Exogenous insulin replacement in type 2 diabetes reverses excessive hepatic glucose release, but not excessive renal glucose release and impaired free fatty acid clearance

In type 2 diabetes renal and hepatic glucose release are increased and free fatty acids (FFA) clearance is reduced. Restoration of normoglycemia by exogenous insulin replacement normalizes overall glucose release and plasma FFA concentrations. However, it is unclear to what extent normalization of overall glucose release is due to suppression of hepatic (HGR) and renal glucose release (RGR) and whether the abnormal FFA clearance is improved. We therefore determined overall, renal, and hepatic glucose release, as well as systemic FFA release and clearance by tracer techniques in type 2 diabetic subjects with (DM⁺) and without (DM^{[minus ]}) physiologic overnight insulin infusion and in nondiabetic volunteers (NV). Insulin infusion normalized plasma glucose (5.3 [plusmn] 0.1 v 5.2 [plusmn] 0.1 mmol/L in NV) and overall glucose release (10.1 [plusmn] 0.7 v 10.6 [plusmn] 0.4 [mu ]mol [middot] kg^{[minus ]1} [middot] min^{[minus ]1} in NV), (both P [gt ] .9). Values in DM^{[minus ]} were 9.1 [plusmn] 0.6 mmol/L and 14.6 [plusmn] 0.8 [mu ]mol [middot] kg^{[minus ]1} [middot] min^{[minus ]1}, respectively (both P [lt ] .001 v DM⁺ and NV). The correction of overall glucose release in DM⁺ was due to suppression of HGR to rates below normal (6.11 [plusmn] 0.53 v 8.67 [plusmn] 0.44 [mu ]mol [middot] kg^{[minus ]1} [middot] min^{[minus ]1} in NV, P [lt ] .03). RGR remained increased (3.91 [plusmn] 0.38 v 1.90 [plusmn] 0.28 [mu ]mol [middot] kg^{[minus ]1} [middot] min^{[minus ]1} in NV, P [lt ] .002) and was similar to DM^{[minus ]} (3.97 [plusmn] 0.33 [mu ]mol [middot] kg^{[minus ]1} [middot] min^{[minus ]1}, P [gt ] .9). Insulin infusion also normalized plasma FFA levels (450 [plusmn] 45 v 476 [plusmn] 42 in NV, P [gt ] .9 and v613 [plusmn] 33 [mu ]mol/L in DM^{[minus ]}, P [lt ] .04). This was due to suppression of FFA release to below normal (4.04 [plusmn] 0.45 v 5.25 [plusmn] 0.25 [mu ]mol [middot] kg^{[minus ]1} [middot] min^{[minus ]1} in NV, P [lt ] .04). Plasma FFA clearance remained reduced (7.2 [plusmn] 1.0 v 11.4 [plusmn] 1.2 mL [middot] kg^{[minus ]1} [middot] min^{[minus ]1} in NV, P [lt ] .04) and was similar to DM^{[minus ]} (7.3 [plusmn] 0.5 mL [middot] kg^{[minus ]1} [middot] min^{[minus ]1}, P [gt ] .9). We conclude that in contrast to the excessive HGR, excessive RGR and impaired FFA clearance are not corrected by acute exogenous insulin replacement.