Metformin increases glucose uptake and acts renoprotectively by reducing SHIP2 activity.

Area of Science:

• Biochemistry
• Pharmacology
• Molecular Biology

Background:

• Metformin is a first-line type 2 diabetes (T2D) drug that suppresses liver gluconeogenesis.
• The precise targets and mechanisms of metformin's glucose uptake enhancement in peripheral tissues are unknown.
• SHIP2 (Src homology 2 domain-containing inositol-5-phosphatase 2) is upregulated in diabetes, impairs insulin signaling by reducing Akt activation, and diminishes glucose uptake.

Purpose of the Study:

• To investigate the direct molecular target of metformin responsible for increased glucose uptake.
• To elucidate the role of SHIP2 in metformin's action on glucose uptake and insulin sensitivity.
• To examine the renoprotective effects of metformin through SHIP2 inhibition in T2D patients.

Main Methods:

• In vitro binding and activity assays of metformin on recombinant SHIP2 phosphatase domain.
• Inhibition of SHIP2 by metformin in cultured cells and in skeletal muscle and kidney tissues of db/db mice.
• Assessment of glucose uptake, glucose transporter 4 (GLUT4) endocytosis, Akt activation, and podocyte apoptosis in SHIP2-overexpressing cells and tissues.
• Analysis of SHIP2 activity and podocyte loss in kidney glomeruli from T2D patients on metformin versus non-metformin medication.

Main Results:

• Metformin directly binds to and reduces the catalytic activity of SHIP2 in vitro.
• Metformin effectively inhibits SHIP2 in various cell types and in vivo models (db/db mice).
• In SHIP2-overexpressing cells, metformin restores glucose uptake by reducing GLUT4 endocytosis and normalizes Akt activity and podocyte apoptosis.
• SHIP2 activity is elevated in T2D patients on non-metformin drugs but not on metformin.
• Metformin treatment reduces podocyte loss in T2D patients' kidneys.

Conclusions:

• Metformin directly inhibits SHIP2 phosphatase activity, representing a novel molecular mechanism for its action.
• Reducing SHIP2 activity by metformin enhances glucose uptake in peripheral tissues.
• Metformin exerts renoprotective effects in T2D by inhibiting SHIP2, mitigating podocyte apoptosis and loss.