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

Abstract

Insulin resistance and associated metabolic sequelae are common in chronic kidney disease (CKD) and are positively and independently associated with increased cardiovascular mortality. However, the pathogenesis has yet to be fully elucidated. 11β-Hydroxysteroid dehydrogenase type 1 (11βHSD1) catalyzes intracellular regeneration of active glucocorticoids, promoting insulin resistance in liver and other metabolic tissues. Using two experimental rat models of CKD (subtotal nephrectomy and adenine diet) which show early insulin resistance, we found that 11βHSD1 mRNA and protein increase in hepatic and adipose tissue, together with increased hepatic 11βHSD1 activity. This was associated with intrahepatic but not circulating glucocorticoid excess, and increased hepatic gluconeogenesis and lipogenesis. Oral administration of the 11βHSD inhibitor carbenoxolone to uremic rats for 2 wk improved glucose tolerance and insulin sensitivity, improved insulin signaling, and reduced hepatic expression of gluconeogenic and lipogenic genes. Furthermore, 11βHSD1 −/− mice and rats treated with a specific 11βHSD1 inhibitor (UE2316) were protected from metabolic disturbances despite similar renal dysfunction following adenine experimental uremia. Therefore, we demonstrate that elevated hepatic 11βHSD1 is an important contributor to early insulin resistance and dyslipidemia in uremia. Specific 11βHSD1 inhibitors potentially represent a novel therapeutic approach for management of insulin resistance in patients with CKD.

Changes in gluconeogenesis and intracellular lipid accumulation characterize uremic human hepatocytes ex vivo

“…It is interesting to note the clear similarities between our data and those recently reported by Chapagain et al (3) in two mouse models of uremia. That same study also found elevations in hepatic expression of 11␤-hydroxysteroid dehydrogenase (HSD) type 1, a key enzyme for cortisol biosynthesis and reported that treatment with an inhibitor of this enzyme led to the normalization of hepatic transcription in uremic animals.…”

“…Although simple, our study comprises what to our knowledge is the first characterization of human hepatocytes under uremic conditions to date, and it evoked a phenotype surprisingly like that seen in the clinical setting (5,7,11,14) and in rodent models of uremia (1,3,8).…”

Glucocorticoid activation by 11β‐hydroxysteroid dehydrogenase enzymes in relation to inflammation and glycaemic control in chronic kidney disease: A cross‐sectional study

“…Alterations in 11β-HSD activity lead to much more pronounced shifts of cortisol-cortisone equilibrium in local tissues than in circulation, 7 renal impairment. We identified inflammation as a major determinant of GC activation by 11β-HSD and as a confounder in the correlation of GC activation with renal impairment, thereby expanding on knowledge from previous studies.…”

“…16,18,19 Elevated 11β-HSD1 activity has been implicated in metabolic disease and insulin resistance. 7,26,27 Whether elevated 11β-HSD1 activity is involved in insulin resistance in the setting of human CKD has not yet been explored. 7,26,27 Whether elevated 11β-HSD1 activity is involved in insulin resistance in the setting of human CKD has not yet been explored.…”

Emerging Liver–Kidney Interactions in Nonalcoholic Fatty Liver Disease

“…In renal medulla, 11bHSD1 activation induced salt-sensitive hypertension, which was reversed by 11bHSD1 inhibition [134]. Recent experimental data demonstrate that, in CKD hepatic and adipose tissue, 11bHSD1 is upregulated as a result of increased oxidative stress and proinflammatory cytokines interleukin (IL)-1, TNF-/, and IL-6, and promotes NAFLD, insulin resistance, hypertension, hyperglycemia, and dyslipidemia, all reversed by the 11bHSD1 inhibitor carbenoxolone [135]. These data make 11bHSD1 inhibition an appealing strategy for managing CKD-associated metabolic disorders: accordingly, in a recent Phase I RCT, the 11bHSD1 inhibitor RO5093151 significantly improved radiological steatosis in NAFLD [136].…”