Q&A: Mechanism Of Action Of Metformin

Initial treatment of patients with type 2 diabetes mellitus includes lifestyle changes focusing on diet, increased physical activity and exercise, and weight reduction, reinforced by consultation with a registered dietitian and diabetes self-management education, when possible.

In this article:
Metformin
MCQ exam: clinical scenario
MCQ exam: answer
MCQ exam: explanation

Metformin

In the absence of contraindications, metformin is considered the initial medication of choice for hyperglycemia in type 2 diabetes. Metformin therapy (in the absence of contraindications) can be initiated, concurrent with lifestyle intervention, at the time of diabetes diagnosis.

Monotherapy with metformin is indicated for most patients, and insulin may be indicated as initial treatment for those who present with catabolic features (polyuria, polydipsia, weight loss). The natural history of most patients with type 2 diabetes is for blood glucose concentrations to rise gradually with time. Most patients require continuous treatment in order to maintain normal or near-normal glycemia.

MCQ exam: clinical scenario

An elderly woman with type 2 diabetes has poorly controlled blood glucose levels despite treatment. The physician decides to try metformin.

Which best describes the mode of action of metformin?

a) Reduces insulin resistance and improves insulin sensitivity
b) Suppresses basal hepatic glucose production
c) Reduces fasting plasma glucose
d) Activates the AMP-activated protein kinase
e) Stimulates first-phase insulin secretion in the pancreatic beta cells

MCQ exam: answer

The correct answer is D.
Activation of the AMP-activated protein kinase (AMPK) best describes the mechanism of action of metformin.

MCQ exam: explanation

An elevated rate of basal hepatic glucose output is the primary determinant of elevated fasting blood glucose levels in patients with type 2 diabetes.

The primary effect of metformin is the suppression of basal hepatic glucose production, thereby reducing fasting plasma glucose. Metformin does not stimulate insulin secretion; in contrast, metformin reduces fasting plasma insulin and improves whole-body insulin-stimulated glucose metabolism (insulin sensitivity).

While it is possible that the beneficial effect of metformin on insulin sensitivity is mediated directly, a more likely explanation is that it is secondary to a reduction in hyperglycemia, triglycerides, and free fatty acids.

Evidence has shown that metformin activates the AMP-activated protein kinase.

Reference(s)
1). UpToDate: Management of persistent hyperglycemia in type 2 diabetes mellitus. Available online: https://www.uptodate.com/contents/management-of-persistent-hyperglycemia-in-type-2-diabetes-mellitus
2). UpToDate: Metformin in the treatment of adults with type 2 diabetes mellitus. Available online: https://www.uptodate.com/contents/metformin-in-the-treatment-of-adults-with-type-2-diabetes-mellitus