Intestinal bile acid sequestration improves glucose control by stimulating hepatic miR-182-5p in type 2 diabetes

Colesevelam is a bile acid sequestrant approved to treat both hyperlipidemia and type 2 diabetes, but the mechanism for its glucose-lowering effects is not fully understood. The aim of this study was to investigate the role of hepatic microRNAs (miRNAs) as regulators of metabolic disease and to investigate the link between the cholesterol and glucose-lowering effects of colesevelam. To quantify the impact of colesevelam treatment in rodent models of diabetes, metabolic studies were performed in Zucker diabetic fatty (ZDF) rats and db/db mice. Colesevelam treatments significantly decreased plasma glucose levels and increased glycolysis in the absence of changes to insulin levels in ZDF rats and db/db mice. High-throughput sequencing and real-time PCR were used to quantify hepatic miRNA and mRNA changes, and the cholesterol-sensitive miR-96/182/183 cluster was found to be significantly increased in livers from ZDF rats treated with colesevelam compared with vehicle controls. Inhibition of miR-182 in vivo attenuated colesevelam-mediated improvements to glycemic control in db/db mice. Hepatic expression of mediator complex subunit 1 (MED1), a nuclear receptor coactivator, was significantly decreased with colesevelam treatments in db/db mice, and MED1 was experimentally validated to be a direct target of miR-96/182/183 in humans and mice. In summary, these results support that colesevelam likely improves glycemic control through hepatic miR-182–5p, a mechanism that directly links cholesterol and glucose metabolism. NEW & NOTEWORTHY Colesevelam lowers systemic glucose levels in Zucker diabetic fatty rats and db/db mice and increases hepatic levels of the sterol response element binding protein 2-responsive microRNA cluster miR-96/182/183. Inhibition of miR-182 in vivo reverses the glucose-lowering effects of colesevelam in db/db mice. Mediator complex subunit 1 (MED1) is a novel, direct target of the miR-96/182/183 cluster in mice and humans.

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Gastrointestinal Mechanisms Underlying the Cardiovascular Effect of Metformin

Pharmaceuticals ◽

10.3390/ph13110410 ◽

2020 ◽

Vol 13 (11) ◽

pp. 410

Author(s):

Malcolm J. Borg ◽

Christopher K. Rayner ◽

Karen L. Jones ◽

Michael Horowitz ◽

Cong Xie ◽

...

Keyword(s):

Type 2 Diabetes ◽

Cardiovascular Risk ◽

Cardiovascular Effect ◽

Elevated Blood ◽

Direct Effects ◽

Mechanistic Studies ◽

Glucose Lowering ◽

Glucose Levels ◽

Blood Glucose Levels

Metformin, the most widely prescribed drug therapy for type 2 diabetes, has pleiotropic benefits, in addition to its capacity to lower elevated blood glucose levels, including mitigation of cardiovascular risk. The mechanisms underlying the latter remain unclear. Mechanistic studies have, hitherto, focused on the direct effects of metformin on the heart and vasculature. It is now appreciated that effects in the gastrointestinal tract are important to glucose-lowering by metformin. Gastrointestinal actions of metformin also have major implications for cardiovascular function. This review summarizes the gastrointestinal mechanisms underlying the action of metformin and their potential relevance to cardiovascular benefits.

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Oral DhHP-6 for the Treatment of Type 2 Diabetes Mellitus

International Journal of Molecular Sciences ◽

10.3390/ijms20061517 ◽

2019 ◽

Vol 20 (6) ◽

pp. 1517 ◽

Cited By ~ 1

Author(s):

Kai Wang ◽

Yu Su ◽

Yuting Liang ◽

Yanhui Song ◽

Liping Wang

Keyword(s):

