Diabetes for Researchers

Jul 14 2021

Mutations of NRG4 contribute to the pathogenesis of non-alcoholic fatty liver disease and related metabolic disorders

Neuregulin 4 (Nrg4), an adipose tissue–enriched endocrine factor, participates in adipocyte-to-hepatocyte communication, eliciting beneficial metabolic effects in non-alcoholic fatty liver disease (NAFLD). Here, we evaluate the physiological roles of Nrg4 in humans and unravel the role of NRG4 variants in the pathogenesis of NAFLD and related metabolic disorders. We identified two rare missense mutations—p. R44H and p.E47Q— in the NRG4 EGFL domain by whole exome sequencing in 224 severely obese subjects and exome genotyping in 2,388 subjects from Shanghai Obesity Study. The over-expression animal models showed wild-type (WT) Nrg4 could attenuate high-fat diet-induced hepatic lipogenesis and improve energy metabolism. Nrg4 E47Q enhanced the protective effect, whereas Nrg4 R44H lost this function. Unlike Nrg4 R44H, Nrg4 E47Q activated the phosphorylation of ErbB4 and negatively regulated the de novo lipogenesis via the ErbB4-STAT5-SREBP1C pathway. The surface plasmon resonance experiments revealed a higher affinity of E47Q Nrg4 than WT to bind ErbB4, while R44H showed no binding. In conclusion, the study suggests that genetic variations in NRG4 could produce mutant proteins with aberrant functions, and impaired or enhanced Nrg4 function could either be a risk factor or protective factor for NAFLD and associated metabolic disorders.

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From Diabetes Journal Publish Ahead of Print articles • Diabetes for Researchers • 0

Jul 14 2021

Inhibition of lncRNA TCONS_00077866 ameliorates the high stearic acid diet-induced mouse pancreatic {beta}-cell inflammatory response by increasing miR-297b-5p to downregulate SAA3 expression

Long-term consumption of a high-fat diet increases the circulating concentration of stearic acid (SA), which has a potent toxic effect on β-cells, but the underlying molecular mechanisms of this action have not been fully elucidated. Here, we evaluated the role of lncRNA TCONS_00077866 (lnc866) in SA-induced β-cell inflammation. lnc866 was selected for study because lncRNA high-throughput sequencing analysis demonstrated it to have the largest fold-difference in expression of five lncRNAs that were affected by SA treatment. Knockdown of lnc866 by virus-mediated shRNA expression in mice or by Smart Silencer in mouse pancreatic β-TC6 cells significantly inhibited the SA-induced reduction in insulin secretion and β-cell inflammation. According to lncRNA-microRNA (miRNAs)-mRNA co-expression network analysis and luciferase reporter assays, lnc866 directly bound to miR-297b-5p, thereby preventing it from reducing the expression of its target serum amyloid A3 (SAA3). Furthermore, overexpression of miR-297b-5p or inhibition of SAA3 also had marked protective effects against the deleterious effects of SA in β-TC6 cells and mouse islets. In conclusion, lnc866 silencing ameliorates SA-induced β-cell inflammation by targeting the miR-297b-5p/SAA3 axis. lnc866 inhibition may represent a new strategy to protect β-cells against the effects of SA during the development of type 2 diabetes.

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From Diabetes Journal Publish Ahead of Print articles • Diabetes for Researchers • 0

Jul 13 2021

Prohibitin Inactivation in Adipocytes Results in Reduced Lipid Metabolism and Adaptive Thermogenesis Impairment

