Sex differences in insulin resistance in GABAB1 knockout mice

Area of Science:

• Neuroendocrinology
• Metabolic Research
• GABAergic Signaling

Background:

• Previous studies indicated that the absence of functional GABA B receptors (GABABRs) disrupts glucose homeostasis.
• This research extends those findings to investigate alterations in GABAB1 knockout (GABAB1KO) mice.

Purpose of the Study:

• To investigate glucose homeostasis and energy balance alterations in GABAB1KO mice.
• To explore potential sexual differences in these metabolic disturbances.

Main Methods:

• Evaluated glucose and insulin tolerance tests (GTT, ITT), and insulin/glucagon secretion tests (IST, GST) in male and female GABAB1KO and WT mice.
• Assessed blood glucose, serum insulin, HOMA-IR, and hypothalamic NPY mRNA expression.
• Determined skeletal muscle insulin signaling pathway components (IRβ, IRS1/2, Akt phosphorylation) and hexokinase-II levels via Western blot.

Main Results:

• GABAB1KO males showed elevated fasting insulin and HOMA-IR, indicating peripheral insulin resistance.
• Both male and female GABAB1KO mice exhibited impaired insulin sensitivity (increased GTT/ITT AUC).
• Akt activation was significantly reduced in GABAB1KO males, but not females, with increased food intake and NPY expression observed in GABAB1KO mice.

Conclusions:

• Metabolic disruptions and energy balance issues were more pronounced in GABAB1KO males, suggesting sex-specific effects of GABABR absence.
• Peripheral insulin resistance in males may stem from augmented insulin secretion.
• Milder metabolic alterations in females could be linked to reproductive disorders.