Diabetes Mellitus ◽

Type 2 Diabetes ◽

Type 2 Diabetes Mellitus ◽

Blood Glucose ◽

Enzymatic Activity ◽

Glucose Levels ◽

Blood Glucose Levels

Type 2 diabetes mellitus (T2DM) is associated with pancreatic β-cell dysfunction which can be induced by oxidative stress. Deuterohemin-βAla-His-Thr-Val-Glu-Lys (DhHP-6) is a microperoxidase mimetic that can scavenge reactive oxygen species (ROS) in vivo. In our previous studies, we demonstrated an increased stability of linear peptides upon their covalent attachment to porphyrins. In this study, we assessed the utility of DhHP-6 as an oral anti-diabetic drug in vitro and in vivo. DhHP-6 showed high resistance to proteolytic degradation in vitro and in vivo. The degraded DhHP-6 product in gastrointestinal (GI) fluid retained the enzymatic activity of DhHP-6, but displayed a higher permeability coefficient. DhHP-6 protected against the cell damage induced by H2O2 and promoted insulin secretion in INS-1 cells. In the T2DM model, DhHP-6 reduced blood glucose levels and facilitated the recovery of blood lipid disorders. DhHP-6 also mitigated both insulin resistance and glucose tolerance. Most importantly, DhHP-6 promoted the recovery of damaged pancreas islets. These findings suggest that DhHP-6 in physiological environments has high stability against enzymatic degradation and maintains enzymatic activity. As DhHP-6 lowered the fasting blood glucose levels of T2DM mice, it thus represents a promising candidate for oral administration and clinical therapy.

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Novel liver-specific TORC2 siRNA corrects hyperglycemia in rodent models of type 2 diabetes

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00158.2009 ◽

2009 ◽

Vol 297 (5) ◽

pp. E1137-E1146 ◽

Cited By ~ 49

Author(s):

Maziyar Saberi ◽

David Bjelica ◽

Simon Schenk ◽

Takeshi Imamura ◽

Gautam Bandyopadhyay ◽

...

Keyword(s):

Type 2 Diabetes ◽

Hepatic Glucose Production ◽

Glucose Production ◽

Primary Mouse Hepatocytes ◽

Primary Mouse ◽

Hepatic Glucose ◽

Zdf Rats ◽

Mouse Hepatocytes

The transcription factor TORC2 [transducer of regulated cAMP-responsive element-binding protein (CREB) activity 2] is a major regulator of hepatic gluconeogenesis and is increased in hyperglycemic rodent models. Because chronic hyperglycemia and increased hepatic glucose production, via increased gluconeogenesis, is a key feature of type 2 diabetes, an effective in vivo method to efficiently knock down TORC2 could provide a potential therapy for treating hyperglycemia and type 2 diabetes. To assess this, primary mouse hepatocytes, high-fat diet (HFD)-fed mice, and Zucker diabetic fatty (ZDF) rats were treated with a siRNA against TORC2 (siTORC2), which was delivered via a novel lipid nanoparticle system, or control siRNA (siCON). Compared with siCON, administration of siTORC2 resulted in highly efficient, sustained (1–3 wk) knockdown of TORC2 and its gluconeogenic target genes phospho enolpyruvate carboxykinase and glucose-6-phophatase in primary mouse hepatocytes and in the livers of HFD-fed mice. In mice, this knockdown was specific to the liver and did not occur in kidney, skeletal muscle, or adipose tissue. In HFD-fed mice, siTORC2 reduced in vivo gluconeogenic capacity, fasting hepatic glucose production, and hyperglycemia, and led to improved hepatic and skeletal muscle insulin sensitivity. siTORC2 treatment also improved systemic hyperglycemia in ZDF rats. In conclusion, these results demonstrate the importance of TORC2 in modulating HGP in vivo and highlight a novel, liver-specific siRNA approach for the potential treatment of hyperglycemia and type 2 diabetes.

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Novel dipeptidyl peptidase IV resistant analogues of glucagon-like peptide-1(7-36)amide have preserved biological activities in vitro conferring improved glucose-lowering action in vivo

Journal of Molecular Endocrinology ◽

10.1677/jme.0.0310529 ◽

2003 ◽

Vol 31 (3) ◽

pp. 529-540 ◽

Cited By ~ 23

Author(s):

BD Green ◽

VA Gault ◽

MH Mooney ◽

N Irwin ◽

CJ Bailey ◽

...

