A New Treatment Strategy of Adding Exenatide to Insulin Therapy for Patients With Type 2 Diabetes and Non-Alcoholic Fatty Liver Disease (NAFLD)

Type 2 diabetes mellitus (T2DM) is a major public health problem in the United States with ~2/3 of Americans that are overweight or frankly obese. Less well recognized is that obesity and T2DM are fueling another "silent epidemic": non-alcoholic fatty liver disease (NAFLD). In NAFLD, hepatic fat accumulation ranges from simple steatosis to severe steatohepatitis (NASH), with necroinflammation and fibrosis that may progress to cirrhosis. Indeed, up to 40% of patients with NAFLD develop NASH and about ~15-20% of patients with NASH develop cirrhosis after 10 years. NASH is believed to be the most common cause of cryptogenic cirrhosis and ranking as the third leading indication for liver transplantation after alcohol and hepatitis C. The distinction between simple steatosis and NASH can only be done by means of a liver biopsy, but strategies that reduce fatty liver disease correlate with a reduction in steatohepatitis and fibrosis.

It is estimated that ~1/3 of the general population of the United States have fatty liver disease as assessed by magnetic resonance imaging and spectroscopy (MRS), the gold-standard technique. It is also affecting the pediatric population, and while the natural history remains to be defined, most biopsies show some degree of fibrosis and cirrhosis has been reported in children as young as 10 years of age. Moreover, in the investigators experience using MRS for the past several years, ~80% of patients with T2DM have NAFLD. If the above is extrapolated to the overall population of the United States, there are ~15 million subjects with T2DM and NAFLD and more than 50 million overweight/obese individuals with NAFLD.

As awareness of NAFLD/NASH increases, health care providers are now confronted with the unique challenge of achieving good metabolic control while treating fatty liver disease in the same subject. Inadequate glycemic control appears to worsen and accelerate progression of fatty liver disease. Paradoxically, most patients with T2DM do not reach established treatment goals. Moreover, it appears that the way metabolic control achieved is important in NAFLD: while metformin may be beneficial in NASH and pioglitazone is highly effective, control of hyperglycemia by insulin therapy alone has modest benefit on hepatic fat accumulation. In addition, long-term insulin therapy in T2DM is frequently associated with inadequate compliance, weight gain, frequent hypoglycemia and overall poor patient satisfaction. This is of great concern as ~35-40% of patients with T2DM are treated with insulin. Therefore, there is an unmet need to find better ways to treat patients that fail oral agent therapy, targeting both hyperglycemia and excessive liver fatty deposition.

The investigators propose a strategy of adding exenatide to insulin therapy as a means to achieve better glycemic control while ameliorating hepatic steatosis (and improving hepatic insulin sensitivity), reduce body weight/total body fat (and visceral fat), decrease the risk of hypoglycemia by allowing a reduction in insulin doses (withdrawal of premeal insulin doses, reduction of basal long-acting insulin), and enhance insulin secretion and insulin action while improving the quality of life of patients with T2DM and NAFLD. As both T2DM and NAFLD will become more prevalent in the near future, this pilot study will likely set the stage for a large controlled multicenter trial with an approach that may be more effective than intensified insulin therapy alone.

The central hypothesis is that insulin resistance and fat-overload play a key role in NAFLD/NASH, a condition believed to arise at the molecular level from the inability of the mitochondria to adapt to fat oversupply. Excessive fatty acid flux from exogenous (dietary) and endogenous (insulin resistant adipose tissue/increased lipolysis) sources drive hepatic lipogenesis. Exenatide would potentially be a good treatment fit against hepatic steatosis by decreasing excess dietary intake and substrate supply, reducing fat mass and plasma FFA and by lowering exogenous insulin needs and chronic hyperinsulinemia. Mitigating chronic hyperinsulinemia and hyperglycemia is important as they drive hepatic fat synthesis through sterol regulatory element-binding protein 1c (SREBP-1c) and carbohydrate regulatory element-binding protein (ChREBP) activity, respectively. Weight loss may also subdue systemic inflammation generated by dysfunctional adipose tissue, and at the local (hepatic) level, ameliorate fat-induced mitochondrial dysfunction (activation of Kupffer cells, local production of cytokines).