Graduation Year

2018

Document Type

Dissertation

Degree

Ph.D.

Degree Name

Doctor of Philosophy (Ph.D.)

Degree Granting Department

Medical Sciences

Major Professor

Javier Cuevas, Ph.D.

Committee Member

Jermoe Breslin, Ph.D.

Committee Member

Vrushank Dave, Ph.D.

Committee Member

Thomas Taylor-Clark, Ph.D.

Keywords

BDE-47, BDE-85, GSIS, Type 2 Diabetes, Thymoquinone

Abstract

Type 2 Diabetes Mellitus (T2DM) is a metabolic disorder characterized by chronic hyperglycemia, which develops as a consequence of peripheral insulin resistance and defective insulin secretion from pancreatic β-cells. A high calorie diet coupled with physical inactivity are known risk factors for the development of T2DM; however, these alone fail to account for the rapid rise of the disease. Recent attention has turned to the role of environmental pollutants in the development of metabolic diseases. PBDEs (polybrominated diphenyl ethers) are environmental pollutants that have been linked to the development of type 2 diabetes (T2D), however, the precise mechanisms are not clear. In particular, their direct effect on insulin secretion is unknown. In this study, we show that two PBDE congeners, BDE-47 and BDE-85, potentiate glucose-stimulated insulin secretion (GSIS) in INS-1 832/13 cells. This effect of BDE-47 and BDE-85 on GSIS was dependent on thyroid receptor (TR). Both BDE-47 and BDE-85 (10 μM) activated Akt during an acute exposure. The activation of Akt by BDE-47 and BDE-85 plays a role in their potentiation of GSIS, as pharmacological inhibition of PI3K, an upstream activator of Akt, significantly lowers GSIS compared to compounds alone. This study suggests that BDE-47 and BDE-85 directly act on pancreatic β-cells to stimulate GSIS, and that this effect is mediated by the thyroid receptor (TR) and Akt activation. This can cause the β-cells to oversecrete insulin, potentially leading to hyperinsulinemia, insulin resistance, and high blood glucose. In contrast to the potential diabetogenic effects of POPs, there are several naturally-derived compounds which accomplish just the opposite, exerting sensitizing effect on the peripheral tissues and sparing effect on β-cells. TQ, a natural occurring quinone and the main bioactive component of plant Nigella sativa, undergoes intracellular redox cycling and re-oxidizes NADH to NAD+. TQ administration (20 mg/kg/bw/day) to the Diet-Induced Obesity (DIO) mice reduced their diabetic phenotype by decreasing fasting blood glucose and fasting insulin levels, and improved glucose tolerance and insulin sensitivity as evaluated by oral glucose and insulin tolerance tests (OGTT and ITT). Furthermore, TQ decreased serum cholesterol levels and liver triglycerides, increased protein expression of phosphorylated Akt, decreased serum levels of inflammatory markers resistin and MCP-1, and decreased the NADH/NAD+ ratio. These changes were paralleled by an increase in phosphorylated SIRT-1 and AMPKα in liver and phosphorylated SIRT-1 in skeletal muscle. TQ also increased insulin sensitivity in insulin-resistant HepG2 cells via a SIRT-1-dependent mechanism These findings are consistent with the TQ-dependent re-oxidation of NADH to NAD+, which stimulates glucose and fatty acid oxidation and activation of SIRT-1-dependent pathways. Taken together, these results demonstrate that TQ ameliorates the diabetic phenotype in the DIO mouse model of type 2 diabetes.

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