Regulation of endogenous glucose output during euglycaemic hyperinsulinaemia

Hyperinsulinaemia dose dependently inhibits endogenous glucose output (Kolterman etal. 1981; DeFronzo 1988), which is mainly of hepatic origin (Ekberg etal. 1999). An important regulator of hepatic glucose release is the relationship of hepatic sinusoidal concentrations of insulin and glucagon (Cherrington 1999). Although irrelevant during a hyperinsulinaemic clamp test performed at euglycaemia, hyperglycaemia per se also exerts a powerful inhibitory effect on endogenous glucose output (Bell etal. 1986). Because glucoregulatory hormones other than insulin, such as glucagon, are only gradually suppressed during hyperinsulinaemic euglycaemic clamp tests (Prager etal. 1987; Lewis etal. 1998), two other factors essentially impact on endogenous glucose output. These factors are the degree of hyperinsulinaemia per se and the insulin sensitivity of hepatic glucose output. Since insulin is physiologically secreted into the splanchnic circulation, portal vein plasma concentrations of insulin exceed those in peripheral and arterial plasma. The physiological range of the ratio between portal venous and peripheral venous insulin concentrations is approximately 2-2.5:1 (Waldhausl etal. 1982). During a clamp experiment, endogenous insulin secretion can be monitored by the measurement of plasma C-peptide concentrations because only endogenous insulin secretion and not insulin infusion is accompanied by C-peptide release. Plasma concentrations of C-peptide decline during exogenous insulin infusion, indicating inhibition of endogenous insulin secretion. It is important to note that this inhibition of endogenous insulin secretion abolishes the physiological gradient of insulin concentrations between portal vein and peripheral venous plasma. Thus, peripheral plasma insulin concentrations roughly correspond to portal vein insulin concentrations during a hyperinsulinaemic clamp test, allowing one to assess endogenous glucose output under conditions of known hepatic sinusoidal insulin concentrations.

In nondiabetic subjects the infusion of insulin at rates of 0.2, 0.25, 0.5 and 1 mU per kilogram bodyweight per minute (mU-kg-1-min-1) during euglycaemic clamp tests reduce hepatic glucose output by ~50, ~68, ~87 and ~98% (Rizza etal. 1981a; DeFronzo etal. 1983). Although the hepatic sinusoidal insulin concentrations remain almost unchanged during low dose insulin infusion, endogenous glucose output is substantially reduced (Prager et al. 1987). This phenomenon is explainable by additional indirect (extrahepatic) effects of insulin on endogenous glucose output, which involve the insulin induced alteration of gluconeogenic substrate flux from the periphery as well as the suppression of adipose tissue lipolysis during peripheral hyperinsulinaemia (Prager etal. 1987; Lewis etal. 1996; McCall etal. 1998; Giaccaetal. 1999).

Several metabolic conditions known to be associated with resistance of insulin induced suppression of endogenous glucose output should be considered when a clamp protocol is planned. For example, impaired glucose tolerance (Bavenholm etal. 2001), type 2 diabetes mellitus and obesity (Kolterman etal. 1981; DeFronzo etal. 1985; Butler etal. 1990; Staehr etal. 2001; Krssak etal. 2004), steroid therapy (Rizza etal. 1982), increased availability of free fatty acids and/or triglycerides (Bajaj et al. 2002; Boden et al. 2002) and fat accumulation in the liver (Seppala-Lindroos etal. 2002; Krssak etal. 2004) are associated with defective insulin induced suppression of endogenous glucose output. In terms of a dose-response curve of insulin action on endogenous glucose output, the curve is shifted to the right under these metabolic conditions, indicative of hepatic insulin resistance (Kolterman etal. 1981). In line with these studies, the half maximal effective plasma insulin concentration to suppress endogenous glucose output is increased more than twofold in patients with type 2 diabetes (~65 ^U/ml), compared to nondiabetic controls (~25 ^U/ml) (Campbell etal. 1988).

In summary, in nonobese, glucose tolerant and otherwise healthy individuals, endogenous glucose output can be assumed zero during euglycaemic clamp tests when the insulin infusion rate is in the range of 1 mU-kg-1 -min-1 or 40 mU-m-2-min-1. In any other case, complete inhibition of endogenous glucose output cannot be assumed and has to be measured.

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