Elevated hepatic 11β-hydroxysteroid dehydrogenase type 1 induces insulin resistance in uremia

Area of Science:

• Metabolic research
• Renal disease
• Endocrinology

Background:

• Insulin resistance and metabolic issues are common in chronic kidney disease (CKD), increasing cardiovascular mortality.
• The exact mechanisms driving these metabolic disturbances in CKD are not fully understood.
• 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1) regenerates active glucocorticoids, worsening insulin resistance in metabolic tissues.

Purpose of the Study:

• To investigate the role of 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1) in the development of insulin resistance in experimental models of chronic kidney disease (CKD).
• To assess the therapeutic potential of 11βHSD1 inhibition for managing metabolic dysfunction in CKD.

Main Methods:

• Utilized two rat models of CKD (subtotal nephrectomy and adenine diet) exhibiting early insulin resistance.
• Measured 11βHSD1 mRNA, protein, and activity in hepatic and adipose tissues.
• Administered 11βHSD1 inhibitors (carbenoxolone and UE2316) to uremic rats and mice, assessing metabolic parameters and gene expression.

Main Results:

• CKD models showed increased hepatic and adipose 11βHSD1 expression and activity, leading to intrahepatic glucocorticoid excess.
• This was associated with enhanced hepatic gluconeogenesis and lipogenesis, contributing to insulin resistance and dyslipidemia.
• Inhibition of 11βHSD1 improved glucose tolerance, insulin sensitivity, and normalized key metabolic gene expression in uremic rats.
• 11βHSD1 knockout mice and rats treated with an inhibitor were protected from metabolic disturbances despite renal impairment.

Conclusions:

• Increased hepatic 11βHSD1 is a significant factor in early insulin resistance and dyslipidemia associated with uremia in CKD.
• Targeting 11βHSD1 with specific inhibitors offers a promising novel therapeutic avenue for managing insulin resistance in patients with chronic kidney disease.