Mitochondrial inhibitor as a new class of insulin sensitizer

Abstract

Insulin resistance is a major risk factor for type 2 diabetes. AMP-activated protein kinase (AMPK) is a drug target in the improvement of insulin sensitivity. Several insulin-sensitizing medicines are able to activate AMPK through inhibition of mitochondrial functions. These drugs, such as metformin and STZ, inhibit ATP synthesis in mitochondria to raise AMP/ATP ratio in the process of AMPK activation. However, chemicals that activate AMPK directly or by activating its upstream kinases have not been approved for treatment of type 2 diabetes in humans. In an early study, we reported that berberine inhibited oxygen consumption in mitochondria, and increased AMP/ATP ratio in cells. The observation suggests an indirect mechanism for AMPK activation by berberine. Berberine stimulates glycolysis for ATP production that offsets the cell toxicity after mitochondria inhibition. The study suggests that mitochondrial inhibition is an approach for AMPK activation. In this review article, literature is critically reviewed to interpret the role of mitochondria function in the mechanism of insulin resistance, which supports that mitochondria inhibitors represent a new class of AMPK activator. The inhibitors are promising candidates for insulin sensitizers. This review provides a guideline in search for small molecule AMPK activators in the drug discovery for type 2 diabetes.

Keywords: Insulin resistance; Insulin sensitizer; Mitochondria; Mitochondria inhibitor; Obesity; Type 2 diabetes.

Figure 1

Mechanism of insulin resistance. There are several hypotheses about insulin resistance. These include mitochondrial dysfunction, endoplasmic reticulum (ER) stress, adiponectin reduction, inflammation, lipotoxicity, AMPK inactivation, oxidative stress, and insulin elevation.

Figure 2

Glucose and fatty acids catabolism in cells. Glucose breaks down into pyruvate in the process of glycolysis. In the hypoxia condition, pyruvate becomes lactic acid in the cytoplasm and released out of cells. In the presence of oxygen, pyruvate is converted into acetyl-CoA by PDH in the mitochondria, and then used in TAC cycle for ATP production. The byproducts are water and carbon dioxide. Fatty acids breaks down into acetyl-CoA through β-oxidation in mitochondria, and then used in ATP production through TCA cycle. In hypoxia condition, fatty acid cannot be used in ATP production.

Figure 3

Mitochondrial inhibition as a new approach for insulin sensitization. In obesity, mitochondria over-activation by substrates and insulin leads to reduction in AMPK activity. Insulin signaling activity is inhibited in the presence of AMPK inactivation. Inhibition of mitochondrial function is an alternative pathway in AMPK activation.