Hepatic PTP1B Deficiency: The Promise of a Treatment for Metabolic Syndrome?

METABOLIC SYNDROME AND HEPATIC INSULIN RESISTANCE

Metabolic syndrome is characterized by a constellation of disorders, including obesity, dyslipidemia, impaired glucose tolerance, cardiovascular disease, and non-alcoholic fatty liver disease (NAFLD) []. Many features of metabolic syndrome are linked to the development of insulin resistance, a condition that precedes the development of type 2 diabetes and often occurs well before diabetes is diagnosed [, ]. The liver plays a central role in the maintenance of normal glucose homeostasis and lipid metabolism, as demonstrated by the phenotype of mice with liver-specific deletion of the insulin receptor (IR) (liver-specific insulin receptor knockout – LIRKO mice). LIRKO mice have “pure” hepatic insulin resistance resulting in incomplete suppression of hepatic glucose production and severe glucose intolerance []. They also develop proatherogenic lipoprotein profiles, as demonstrated by increased VLDL cholesterol and decreased HDL cholesterol, and are more susceptible to cholesterol gallstone formation [–]. Chronic inflammation associated with obesity is thought to induce insulin resistance in the liver via induction of inflammatory cytokines and adipokines, which impair insulin signaling in hepatocytes [].

A hallmark feature of metabolic syndrome is the accumulation of fat in the liver, which can progress from benign fatty liver to steatohepatitis and cirrhosis []. Although the molecular mechanisms responsible for hepatic lipid accumulation are not well understood, they appear to be associated with the development of insulin resistance []. Therefore, improvements in insulin resistance should have important therapeutic implications for the prevention and/or treatment of early stage fatty liver and the associated diabetes risk. In fact, recent studies using insulin-sensitizing agents (thiazolidinediones and metformin) showed promising results in this regard []. It should be noted, however, that a causal link between the development of hepatic insulin resistance and fatty liver has been difficult to prove; the study of genetically altered mouse models should prove useful in sorting out which features of metabolic syndrome are a direct result of impaired insulin signaling []. Furthermore, although the detailed mechanism(s) underlying the development of insulin resistance remain controversial [–], there is general agreement that impaired post-IR signaling is involved [].

Keywords

metabolic syndrome, diabetes, PTP1B, liver, insulin, phosphatase,