Thirty-two subjects with impaired fasting glucose (IFG) and 28 subjects with normal fasting glucose (NFG) ingested a labeled meal and 75 g glucose (oral glucose tolerance test) on separate occasions. Fasting glucose, insulin, and C-peptide were higher (P < 0.05) in subjects with IFG than in those with NFG, whereas endogenous glucose production (EGP) did not differ, indicating hepatic insulin resistance. EGP was promptly suppressed, and meal glucose appearance comparably increased following meal ingestion in both groups. In contrast, glucose disappearance (R d ) immediately after meal ingestion was lower (P < 0.001) in subjects with IFG/impaired glucose tolerance (IGT) and IFG/diabetes but did not differ in subjects with IFG/normal glucose tolerance (NGT) or NFG/NGT. Net insulin action (S i ) and insulin-stimulated glucose disposal (S i *) were reduced (P < 0.001, ANOVA) in subjects with NFG/IGT, IFG/IGT, and IFG/diabetes but did not differ in subjects with NFG/NGT or IFG/NGT. Defective insulin secretion also contributed to lower postprandial R d since disposition indexes were lower (P < 0.001, ANOVA) in subjects with NFG/IGT, IFG/IGT, and IFG/diabetes but did not differ in subjects with NFG/NGT and IFG/NGT. We conclude that postprandial hyperglycemia in individuals with early diabetes is due to lower rates of glucose disappearance rather than increased meal appearance or impaired suppression of EGP, regardless of their fasting glucose. In contrast, insulin secretion, action, and the pattern of postprandial turnover are essentially normal in individuals with isolated IFG. Diabetes 55: 3536 -3549, 2006

OBJECTIVE-To determine the contribution of hepatic insulin resistance to the pathogenesis of impaired fasting glucose (IFG).RESEARCH DESIGN AND METHODS-Endogenous glucose production (EGP) and glucose disposal were measured in 31 subjects with IFG and 28 subjects with normal fasting glucose (NFG) after an overnight fast and during a clamp when endogenous secretion was inhibited with somatostatin and insulin infused at rates that approximated portal insulin concentrations present in IFG subjects after an overnight fast (ϳ80 pmol/l, "preprandial") or within 30 min of eating (ϳ300 pmol/l, "prandial").RESULTS-Despite higher (P Ͻ 0.001) insulin and C-peptide concentrations and visceral fat (P Ͻ 0.05), fasting EGP and glucose disposal did not differ between IFG and NFG subjects, implying hepatic and extrahepatic insulin resistance. This was confirmed during preprandial insulin infusion when glucose disposal was lower (P Ͻ 0.05) and EGP higher (P Ͻ 0.05) in IFG than in NFG subjects. Higher EGP was due to increased (P Ͻ 0.05) rates of gluconeogenesis in IFG. EGP was comparably suppressed in IFG and NFG groups during prandial insulin infusion, indicating that hepatic insulin resistance was mild. Glucose disposal remained lower (P Ͻ 0.01) in IFG than in NFG subjects.CONCLUSIONS-Hepatic and extrahepatic insulin resistance contribute to fasting hyperglycemia in IFG with the former being due at least in part to impaired insulin-induced suppression of gluconeogenesis. However, since hepatic insulin resistance is mild and near-maximal suppression of EGP occurs at portal insulin concentrations typically present in IFG subjects within 30 min of eating, extrahepatic (but not hepatic) insulin resistance coupled with accompanying defects in insulin secretion is the primary cause of postprandial hyperglycemia. Diabetes

Glucocorticoids are potent regulators of protein, fat, and carbohydrate metabolism. To determine if cortisol production occurs within the splanchnic bed in humans, 11 nondiabetic subjects were studied using the hepatic/ leg catheterization method along with an infusion of [9,11,12,12-2 H 4 ] cortisol (D4-cortisol) as proposed by Andrews et al. In the fasting state, there was net release (P < 0.05) of cortisol from the splanchnic bed (6.1 ؎ 2.6 g/min) and net uptake (P < 0.05) by the leg (1.7 ؎ 0.7 g/min). This, along with cortisol production by other tissues (e.g., the adrenals), resulted in a total-body cortisol appearance rate of 18.1 ؎ 1.9 g/min. Fractional splanchnic D4-cortisol extraction averaged 12.9 ؎ 1.3% (P < 0.001), splanchnic cortisol uptake 14.8 ؎ 2.0 g/min (P < 0.001), and splanchnic cortisol production 22.2 ؎ 3.3 g/min (P < 0.001). On the other hand, fractional leg D4-cortisol extraction averaged 5.6 ؎ 1.8% (P < 0.02), leg cortisol uptake 2.3 ؎ 0.7 g/min (P < 0.01), and leg cortisol production 0.4 ؎ 0.4 g/min, which did not differ from zero. Because D4-cortisol loses a deuterium during conversion to [9,12,12-2 H 3 ] cortisone (D3-cortisone), which in turn generates [9,12,12 2 H 3 ] cortisol (D3-cortisol) via 11-␤ hydroxysteroid dehydrogenase (11␤-HSD) type 1, D3-cortisol production can be used as an index of 11␤-HSD type 1 activity. Net splanchnic D3-cortisol release (3.9 ؎ 0.4 g/min) and splanchnic D3-cortisol production (7.1 ؎ 0.7 g/min) occurred (P < 0.01) in all subjects. In contrast, there was minimal leg D3-cortisol production (0.04 ؎ 0.01 g/min), resulting in a strong correlation between splanchnic D3-cortisol production and total-body 3D-cortisol production in both the fasting state (r ‫؍‬ 0.84; P < 0.02) and during an infusion of insulin (r ‫؍‬ 0.97; P < 0.01). Thus, splanchnic production of cortisol occurs in nondiabetic humans at rates approximating that which occurs in the remainder of the body. These data support the possibility that alterations in splanchnic cortisol production contribute to visceral fat accumulation and the hepatic insulin resistance of obesity or type 2 diabetes.

Although large amounts of cortisol are produced within the splanchnic bed, implying high intrahepatic glucocorticoid concentrations, rates do not differ in lean and obese nondiabetic humans and are not influenced by the presence of type 2 diabetes mellitus. On the other hand, obesity but not diabetes increases splanchnic cortisol uptake.