Oral hypoglycemic drugs lower blood glucose level and are effective orally, unlike insulin which must be given by injection (mainly by subcutaneous injection and in emergencies by intravenous injection) which is the major drawback of insulin. Due to the drawback of insulin (must be given by injection) orally effective drugs in diabetes have always been searched.

In the early 1940s, it was noticed that antibiotics sulfonamides have hypoglycemia as side effect and taking this as lead the first orally acting drug which can lower blood sugar level, tolbutamide was introduced in 1957 and subsequently many other drugs followed and by 1970s many oral hypoglycemic drugs were available for better management of type-2 diabetes.

Sulfonylureas are still the mainstay of oral antidiabetic therapy, in type-2 diabetes since the early 1950s. Sulfonylureas are of first generation (Chlorpropamide, Tolbutamide, Tolazamide etc.) and second generation (Glimepiride, Glipizide, Glyburide, Glibenclamide).

Sulfonylureas are most effective in individuals with type-2 diabetes of relatively recent onset (i.e. less than 5 years) with good residual endogenous insulin production. First generation sulfonylureas are similar in potency (at maximum doses,) to second-generation agents but have a longer half-life, a greater incidence of hypoglycemia, and more frequent drug interactions, so second-generation sulfonylureas are generally preferred. Second generation sulfonylureas have advantage of more rapid onset of action and better coverage of the postprandial glucose rise, although have shorter half-life and requires more than once-a-day dosing.

At present only one biguanide is available, metformin. Due to high risk of lactic acidosis, phenformin is no more available. Biguanides are different from sulfonylureas, and do not cause hypoglycemia as they do not stimulate beta-cells of pancreas. Metformin improve lipid profile and is preferred among obese diabetic patients.

Mechanism of Action of Biguanides:

The exact mechanism of action of biguanides is not clearly understood. Although biguanides do not cause (increase) insulin release, presence of some insulin is essential for the action of biguanides. Some of the possible explanations of mechanism of action of biguanides are given here:

These are recently developed oral hypoglycemic drugs and examples are repaglinide and nateglinide. They are short acting and given immediately before meal to reduce meal related glucose level in type-2 diabetes patients. Meglitinides are derivatives of amino acid phenylalanine (D-isomer).

Mechanism of action of meglitinides:

The mechanism of action of meglitinides (repaglinide and nateglinide) is same as sulfonylureas and act by binding on the “sulfonylurea receptors”, although they are not sulfonylureas.

Thiazolidinediones belongs to novel oral antidiabetic (hypoglycemic) drugs. At present there are two thiazolidinediones available namely rosiglitazone and pioglitazone. Fat cells are the major site of action of thiazolidinediones.

Thiazolidinediones acts by selective agonism of “peroxisome proliferators activated receptor gamma”, which increases transcription of several insulin responsive genes. The genes cause reversal of insulin resistance by stimulation of GLUT4 (Glucose Transporter 4, which is the major glucose transporter in skeletal muscles) for expression and translocation, which improve entry of glucose to muscles and fat. The gluconeogenesis in liver is also suppressed by thiazolidinediones. There are also some other mechanisms involved in prevention of insulin resistance such as activation of genes which regulate fatty acid metabolism and lipogenesis in adipose tissues, increase in adipocyte (fat cells) turnover and differentiation etc.