Abstract
Non-alcoholic fatty liver disease (NAFLD), ranging from non-alcoholic fatty liver to non-alcoholic steatohepatitis, can be prevalent in patients with type 2 diabetes mellitus (T2DM). However, no antidiabetic drug has been approved for the treatment of NAFLD in T2DM patients. Multiple daily injections of basal-bolus insulin are often the final therapeutic option for T2DM. We found that insulin treatment aggravated hepatic steatosis and oxidative stress in Zucker diabetic fatty (ZDF) rats. In addition to glycaemic control, we demonstrated the stimulatory role of liraglutide in relieving hepatic steatosis and liver injury in ZDF rats. Interestingly, liraglutide could also alleviate insulin-aggravated hepatic fatty accumulation. The glucagon-like peptide-1 (GLP-1) agonists liraglutide and Ex-4 activated the expression of peroxisome proliferator-activated receptor alpha (PPARα) via a GLP-1 receptor-dependent 5′ AMP-activated protein kinase pathway. As a nuclear transcription factor, PPARα could mediate the effect of GLP-1 in alleviating hepatic steatosis by differentially regulating the expression of its target genes, including acetyl CoA carboxylase and carnitine palmitoyl transferase la both in vitro and in vivo. Moreover, GLP-1 could relieve liver injury by decreasing oxidative stress stimulated by hepatic steatosis. Insulin might aggravate hepatic steatosis and liver injury by inhibiting GLP-1R expression. The findings indicate the feasibility of liraglutide treatment combined with basal insulin in attenuating hepatic steatosis and liver injury in ZDF rats. This knowledge, and the evidence for the underlying mechanism, provide a theoretical basis for the combination treatment recommended by the latest clinical practice guidelines for T2DM.
Highlights
Diabetes mellitus (DM) is a common non-communicable disease that affects the global population, including an estimated 11.6% of the Chinese adult population (Wang et al, 2017)
At of 12 weeks age, the Zucker diabetic fatty (ZDF) rats were randomly divided into four groups: 1) diabetic control group (PC, n 7); 2) diabetic group treated with insulin glargine (INS, n 7); 3) diabetic group treated with the saxagliptin inhibitor dipeptidyl peptidase 4 (DPP-4) (Saxag, n 7); and 4) diabetic group treated with the glucagon-like peptide-1 (GLP-1) analogue liraglutide (Lirag, n 9)
To confirm the effects of GLP-1 on glycaemic control, both liraglutide and saxagliptin, were used to treat ZDF rats
Summary
Diabetes mellitus (DM) is a common non-communicable disease that affects the global population, including an estimated 11.6% of the Chinese adult population (Wang et al, 2017). 50–70% of diabetics in China have type 2 DM (T2DM). They are more likely to develop nonalcoholic fatty liver disease (NAFLD) (Fruci et al, 2013). Diabetes increases the mortality rate of hepatic diseases by accelerating the progression of NAFLD from excessive hepatic fat deposition into non-alcoholic steatohepatitis (NASH), hepatic fibrosis and even hepatic carcinoma (Diehl and Day, 2017). T2DM is characterized by insulin resistance and lesions of pancreatic beta cells, resulting in a worsening glycaemic control and an increasing use of antidiabetic drugs including insulin (Kahn et al, 2009). If synthetic antidiabetic drugs or basal insulin is unable to achieve glycaemic control, the final therapeutic step is often multiple daily injections of basal-bolus insulin (American Diabetes Association, 2018). A combination treatment has been suggested by the latest American Association of Clinical Endocrinology/American College of Endocrinology (AACE/ACE) clinical practice guidelines (American Diabetes Association, 2019; Garber et al, 2019)
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