Tissue Iron Predicts Metformin Responsiveness in a Mouse Model and in Humans with Type 2 Diabetes

Area of Science:

• Biochemistry
• Endocrinology
• Metabolic Diseases

Background:

• Metformin is a first-line pharmacologic treatment for type 2 diabetes (T2D).
• The precise mechanism of metformin action is not fully understood.
• Metformin's induction of an iron starvation response in yeast suggests a link between tissue iron and treatment efficacy.

Purpose of the Study:

• To investigate the influence of varying tissue iron levels on metformin's action.
• To determine if iron status affects metformin's glycemic control in type 2 diabetes.

Main Methods:

• Examined glycemic responses and downstream targets of metformin in mice fed diabetogenic diets with differing iron content.
• Conducted a retrospective study on human patients to assess metformin effectiveness relative to serum ferritin levels (a marker of tissue iron).

Main Results:

• Metformin yielded the greatest glycemic benefit in mice on a normal-iron diet; low-iron diets alone improved glycemic control, negating metformin's additional benefit.
• Dietary iron influenced metformin's downstream targets, including AMP-dependent kinase and glycerol-3-phosphate dehydrogenase 2.
• Increased O-linked N-acetylglucosamine (O-GlcNAc) modified proteins mimicked low-iron effects and reduced metformin's impact on glycemia and downstream markers.
• Human patients with high or low serum ferritin levels showed diminished HbA1c response to metformin.

Conclusions:

• Dietary iron levels and serum ferritin predict glycemic response to metformin in both mouse models and human type 2 diabetes patients.
• Protein O-GlcNAcylation may mediate the observed interactions between iron status and metformin efficacy.