Resistance to insulin's acute direct hepatic effect in suppressing steady-state glucose production in individuals with type 2 diabetes

We and others have shown that insulin acutely suppresses glucose production in fasting nondiabetic humans and dogs, by both a direct hepatic effect an d an indirect (extrahepatic) effect, and in diabetic dogs by an indirect ef fect alone. In type 2 diabetes, there is resistance to insulin's ability to suppress hepatic glucose production, but it has not previously been determ ined whether the resistance is primarily at the level of the hepatocyte or the peripheral tissues. To determine whether the diabetic state reduces the direct effect of insulin in humans, we studied nine patients with untreate d type 2 diabetes who underwent three studies each, 4-6 weeks apart. 1) Por tal study (POR): intravenous tolbutamide was infused for 3 h with calculati on of pancreatic insulin secretion from peripheral plasma C-peptide. 2) Per ipheral study (PER): equidose insulin was infused by peripheral vein. 3) Ha lf-dose peripheral insulin study (1/2 PER): matched peripheral insulin leve ls with study I. In all studies, glucose was clamped at euglycemia, glucose turnover was measured with the constant specific activity method, and 3-[H -3]glucose was purified by high-performance Liquid chromatography: Peripher al insulin was lower in POR versus PER but slightly higher in FOR versus 1/ 2 PER, although most of the difference could be accounted for by higher pro insulin levels in FOR (stimulated by tolbutamide). Calculated portal insuli n was similar to 1.3-fold higher in FOR versus PER and similar to 2.2-fold higher in POR versus 1/2 PER. In the final 30 min of the clamp, glucose pro duction reached a lower steady-state level in PER than in FOR (4.0 +/- 0.4 vs. 5.3 +/- 0.5 mu mol.kg(-1).min(-1), P < 0.05), despite the higher hepati c insulin level in FOR. In contrast with our studies in nondiabetic individ uals, glucose production was not more suppressed at steady state in FOR ver sus 1/2 PER (5.3 +/- 0.4 mu mol.kg(-1).min(-1)), despite much higher hepati c insulin levels in FOR In conclusion, this is the first study in patients with type 2 diabetes to characterize insulin resistance to the acute direct suppressive effect of insulin on hepatic glucose production.