Prohibitin-1 (PHB) is a multifunctional protein previously reported to be important for adipocyte function. PHB is expressed on the surface of adipose cells, where it interacts with a long chain fatty acid (LCFA) transporter. Here, we show that mice lacking PHB in adipocytes (PHB Ad-KO) have a defect in fat tissue accumulation despite having larger lipid droplets in adipocytes due to reduced lipolysis. Although PHB Ad-KO mice do not display glucose intolerance, they are insulin resistant. We show that PHB Ad-KO mice are lipid intolerant due to a decreased capacity of adipocytes for LCFA uptake. Instead, PHB Ad-KO mice have increased expression of glucose transporter GLUT1 in various tissues and use glucose as a preferred energy source. We demonstrate that PHB Ad-KO mice have defective brown AT, are cold-intolerant, and display a reduced basal energy expenditure. Systemic repercussions of PHB inactivation in adipocytes were observed in both males and females. Consistent with lower cellular mitochondrial content and reduced UCP1 protein expression, brown adipocytes lacking PHB display decreased proton leak and switch from aerobic metabolism to glycolysis. Treatment of differentiating brown adipocytes with small molecules targeting PHB suppressed mitochondrial respiration and uncoupling. Our results demonstrate that PHB in adipocytes is essential for normal fatty acid uptake, oxidative metabolism, and adaptive thermogenesis. We conclude that PHB inhibition could be investigated as an approach to altering energy substrate utilization.

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From Diabetes Journal Publish Ahead of Print articles • Diabetes for Researchers • 0

Jul 13 2021

Intraglomerular dysfunction predicts kidney failure in type 2 diabetes

No longitudinal data link intraglomerular hemodynamic dysfunction with end-stage kidney disease (ESKD) in people with type 2 diabetes (T2D). Afferent (RA) and efferent (RE) arteriolar tone and intraglomerular pressure (PGLO) are not directly measurable in humans but are estimable from glomerular filtration rate (GFR), renal plasma flow (RPF), blood pressure, hematocrit, and plasma oncotic pressure. We examined the association of the RA/RE ratio and PGLO with ESKD incidence in 237 Pima Indian persons with T2D who underwent serial measures of GFR (iothalamate) and RPF (p-aminohippurate). Their association with kidney structural lesions was also examined in a subset of 111 participants. Of the 237 participants (mean age 42 years, diabetes duration 11 years, GFR 153 ml/min, median ACR 36 mg/g), 69 progressed to ESKD during median follow-up of 17.5 years. In latent class analysis, distinct trajectories characterized by increasing RA/RE ratio (HR: 4.60, 95% CI 2.55-8.31) or elevated PGLO followed by a rapid decline (HR: 2.96, 95% CI 1.45-6.02) strongly predicted incident ESKD. PGLO (R2=21%, p<0.0001) and RA/RE (R2=15%, p<0.0001) also correlated with mesangial fractional volume, a structural predictor of DKD progression.In conclusion, intraglomerular hemodynamic parameters associated strongly with incident ESKD and correlated with structural lesions of DKD.

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From Diabetes Journal Publish Ahead of Print articles • Diabetes for Researchers • 0

Jul 09 2021

The Role of GIP in the Regulation of GLP-1 Satiety and Nausea

Gastric inhibitory peptide (GIP) is best known for its role as an incretin hormone in control of blood glucose concentrations. As a classic satiation signal, however, the literature illustrates a mixed picture of GIP involvement with an at best weak anorectic response profile being reported for GIP receptor (GIPR) signaling. Not surprisingly, the pursuit of exploiting the GIP system as a therapeutic target for diabetes and obesity has fallen behind that of the other gastrointestinal-derived incretin, glucagon-like peptide 1 (GLP-1). However, recent discoveries highlighted here support potential therapeutic advantages of combinatorial therapies targeting GIP and GLP-1 systems together, with perhaps the most surprising finding that GIPR agonism may have antiemetic properties. As nausea and vomiting are the most common side effects of all existing GLP-1 pharmacotherapies, the ability for GIP agonism to reduce GLP-1–induced illness behaviors but retain (if not enhance) weight loss and glycemic control may offer a new era in the treatment of obesity and diabetes.

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From Diabetes Journal Publish Ahead of Print articles • Diabetes for Researchers • 0