Insulin action in the double incretin receptor knockout mouse

Area of Science:

• Metabolic Research
• Endocrinology
• Animal Models

Background:

• Incretins, such as glucagon-like peptide 1 and glucose-dependent insulinotropic polypeptide, are implicated in insulin action regulation.
• The precise mechanisms by which incretins influence insulin sensitivity remain unclear.
• Double incretin receptor knockout (DIRKO) mice offer a model to investigate endogenous incretin function.

Purpose of the Study:

• To elucidate the sites of insulin action modulation in DIRKO mice.
• To determine the impact of lacking incretin signaling on metabolic responses to diet.
• To assess the role of incretins in diet-induced obesity and insulin resistance.

Main Methods:

• Hyperinsulinemic-euglycemic clamp technique was employed in DIRKO and wild-type mice.
• Mice were subjected to either a regular chow or a high-fat diet for 4 months.
• Metabolic parameters, including glucose infusion rate, glucose production/disappearance, and tissue glucose uptake, were measured.

Main Results:

• DIRKO mice exhibited reduced fat and muscle mass with increased energy expenditure compared to wild-type mice.
• While chow-fed DIRKO mice showed no difference in glucose metabolism, they had lower insulin levels and increased Akt activation in the liver.
• High-fat feeding induced insulin resistance in wild-type mice, whereas DIRKO mice were protected, showing preserved glucose uptake and enhanced Akt activation in liver and muscle.

Conclusions:

• DIRKO mice demonstrate enhanced insulin action on a standard diet.
• Absence of incretin signaling protects mice from high-fat diet-induced obesity and insulin resistance.
• These findings highlight the critical role of incretins in maintaining metabolic homeostasis.