2. Drugs that alter insulin action

a. Metformin -  Metformin (1,1-dimethylbiguanide hydrochloride) is used, either alone or in conjunction with other oral agents or insulin, in the treatment of patients with type 2 diabetes.

Metformin’s primary action is on the liver, reducing hepatic gluconeogenesis by activating adenosine monophosphate-activated protein kinase (AMPK), which acts as an intracellular energy sensor, and has a critical role regulating gluconeogenesis. LKB1 is a protein threonine kinase that phosphorylates and activates AMPK; it was recently reported that deletion of LKB1 function in the liver results in hyperglycemia with increased gluconeogenic and lipogenic gene expression. The deletion of LKB1 also eliminated the glucose lowering effect of metformin, providing genetic proof for the hypothesis that metformin lowers glucose levels by AMP kinase activation.

Metformin has a half-life of 1.5-3 hours, is not bound to plasma proteins, and is not metabolized in humans, being excreted unchanged by the kidneys.

Metformin may be used as an adjunct to diet for the control of hyperglycemia and its associated symptoms in patients with type 2 diabetes, particularly those who are obese or are not responding optimally to maximal doses of sulfonylureas. A side benefit of metformin therapy is its tendency to improve both fasting and postprandial hyperglycemia and hypertriglyceridemia in obese diabetics without the weight gain associated with insulin or sulfonylurea therapy. Metformin is not indicated for patients with type 1 diabetes and is contraindicated in diabetics with serum creatinine levels of 1.5 mg/dL or higher, hepatic insufficiency, alcoholism, or a propensity to develop tissue hypoxia.

Metformin is dispensed as 500 mg, 850 mg, and 1000 mg tablets. A 500 mg extended-release preparation is also available. Although the maximal dosage is 2.55 g, little benefit is seen above a total dose of 2000 mg. It is important to begin with a low dose and increase the dosage very gradually in divided doses - taken with meals - to reduce minor gastrointestinal upsets. A common schedule would be one 500 mg tablet three times a day with meals or one 850 mg or 1000 mg tablet twice daily at breakfast and dinner. One to four tablets of the extended-release preparation can be given once a day.

The most frequent side effects of metformin are gastrointestinal symptoms (anorexia, nausea, vomiting, abdominal discomfort, diarrhea), which occur in up to 20% of patients. These effects are dose-related, tend to occur at onset of therapy, and often are transient. However, in 3-5% of patients, therapy may have to be discontinued because of persistent diarrheal discomfort.

Hypoglycemia does not occur with therapeutic doses of metformin, which permits its description as a “euglycemic” or “antihyperglycemic” drug rather than an oral hypoglycemic agent. Dermatologic or hematologic toxicity is rare.

Lactic acidosis has been reported as a side effect but is uncommon with metformin in contrast to phenformin. While therapeutic doses of metformin reduce lactate uptake by the liver, serum lactate levels rise only minimally if at all, since other organs such as the kidney can remove the slight excess. However, if tissue hypoxia occurs, the metformin-treated patient is at higher risk for lactic acidosis due to compromised lactate removal. Similarly, when renal function deteriorates, affecting not only lactate removal by the kidney but also metformin excretion, plasma levels of metformin rise far above the therapeutic range and block hepatic uptake enough to provoke lactic acidosis without associated increases in lactic acid production. Almost all reported cases have involved subjects with associated risk factors that should have contraindicated its use (renal, hepatic, or cardiorespiratory insufficiency, alcoholism, advanced age). Acute renal failure can occur rarely in certain patients receiving radiocontrast agents. Metformin therapy should therefore be temporarily halted on the day of the test and for 2 days following injection of radiocontrast agents to avoid potential lactic acidosis if renal failure occurs.