Insulin Resistance: The Hepatic Scene
Normally, during an overnight fast the liver is the major contributor to plasma glucose through glycogenolysis and gluconeogenesis. This basal hepatic glucose production is increased in type 2 diabetics due to incomplete suppression of endogenous glucose production by the liver. Metabolism. 1988 Jan;37(1):15-21 This is despite the fasting hyperinsulinaemia, reflecting the insulin-resistance to carbohydrate metabolism in the liver. This increased HGP is predominantly due to gluconeogenesis (proved by deuterated water and MRI).
So what causes this insulin resistance in the liver? Hepatic fatty infiltration has been closely correlated to hepatic insulin resistance, independent of general obesity. J Biol Chem. 2000 Mar 24;275(12):8456-60. Ectopic fat storage hypothesis assumes that overwhelming of the adipocyte storage space diverts triglycerides to the liver (and muscle) producing steatohepatitis resulting in resistance to insulin action at this site. Ann N Y Acad Sci. 2002 Jun;967:363-78. In this context, it is important to note that insulin is unable to suppress hepatic glucose production in mice lacking the insulin receptor in the liver. Mol Cell. 2000 Jul;6(1):87-97.
Resistance to insulin's actions on lipid metabolism in the liver results in a lack of suppression of VLDL output by the liver. This excess VLDL production by the liver is partly due to increased substrate (NEFA) delivery of to the liver from unsuppressed lipolysis in the adipose tissue due to local insulin resistance at that site, and partly due to a hepatic defect in suppression of VLDL production. Diabetologia. 1997 Apr;40(4):454-62. This excess triglyceride (VLDL) production by the liver results in increased CETP-mediated transfer of triglycerides to HDL, thus converting HDL to HDL3. The increased transfer of triglycerides to HDL results in its increased clearance from circulation by hepatic lipase producing the characteristic profile in insulin resistant states. Triglyceride transfer also occurs from VLDL to LDL, thus making LDL also more susceptible to hepatic lipase, converting it into the smaller dense LDL particles which is atherogenic.
Interestingly people with IGT have normal HGP and normal fasting glucose despite marked fasting hyperinsulinaemia. This is probably due to the high post absorptive plasma insulin levels being sufficient to overcome the hepatic insulin resistance thus maintaining the basal HGP normal. The high post absorptive plasma insulin levels in this setting is attributed to the defective first phase insulin response resulting in hyperglycemia which stimulates a higher than usual second phase response of insulin secretion.
So what causes this insulin resistance in the liver? Hepatic fatty infiltration has been closely correlated to hepatic insulin resistance, independent of general obesity. J Biol Chem. 2000 Mar 24;275(12):8456-60. Ectopic fat storage hypothesis assumes that overwhelming of the adipocyte storage space diverts triglycerides to the liver (and muscle) producing steatohepatitis resulting in resistance to insulin action at this site. Ann N Y Acad Sci. 2002 Jun;967:363-78. In this context, it is important to note that insulin is unable to suppress hepatic glucose production in mice lacking the insulin receptor in the liver. Mol Cell. 2000 Jul;6(1):87-97.
Resistance to insulin's actions on lipid metabolism in the liver results in a lack of suppression of VLDL output by the liver. This excess VLDL production by the liver is partly due to increased substrate (NEFA) delivery of to the liver from unsuppressed lipolysis in the adipose tissue due to local insulin resistance at that site, and partly due to a hepatic defect in suppression of VLDL production. Diabetologia. 1997 Apr;40(4):454-62. This excess triglyceride (VLDL) production by the liver results in increased CETP-mediated transfer of triglycerides to HDL, thus converting HDL to HDL3. The increased transfer of triglycerides to HDL results in its increased clearance from circulation by hepatic lipase producing the characteristic profile in insulin resistant states. Triglyceride transfer also occurs from VLDL to LDL, thus making LDL also more susceptible to hepatic lipase, converting it into the smaller dense LDL particles which is atherogenic.
Interestingly people with IGT have normal HGP and normal fasting glucose despite marked fasting hyperinsulinaemia. This is probably due to the high post absorptive plasma insulin levels being sufficient to overcome the hepatic insulin resistance thus maintaining the basal HGP normal. The high post absorptive plasma insulin levels in this setting is attributed to the defective first phase insulin response resulting in hyperglycemia which stimulates a higher than usual second phase response of insulin secretion.