The Status of Current Research Findings

The insulin production and glucose burning in normal human body is controlled through the well balanced functioning of at least three different regions of the body, namely:

• Insulin secretion by the pancreas.
• Glucose uptake, primarily in the muscle, liver, gut and fat.
• Hepatic glucose production or HGP.

• An impaired intake of glucose by the muscles (known as insulin resistance).
• An increase in glycogen deposition.
• Failure in the inhibition mechanism that controls HGP.
• An erratic secretion of insulin by the -cells.

Insulin resistance is one of the early and strongest predictors of type 2 diabetes[7]. It is the inability of the peripheral tissues (mostly muscles) to intake glucose and convert it into glycogen (starch) or of the adipose tissues into "fat" . Although the mechanism is not exactly known, it is observed that free fatty acids (obesity) may induce insulin resistance through inhibition of glucose transport activity. Also it is understood that insulin resistance and the inability of the glucose transporters (proteins that enable glucose to enter cells) and enzymes essential for the metabolism of glucose inside the cell are all correlated. At this stage, administration of thiazolidinediones drugs³ are found to be effective (mostly in obese patients) for controlling glucose levels by increasing the insulin sensitivity of peripheral tissues. While peripheral insulin resistance is what develops into type 2 diabetes, insulin resistance alone will not inevitably result in type 2 diabetes. In fact, the body's response to insulin resistance will largely determine whether the disorder will progress to full-blown type 2 diabetes[14]. When the intake of glucose in the peripheral tissues decreases, the -cells have to produce excess insulin to compensate for the excess glucose levels in the blood. Weyer et al.[9] found that even before the increased blood glucose levels characterising type 2 diabetes is observed, the pathogenesis takes the route of an increasing insulin resistance and a decline in the acute insulin secretory response of the -cells (Impaired Glucose Tolerance or IGT) to intravenous glucose. It is indicative of the failure of the -cells. This failure does not mean the destruction of beta cells, but rather to a functional impairment, a loss in the ability of the -cell to respond normally to the glucose signal with appropriately increased insulin secretion. It is not clear whether the failure is due to some genetic abnormalities of the -cells causing glucose-toxicity, a process in which the -cells become less and less sensitive to the glycemic stimulus. In lean patients, type 2 diabetes evolves primarily from this defect in insulin secretion. Administration of sulfonylurea, an insulin secretagogue is found to be effective in such cases.

An increase in the fasting blood sugar levels is also symptomatic in type 2 diabetes. As mentioned above, during fasting hours, the glucose intake of peripheral tissues is minimal(15-20%) and thus fasting blood sugar is caused by some mechanism other than insulin resistance. Increased hepatic glucose production (HGP) through increased gluconeogenesis is believed to be primarily responsible for fasting glucose levels. The explanation for the increased gluconeogenesis is not clear, but may be related to alterations in glucose metabolic pathways, resulting in increased substrates for gluconeogenesis. For example, peripheral insulin resistance may be related to a defect in muscle glycogen synthetase activation. This in turn leads to decreased storage of glucose as glycogen, and increased production of lactate, pyruvate and alanine, all substrates for gluconeogenesis. Alterations in fatty acid metabolism may also affect HGP. Fatty acids stimulate several gluconeogenic enzymes, and their metabolism is an important energy source for this metabolic pathway[10]. Oral hypoglycemic agents to increase the insulin production ability of the -cells or insulin injections are administered to reverse the hepatic glucose production. Since night time is when hepatic glucose production is maximum (it is when endogenous insulin production is minimal), night time injection of insulin also proves useful to control HGP. Drugs such as metformin can inhibit the hepatic glucose production to considerable levels.

Studies reveal the close association between type 2 diabetes and obesity. Obesity is the result of an imbalance between energy intake and energy expenditure in the body. A major finding of this area of research was the discovery of hormone leptin and many other similar hormones that control food intake habits. Leptin hormone is secreted by fat cells and acts on a receptor on cells in the brain and tissues to help regulate food intake and energy balance. Modern cloning techniques enabled researchers to clone the leptin gene and the gene for the leptin receptors. Defects in these and other genes resulting in obesity in rodents (mice, rats etc), and their roles in human obesity, are under intensive investigation. Some hormones stimulate appetite while others inhibit the hunger signal giving the feeling of satiety. In addition, two Uncoupling Proteins (UCP-2 and UCP-3) are known to increase the rate of energy expenditure in the body and is also under through investigation.