Combined berberine and probiotic treatment as an effective regimen for improving postprandial hyperlipidemia in type 2 diabetes patients: a double blinded placebo controlled randomized study.

Non-fasting lipidemia (nFL), mainly contributed by postprandial lipidemia (PL), has recently been recognized as an important cardiovascular disease (CVD) risk as fasting lipidemia (FL). PL serves as a common feature of dyslipidemia in Type 2 Diabetes (T2D), albeit effective therapies targeting on PL were limited. In this study, we aimed to evaluate whether the therapy combining probiotics (Prob) and berberine (BBR), a proven antidiabetic and hypolipidemic regimen via altering gut microbiome, could effectively reduce PL in T2D and to explore the underlying mechanism. Blood PL (120 min after taking 100 g standard carbohydrate meal) was examined in 365 participants with T2D from the Probiotics and BBR on the Efficacy and Change of Gut Microbiota in Patients with Newly Diagnosed Type 2 Diabetes (PREMOTE study), a random, placebo-controlled, and multicenter clinical trial. Prob+BBR was superior to BBR or Prob alone in improving postprandial total cholesterol (pTC) and low-density lipoprotein cholesterol (pLDLc) levels with decrement of multiple species of postprandial lipidomic metabolites after 3 months follow-up. This effect was linked to the changes of fecal Bifidobacterium breve level responding to BBR alone or Prob+BBR treatment. Four fadD genes encoding long-chain acyl-CoA synthetase were identified in the genome of this B. breve strain, and transcriptionally activated by BBR. In vitro BBR treatment further decreased the concentration of FFA in the culture medium of B. breve compared to vehicle. Thus, the activation of fadD by BBR could enhance FFA import and mobilization in B. breve and diliminish the intraluminal lipids for absorption to mediate the effect of Prob+BBR on PL. Our study confirmed that BBR and Prob (B. breve) could exert a synergistic hypolipidemic effect on PL, acting as a gut lipid sink to achieve better lipidemia and CVD risk control in T2D.

Gut microbiome-related effects of berberine and probiotics on type 2 diabetes (the PREMOTE study).

Human gut microbiome is a promising target for managing type 2 diabetes (T2D). Measures altering gut microbiota like oral intake of probiotics or berberine (BBR), a bacteriostatic agent, merit metabolic homoeostasis. We hence conducted a randomized, double-blind, placebo-controlled trial with newly diagnosed T2D patients from 20 centres in China. Four-hundred-nine eligible participants were enroled, randomly assigned (1:1:1:1) and completed a 12-week treatment of either BBR-alone, probiotics+BBR, probiotics-alone, or placebo, after a one-week run-in of gentamycin pretreatment. The changes in glycated haemoglobin, as the primary outcome, in the probiotics+BBR (least-squares mean [95% CI], -1.04[-1.19, -0.89]%) and BBR-alone group (-0.99[-1.16, -0.83]%) were significantly greater than that in the placebo and probiotics-alone groups (-0.59[-0.75, -0.44]%, -0.53[-0.68, -0.37]%, P < 0.001). BBR treatment induced more gastrointestinal side effects. Further metagenomics and metabolomic studies found that the hypoglycaemic effect of BBR is mediated by the inhibition of DCA biotransformation by Ruminococcus bromii. Therefore, our study reports a human microbial related mechanism underlying the antidiabetic effect of BBR on T2D. (Clinicaltrial.gov Identifier: NCT02861261).

Atorvastatin Targets the Islet Mevalonate Pathway to Dysregulate mTOR Signaling and Reduce ß-Cell Functional Mass.

Statins are cholesterol-lowering agents that increase the incidence of diabetes and impair glucose tolerance via their detrimental effects on nonhepatic tissues, such as pancreatic islets, but the underlying mechanism has not been determined. In atorvastatin (ator)-treated high-fat diet-fed mice, we found reduced pancreatic ß-cell size and ß-cell mass, fewer mature insulin granules, and reduced insulin secretion and glucose tolerance. Transcriptome profiling of primary pancreatic islets showed that ator inhibited the expression of pancreatic transcription factor, mechanistic target of rapamycin (mTOR) signaling, and small G protein (sGP) genes. Supplementation of the mevalonate pathway intermediate geranylgeranyl pyrophosphate (GGPP), which is produced by 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase, significantly restored the attenuated mTOR activity, v-maf musculoaponeurotic fibrosarcoma oncogene homolog A (MafA) expression, and ß-cell function after ator, lovastatin, rosuvastatin, and fluvastatin treatment; this effect was potentially mediated by sGP prenylation. Rab5a, the sGP in pancreatic islets most affected by ator treatment, was found to positively regulate mTOR signaling and ß-cell function. Rab5a knockdown mimicked the effect of ator treatment on ß-cells. Thus, ator impairs ß-cell function by regulating sGPs, for example, Rab5a, which subsequently attenuates islet mTOR signaling and reduces functional ß-cell mass. GGPP supplementation could constitute a new approach for preventing statin-induced hyperglycemia.

Analyses of gut microbiota and plasma bile acids enable stratification of patients for antidiabetic treatment.

Antidiabetic medication may modulate the gut microbiota and thereby alter plasma and faecal bile acid (BA) composition, which may improve metabolic health. Here we show that treatment with Acarbose, but not Glipizide, increases the ratio between primary BAs and secondary BAs and plasma levels of unconjugated BAs in treatment-naive type 2 diabetes (T2D) patients, which may beneficially affect metabolism. Acarbose increases the relative abundances of Lactobacillus and Bifidobacterium in the gut microbiota and depletes Bacteroides, thereby changing the relative abundance of microbial genes involved in BA metabolism. Treatment outcomes of Acarbose are dependent on gut microbiota compositions prior to treatment. Compared to patients with a gut microbiota dominated by Prevotella, those with a high abundance of Bacteroides exhibit more changes in plasma BAs and greater improvement in metabolic parameters after Acarbose treatment. Our work highlights the potential for stratification of T2D patients based on their gut microbiota prior to treatment.

Liraglutide protects pancreatic beta cells during an early intervention in Gato-Kakizaki rats.

BACKGROUND: Glucagon-like peptide-1 (GLP-1) analogues have emerged as insulin secretagogues and are widely used in type 2 diabetic patients. GLP-1 analogues also demonstrate a promotion of beta cell proliferation and reduction of apoptosis in rodents. In the present study, we investigated the protection of pancreatic beta cells by early use (at the age of 2 weeks) of GLP-1 analogue, liraglutide in Gato-Kakizaki (GK) rats and explored the underlying mechanisms. METHODS: The effects of liraglutide on glucose tolerance were evaluated by intraperitoneal glucose tolerance test (IPGTT) and insulin release tests (IRT). Ki67 and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) immunostaining, Western blots and real-time polymerase chain reaction were applied to evaluate cell proliferation, apoptosis and related gene expressions. RESULTS: Our results demonstrated that early use of liraglutide improved glucose tolerance during liraglutide treatment in GK rats. Liraglutide increased pancreatic insulin contents and markedly reduced beta cell apoptosis. Liraglutide also downregulated pro-apoptotic gene expressions and reduced intra-islet macrophage infiltration. CONCLUSIONS: This experiment reported for the first time that early use of liraglutide could protect beta cell failure in pre-diabetic GK rats through reduction of beta cell apoptosis and ameliorating islet inflammation.