Inhibition of obesity-induced hepatic ER stress by early insulin therapy in obese diabetic rats

Abstract

To understand the mechanism by which early insulin therapy improves insulin sensitivity in type 2 diabetes, we investigated endoplasmic reticulum (ER) stress in the liver of type 2 diabetic rats. A high fat diet plus a low dose of streptozotocin (STZ) in Sprague–Dawley (SD) rats was implemented to create an animal model mimicking diabetes. After 3 weeks of insulin treatment, the rats were examined for insulin sensitivity and ER stress in the liver. To investigate insulin sensitivity within the liver, serine phosphorylation of IRS-1 (Ser307) and Akt (Ser473) and expression of gluconeogenic genes, PEPCK and G6Pase, were tested. Protein levels of ER stress markers, such as immunoglobulin binding protein (Bip), inositol-requiring protein 1 alpha (IRE1α), and unspliced and spliced x-box binding protein-1 (XBP-1), were determined to assess ER stress. In the diabetic (DM) group, IRS-1 phosphorylation was increased (P < 0.05), Akt phosphorylation was reduced (P < 0.05), expression of PEPCK and G6Pase was elevated (P < 0.05), and ER stress markers were up-regulated (P < 0.05) relative to the non-diabetic rats. In the insulin (INS) therapy group, all of aforementioned changes were attenuated or reversed (P < 0.05). In addition, c-Jun N-terminal kinase (JNK) activity and SREBP-1 expression were decreased (P < 0.05). Adipose tissue mass was increased (P < 0.05). These data suggest that short-term insulin therapy relieved ER stress and enhanced insulin sensitivity in the liver of diabetic rats. The mechanism is likely related to fat redistribution from liver to adipose tissue. These cellular and molecular responses may represent a mechanism for improvement of insulin sensitivity in type 2 diabetic rats by insulin therapy.

Role of SREBPs in Liver Diseases: A Mini-review

“… 20 , 70 In contrast, AMPK activation down-regulates SREBP 1c expression and alleviates ER stress response through suppression of mechanistic target of rapamycin complex 1 signaling in the ER stress-induced hepatocytes. 41 In the study by Sun et al 71 , early insulin therapy reduced c-Jun N-terminal kinase and IRS-1 expression; it also improved ER stress and steatosis in the rat liver. Several pharmacologic agents, including rosiglitazone, naltrexone and tauroursodeoxycholic acid, also attenuated ER stress liver injury and down-regulated both SREBP1 and SREBP2 expression.…”

Caveolin-1 Is Essential for the Improvement of Insulin Sensitivity through AKT Activation during Glargine Treatment on Diabetic Mice

“…Fasting Blood Glucose in CAV-1 Silenced Diabetic Mice. During the course of glargine treatment, the starting dose administered was 0.4 u/d and then adjusted ±0.1 u/d to maintain the fasting blood glucose between 72 mg/dL and 144 mg/dL [18]. Higher doses of glargine were administered, ranging from 0.4 u/d to 1.6 u/d in the CAV-1-shRNA group, while the insulin group received stable doses between 0.4 u/d and 0.8 u/d (Figure 6(a)).…”

The Novel Peptide Chm-273s Has Therapeutic Potential for Metabolic Disorders: Evidence from In Vitro Studies and High-Sucrose Diet and High-Fat Diet Rodent Models

“…Analysis of p-Akt (Ser473), p-Akt (Thr308), and p-p70S6K (Thr421/Ser424) protein expression in the liver revealed a significant reduction in p-Akt (Thr308) in the hepatocytes of HSD rats, suggesting impaired insulin signaling. Studies of metabolic conditions associated with insulin resistance have shown decreased Akt phosphorylation at Thr308 and Ser473 in response to insulin [ 76 , 77 , 78 ]. Low p-Akt levels are also characteristic of animal models of metabolic dysfunctions, such as HFD [ 79 ] and transgenic models [ 80 ].…”