Keyword(s):

Type 2 Diabetes ◽

Biological Activities ◽

Dipeptidyl Peptidase ◽

Dipeptidyl Peptidase Iv ◽

Glucose Lowering ◽

Dpp Iv ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1

Although the incretin hormone glucagon-like peptide-1 (GLP-1) is a potent stimulator of insulin release, its rapid degradation in vivo by the enzyme dipeptidyl peptidase IV (DPP IV) greatly limits its potential for treatment of type 2 diabetes. Here, we report two novel Ala(8)-substituted analogues of GLP-1, (Abu(8))GLP-1 and (Val(8))GLP-1 which were completely resistant to inactivation by DPP IV or human plasma. (Abu(8))GLP-1 and (Val(8))GLP-1 exhibited moderate affinities (IC(50): 4.76 and 81.1 nM, respectively) for the human GLP-1 receptor compared with native GLP-1 (IC(50): 0.37 nM). (Abu(8))GLP-1 and (Val(8))GLP-1 dose-dependently stimulated cAMP in insulin-secreting BRIN BD11 cells with reduced potency compared with native GLP-1 (1.5- and 3.5-fold, respectively). Consistent with other mechanisms of action, the analogues showed similar, or in the case of (Val(8))GLP-1 slightly impaired insulin releasing activity in BRIN BD11 cells. Using adult obese (ob/ob) mice, (Abu(8))GLP-1 had similar glucose-lowering potency to native GLP-1 whereas the action of (Val(8))GLP-1 was enhanced by 37%. The in vivo insulin-releasing activities were similar. These data indicate that substitution of Ala(8) in GLP-1 with Abu or Val confers resistance to DPP IV inactivation and that (Val(8))GLP-1 is a particularly potent N-terminally modified GLP-1 analogue of possible use in type 2 diabetes.

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Results of the glucose-lowering effect of WelChol study (GLOWS): A randomized, double-blind, placebo-controlled pilot study evaluating the effect of colesevelam hydrochloride on glycemic control in subjects with type 2 diabetes

Clinical Therapeutics ◽

10.1016/j.clinthera.2007.01.003 ◽

2007 ◽

Vol 29 (1) ◽

pp. 74-83 ◽

Cited By ~ 162

Author(s):

Franklin J. Zieve ◽

Marcia F. Kalin ◽

Sherwyn L. Schwartz ◽

Michael R. Jones ◽

William L. Bailey

Keyword(s):

Type 2 Diabetes ◽

Pilot Study ◽

Glycemic Control ◽

Double Blind ◽

Glucose Lowering ◽

Double Blind Placebo ◽

Lowering Effect ◽

Glucose Lowering Effect

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Microbiome Changes after Type 2 Diabetes Treatment: A Systematic Review

Medicina ◽

10.3390/medicina57101084 ◽

2021 ◽

Vol 57 (10) ◽

pp. 1084

Author(s):

Kajus Merkevičius ◽

Ričardas Kundelis ◽

Almantas Maleckas ◽

Džilda Veličkienė

Keyword(s):

Type 2 Diabetes ◽

Bariatric Surgery ◽

Glycemic Control ◽

Gut Microbiome ◽

Library Science ◽

Cochrane Library ◽

Oral Glucose ◽

Glucose Lowering ◽

Metabolic Outcomes

Background and objectives: Although the role of the gut microbiome in type 2 diabetes (T2D) pathophysiology is evident, current systematic reviews and meta-analyses analyzing T2D treatment mainly focus on metabolic outcomes. The objective of this study is to evaluate the microbiome and metabolic changes after different types of treatment in T2D patients. Materials and Methods: A systematic search of PubMed, Wiley online library, Science Direct, and Cochrane library electronic databases was performed. Randomized controlled clinical trials published in the last five years that included T2D subjects and evaluated the composition of the gut microbiome alongside metabolic outcomes before and after conventional or alternative glucose lowering therapy were selected. Microbiome changes were evaluated alongside metabolic outcomes in terms of bacteria taxonomic hierarchy, intestinal flora biodiversity, and applied intervention. Results: A total of 16 eligible studies involving 1301 participants were reviewed. Four trials investigated oral glucose-lowering treatment, three studies implemented bariatric surgery, and the rest analyzed probiotic, prebiotic, or synbiotic effects. The most common alterations were increased abundance of Firmicutes and Proteobacteria parallel to improved glycemic control. Bariatric surgery, especially Roux-en-Y gastric bypass, led to the highest variety of changed bacteria phyla. Lower diversity post-treatment was the most significant biodiversity result, which was present with improved glycemic control. Conclusions: Anti-diabetic treatment induced the growth of depleted bacteria. A gut microbiome similar to healthy individuals was achieved during some trials. Further research must explore the most effective strategies to promote beneficial bacteria, lower diversity, and eventually reach a non-T2D microbiome.

