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Published on: May 6, 2013
Tetrahydroindenoindole inhibits the progression of diabetes in mice
Howard G Shertzer1, Scott N Schneider, Eric L Kendig
1Department of Environmental Health and Center for Environmental Genetics; University of Cincinnati Medical Center, Cincinnati, OH, 45267, USA.
Abstract:
Diabetes is characterized by elevated fasting blood glucose (FBG) resulting from improper insulin regulation and/or insulin resistance. Herein we used female C57BL/6J mouse models for type 1 diabetes (streptozotocin [STZ] treatment) and type 2 diabetes (high-fat diet) to examine the ability of 4b,5,9b,10-tetrahydroindeno[1,2-b]indole (THII) to intervene in the progression of diabetes. THII (100 microM in drinking water) significantly diminished and partially reversed the increase in FBG levels produced by STZ. After 10 weeks on a high-fat diet, mice had normal FBG levels, but exhibited fasting hyperinsulemia and loss of glucose tolerance. THII significantly diminished these changes in glucose and insulin. In isolated liver mitochondria, THII inhibited succinate-dependent H(2)O(2) production, while in white adipose tissue, THII inhibited NADPH oxidase-mediated H(2)O(2) production and lipid peroxidation. Without intervention, such oxidative processes might otherwise promote diabetogenesis via inflammatory pathways. THII also increased O(2) consumption and lowered respiratory quotient (CO(2) produced/O(2) consumed) in vivo, indicating a greater utilization of fat for metabolic fuel. Increased metabolic utilization of fat correlated with a decrease in the rate of body weight gain in THII-treated mice fed the high-fat diet. We conclude that THII may retard the progression of diabetes via multiple pathways, including the inhibition of oxidative and inflammatory pathways.
Insights
The compound 4b,5,9b,10-tetrahydroindeno[1,2-b]indole (THII) shows promise in managing diabetes. It effectively reduced blood glucose and improved insulin sensitivity in mouse models, suggesting potential therapeutic benefits for diabetes progression.
Area of Science:
- Biochemistry
- Metabolic Diseases
- Pharmacology
Background:
- Diabetes mellitus is a metabolic disorder characterized by hyperglycemia due to impaired insulin secretion or action.
- Oxidative stress and inflammation are implicated in the pathogenesis of diabetes.
- Developing novel therapeutic agents to counteract these processes is crucial.
Purpose of the Study:
- To investigate the potential of 4b,5,9b,10-tetrahydroindeno[1,2-b]indole (THII) to ameliorate diabetes progression.
- To explore the mechanisms underlying THII's effects on glucose metabolism and oxidative stress.
Main Methods:
- Utilized female C57BL/6J mouse models for type 1 diabetes (streptozotocin-induced) and type 2 diabetes (high-fat diet-induced).
- Administered THII (100 microM) in drinking water.
- Assessed fasting blood glucose, fasting insulin, glucose tolerance, mitochondrial hydrogen peroxide production, adipose tissue oxidative stress markers, oxygen consumption, and respiratory quotient.
Main Results:
- THII significantly reduced elevated fasting blood glucose in type 1 diabetic mice.
- THII ameliorated fasting hyperinsulinemia and impaired glucose tolerance in type 2 diabetic mice.
- THII inhibited mitochondrial and adipose tissue hydrogen peroxide production, reduced lipid peroxidation, increased oxygen consumption, and promoted fat utilization, correlating with decreased body weight gain.
Conclusions:
- THII demonstrates efficacy in mitigating diabetes progression in preclinical models.
- THII's therapeutic effects are likely mediated by the inhibition of oxidative stress and inflammatory pathways.
- THII may represent a novel therapeutic strategy for managing diabetes through multiple mechanisms.
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