Effect of bile acid sequestrants on glucose metabolism, hepatic de novo lipogenesis, and cholesterol and bile acid kinetics in type 2 diabetes: a randomised controlled study

Abstract

Aims/hypothesis The primary aim of this completed multicentre randomised, parallel, double-blind placebo-controlled study was to elucidate the mechanisms of glucose-lowering with colesevelam and secondarily to investigate its effects on lipid metabolism (hepatic de novo lipogenesis, cholesterol and bile acid synthesis). Methods Participants with type 2 diabetes (HbA 1c 6.7-10.0% [50-86 mmol/mol], fasting glucose <16.7 mmol/l, fasting triacylglycerols <3.9 mmol/l and LDL-cholesterol >1.55 mmol/l) treated with diet and exercise, sulfonylurea, metformin or a combination thereof, were randomised by a central coordinator to either 3.75 g/day colesevelam (n=30) or placebo (n=30) for 12 weeks at three clinical sites in the USA. The primary measure was the change from baseline in glucose kinetics with colesevelam compared to placebo treatment. Fasting and postprandial glucose, lipid and bile acid pathways were measured at baseline and post-treatment using stable isotope techniques. Plasma glucose, insulin, total glucagon-like peptide-1 (GLP-1), total glucose-dependent insulinotropic polypeptide (GIP), glucagon and fibroblast growth factor-19 (FGF-19) concentrations were measured during the fasting state and following a meal tolerance test. Data was collected by people blinded to treatment. Colesevelam increased cholesterol and bile acid synthesis and decreased FGF-19 concentrations. However, no effect was seen on fractional hepatic de novo lipogenesis. Conclusions/interpretation Colesevelam, a non-absorbed bile acid sequestrant, increased circulating incretins and improved tissue glucose metabolism in both the fasting and postprandial states in a manner different from other approved oral agents.Trial registration: ClinicalTrials.gov NCT00596427 Funding: The study was funded by Daiichi Sankyo.

Bile acid receptors as targets for the treatment of dyslipidemia and cardiovascular disease

“…In diabetic rat models, BAS decrease plasma glucose and improve glucose tolerance associated with an increase in plasma GLP-1 ( 164, 165 ). Beysen et al further observe no effect of BAS treatment on hepatic glucose production ( 163 ), similar to that reported in a diabetic mouse model ( 166 ). Thus, the contribution of FXR to the effects of BAS is unclear.…”

“…In contrast, one week administration of colestimide in T2D patients (n = 16) lowers plasma glucose and increases postprandial GLP-1 ( 162 ). A second study evaluating glucose kinetics in T2D patients after BAS treatment fi nds improved glucose clearance and increased GLP-1 and gastric inhibitory peptide (GIP) concentrations ( 163 ). In diabetic rat models, BAS decrease plasma glucose and improve glucose tolerance associated with an increase in plasma GLP-1 ( 164, 165 ).…”

Colesevelam suppresses hepatic glycogenolysis by TGR5-mediated induction of GLP-1 action in DIO mice

“…The putative effects of GLP-1 receptor (GLP-1R) activation optimize insulin secretion, reduce glucagon secretion, and improve insulin sensitivity in liver and peripheral tissues (14). Sequestrant treatments are associated with altered levels of gut hormones (4,19,36,50), including a rise in 19,50), which appears to require TGR5 activation (19).The metabolic mechanism of improved glucose homeostasis during sequestrant treatment has been attributed to increased energy expenditure (56), improved glucose disposal (46), and reduced glucose production (4). Humans treated with colesevelam have reduced rates of glycogenolysis (4), a pathway partly mediated by GLP-1 (1), and a contributor to glycemic dysregulation during insulin resistance (2).…”

“…The putative effects of GLP-1 receptor (GLP-1R) activation optimize insulin secretion, reduce glucagon secretion, and improve insulin sensitivity in liver and peripheral tissues (14). Sequestrant treatments are associated with altered levels of gut hormones (4,19,36,50), including a rise in 19,50), which appears to require TGR5 activation (19).…”

“…The metabolic mechanism of improved glucose homeostasis during sequestrant treatment has been attributed to increased energy expenditure (56), improved glucose disposal (46), and reduced glucose production (4). Humans treated with colesevelam have reduced rates of glycogenolysis (4), a pathway partly mediated by GLP-1 (1), and a contributor to glycemic dysregulation during insulin resistance (2).…”