manual searches in the reference lists of relevant papers. The analyses will be performed based on individual patient data and summarised data. The primary meta-analysis will be performed using random effects models owing to expected intertrial heterogeneity. Dichotomous data will be analysed using risk difference and continuous data using weighted mean differences, both with 95% CIs. Ethics and dissemination The study will evaluate the potential of BASs as glucose-lowering agents and possibly contribute to the clinical management of patients with T2DM. Results The study will be disseminated by peer-review publication and conference presentation. Protocol registration PROSPERO CRD42012002552.

Sevelamer in a diabetologist's perspective: a phosphate-binding resin with glucose-lowering potential

Sevelamer is a calcium‐free and metal‐free phosphate‐binding oral drug used in the management of hyperphosphataemia in chronic kidney disease. Preclinical and clinical trials have shown glucose and lipid‐lowering effects of sevelamer, thereby giving rise to a potential role of the drug in the treatment of patients with type 2 diabetes. These ‘novel’ effects are most probably derived from the bile acid‐binding properties of sevelamer. The proposed potential is supported by the approval of the bile acid sequestrant colesevelam in the United States for the treatment of type 2 diabetes and hypercholesterolaemia. This article offers a brief review on the effects of sevelamer and a perspective on the potential mechanisms behind the glucose‐lowering effect of the drug.