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Insulin, Diabetes and Obesity

Insulin Release and Signaling

Insulin is a peptide consisting of 51 amino acids. It is stored in the secretory granules of beta cells. Glucose may enter beta cells via the glucose transporter (GLUT2) to produce ATP. The beta cell membrane contains ATP-sensitive potassium (KATP) channels which are open in the absence of ATP and closed upon ATP binding. The increase in cellular ATP concentration causes more KATP channels to close, resulting in membrane depolarization. This in turn opens the voltage-gated Ca2+ channels. The influx of Ca2+ stimulates the release of insulin from the secretory granules (see JBC, 2002, Fig.1).

The released insulin may circulate through the bloodstream and bind to its receptors on the surface of target cells. The insulin receptor is a receptor tyrosine kinase which, upon activation, phosphorylates the intracellular insulin receptor substrate (IRS). Subsequently, IRS binds various proteins containing the SH2 domain to transmit the signal. The major metabolic actions of insulin is transmitted by PI3K (class IA) via downstream effectors such as PDK1 and Akt (review).

Insulin Resistance

The type 2 diabetes begins with insulin resistance - a condition in which normal insulin signaling pathways are impaired. About 80 percent of people with type 2 diabetes are associated with obesity. While the detailed mechanism of insulin resistance is not fully understood. It has been well established that adipokines (such as leptin and adiponectin) play an important role. As mentioned in the chapter, Leptin and Obesity, both leptin and adiponectin can activate AMPK to reduce fats. The AMPK activation also has an insulin-sensitizing effect (review). Therefore, insulin resistance could result from insufficient AMPK activation by leptin and adiponectin in obese people due to leptin resistance and downregulation of adiponectin. This explains why diabetes is often associated with obesity.

 

Review Articles

Adipokines and Insulin Resistance - Molecular Medicine, 2008.

Insulin resistance and pancreatic β cell failure - J. Clin. Invest., 2006.

AMP-activated protein kinase signaling in metabolic regulation - J. Clin. Invest., 2006.

Adiponectin and adiponectin receptors in insulin resistance, diabetes, and the metabolic syndrome - J. Clin. Invest., 2006.