Results of epidemiological studies show that obesity and type 2 diabetes mellitus have become a public health concern globally, which has substantial health, social and economic impacts. A common characteristic of human obesity and type 2 diabetes is insulin resistance, which a given amount of insulin produces less than normal physiological responses, usually demonstrated as diminished glucose lowering effect of insulin. Daily feeding cycles lead to the variations of nutrient and hormone levels. Insulin from pancreatic β-cells acts on the liver to control short-term and long-term metabolic homeostasis. The long-term effects of insulin can be attributed, partially, to insulin-regulated expressions of genes involved in glucose and lipid metabolism. In an insulin-sensitive liver, insulin suppresses expressions of gluconeogenic genes, and increases expressions of lipogenic genes. In an insulin-resistant liver, insulin fails to suppress expressions of gluconeogenic genes, while expression levels of lipogenic genes are elevated. This may cause a vicious cycle that drives β-cell failure and over diabetes. Using sterol-regulatory element binding protein 1c (Srebp-1c) and phosphoenolpyruvate carboxykinase (Pck1) genes as model genes of insulin-regulated expression, we found that insulin failed to regulate their expressions in primary hepatocytes from Zucker fatty rats fed ad libitum, and Zucker lean rats after over-eating. For the first time, we observed the presence of hepatic insulin resistance at gene expression (HIRAGE). This review was aimed to summarize the current understanding of insulin-regulated hepatic gene expression. It focuses on the potential roles of nutrient fluxes in the development of HIRAGE, which is supported by clinical observations of bariatric surgery studies. It argues that a transient and dynamic HIRAGE exists after overnutrition and precedes a systemic insulin resistance in a wildtype animal. The underlying mechanisms of HIRAGE may help us to identify intervention points for the prevention and treatment of hepatic insulin resistance and type 2 diabetes.
Insulin; Liver; Hepatic insulin resistance; Gene expression; Diabetes; Bariatric surgery