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The Accuracy of Hemoglobin A1c and Fructosamine Evaluated by Long-Term Continuous Glucose Monitoring in Patients with Type 2 Diabetes Undergoing Hemodialysis

Blood Purification ◽

10.1159/000519050 ◽

2021 ◽

pp. 1-9

Author(s):

Tobias Bomholt ◽

Marianne Rix ◽

Thomas Almdal ◽

Filip K. Knop ◽

Susanne Rosthøj ◽

...

Keyword(s):

Type 2 Diabetes ◽

Glycemic Control ◽

Continuous Glucose Monitoring ◽

Plasma Glucose ◽

Hemoglobin A1c ◽

Glucose Monitoring ◽

Control Group ◽

Glucose Levels ◽

Sensor Glucose

Introduction: The accuracy of hemoglobin A1c (HbA1c) as a glycemic marker in patients with type 2 diabetes (T2D) receiving hemodialysis (HD) remains unknown. To assess accuracy, we compared HbA1c and fructosamine levels with interstitial glucose measured by continuous glucose monitoring (CGM) in patients with T2D receiving HD. Methods: Thirty patients in the HD group and 36 patients in the control group (T2D and an estimated glomerular filtration rate >60 mL/min/1.73 m2) completed the study period of 17 weeks. CGM (Ipro2®, Medtronic) was performed 5 times for periods of up to 7 days (with 4-week intervals) during a 16-week period. HbA1c (mmol/mol), the estimated mean plasma glucose from HbA1c (eMPGA1c [mmol/L]) and fructosamine (μmol/L) was measured at week 17 and compared with mean sensor glucose levels from CGM. Findings: In the HD group, mean sensor glucose was 1.4 mmol/L (95% confidence interval [CI]: 1.0–1.8) higher than the eMPGA1c, whereas the difference for controls was 0.1 mmol/L (95% CI: −0.1–[0.4]; p < 0.001). Adjusted for mean sensor glucose, HbA1c was lower in the HD group (−7.3 mmol/mol, 95% CI: −10.0–[−4.7]) than in the control group (p < 0.001), with no difference detected for fructosamine (p = 0.64). Discussion: HbA1c evaluated by CGM underestimates plasma glucose levels in patients receiving HD. The underestimation represents a clinical challenge in optimizing glycemic control in the HD population. Fructosamine is unaffected by the factors affecting HbA1c and appears to be more accurate for glycemic monitoring. CGM or fructosamine could thus complement HbA1c in obtaining more accurate glycemic control in this patient group.

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What are the determinants of a concerned vision of the future when living with type 2 diabetes? Results from the E3N-AfterDiab study

Chronic Illness ◽

10.1177/1742395318801934 ◽

2018 ◽

Vol 15 (3) ◽

pp. 236-241

Author(s):

Guy Fagherazzi ◽

Clélia Chambraud ◽

Courtney Dow ◽

Francesca Romana Mancini ◽

Aurélie Affret ◽

...

Keyword(s):

Type 2 Diabetes ◽

Regression Models ◽

Diabetes Management ◽

Negative Experience ◽

Glucose Lowering ◽

Logistic Regression Models ◽

Glucose Levels ◽

The Future ◽

Hba1c Levels

Objectives Identification of characteristics associated with a negative experience with type 2 diabetes may help to develop novel intervention to improve the outlook of people with the disease. Our aim was to identify determinants of a self-reported concerned vision about the future when living with type 2 diabetes. Methods In 2630 women with type 2 diabetes from the E3N-AfterDiab study, we used multivariable logistic regression models to derive odds-ratios and 95% confidence intervals. Results Women with elevated HbA1c levels (OR = 2.42 (1.67–3.49) for ≥7.2% when compared to <6.2%), or treated with injected glucose lowering treatments (OR = 1.37 [1.05–1.81]) had a higher risk of a concerned vision of the future. Age and obesity were associated with a decreased risk. Hypertension, duration of diabetes, smoking, fasting glucose levels, and years of education were not associated with a concerned vision of the future. Discussion Our findings highlight the importance of both glycemic control and the type of treatment on the perception of the future when living with type 2 diabetes. Subgroups of patients based on these characteristics may receive a specific attention from healthcare professionals to address potential concerns related with diabetes management or the fear of complications.

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