Viewpoints on the Way to a Consensus Session

Abstract

Insulin resistance and the insulin resistance syndrome refer to a constellation of anthropometric and metabolic features that may be summarized as overweight/obesity, glucose intolerance, dyslipidemia, and hypertension. These anthropometric and metabolic abnormalities are associated with type 2 diabetes, cardiovascular disease, polycystic ovary syndrome, and nonalcoholic fatty liver disease. The liver plays a central role in the regulation of whole-body glucose, fatty acid, and amino acid metabolism. It is the main source of endogenous glucose production, it is a major site of fatty acid disposal (esterification and oxidation) and of amino acid metabolism, and it is the primary site of insulin degradation. ### Tissue-specific insulin receptor knockout mice Studies using tissue-specific insulin receptor knockout have demonstrated that mice lacking the muscle insulin receptor alone (MIRKO) are characterized by reduced insulin-stimulated muscle glucose uptake, but total-body glucose homeostasis remained normal (1). Adipose tissue insulin receptor knockout mice (FIRKO) had impaired adipose tissue glucose uptake but were protected against obesity, glucose intolerance, and dyslipidemia and manifested a prolonged lifespan (1). In contrast, knockout of the insulin receptor in the liver resulted in both fasting and postprandial hyperglycemia and the subsequent development of peripheral (muscle) insulin resistance. Collectively, these observations support the view that hepatic insulin resistance is the primary event and leads to the subsequent development of peripheral (muscle and adipose) tissue insulin resistance. ### The model of nonalcoholic fatty liver disease Nonalcoholic fatty liver disease (NAFLD) is part of the broad spectrum of nonalcoholic fatty liver diseases, which also includes steatosis. The distinction between fatty liver and steatohepatitis only can be made by examination of liver histology, which allows the assessment of inflammatory infiltrate, cellular degeneration, and necrosis and fibrosis, and cannot be made on the basis of clinical or laboratory parameters. Despite the weak correlation between liver function tests and the severity of liver disease, epidemiological studies have shown that transaminases, and, in particular, elevated …