. Plasma glucose concentrations decreased by ~10% (P < 0.01), whereas plasma insulin increased by ~47% (P = 0.02) after 9 h of lipid infusion. EGP declined from 9.3 ± 0.5 (lipid) and 9.0 ± 0.8 µmol · kg -1 · min -1 (glycerol) to 8.4 ± 0.5 and 8.2 ± 0.7 µmol · kg -1 · min -1 , respectively (P < 0.01). Contribution of GNG similarly rose (P < 0.01) from 46 ± 4 and 52 ± 3% to 65 ± 8 and 78 ± 7%. To exclude interaction of FFAs with insulin secretion, the study was repeated at fasting plasma insulin (~35 pmol/l) and glucagon (~90 ng/ml) concentrations using somatostatin-insulin-glucagon clamps. Plasma glucose increased by ~50% (P < 0.005) during lipid but decreased by ~12% during glycerol infusion (P < 0.005). EGP remained unchanged over the 9-h period (9.9 ± 1.2 vs. 9.0 ± 1.1 µmol · kg -1 · min -1 ). GNG accounted for 62 ± 5 (lipid) and 60 ± 6% (glycerol) of EGP at time 0 and rose to 74 ± 3% during lipid infusion only (P < 0.05 vs. glycerol: 64 ± 4%). In conclusion, high plasma FFA concentrations increase the percent contribution of GNG to EGP and may contribute to increased rates of GNG in patients with type 2 diabetes. Diabetes 49:701-707, 2000 E levation of plasma free fatty acid (FFA) concentrations is often associated with obesity (1) and type 2 diabetes (2). The close correlation between whole-body glucose uptake and fasting plasma FFA concentrations in lean normoglycemic offspring of type 2 diabetic parents (3) indicates that FFAs might play a pivotal role in the early events leading to insulin resistance (4,5).Plasma FFA elevation induced by lipid/heparin infusions during hyperinsulinemic clamps has repeatedly been shown to decrease insulin-dependent whole-body glucose disposal (5-8). Reports on a correlation between plasma FFAs and hepatic insulin sensitivity are more controversial. Fasting plasma FFAs correlate with the magnitude of hyperglycemia and endogenous glucose production (EGP) (9), which has been attributed to increased lipid oxidation in type 2 diabetes (10). Under hyperinsulinemic conditions, lipid/heparin infusion either increased (6,11) or had no effect on (12-14) EGP. At postabsorptive plasma insulin concentrations, plasma FFA elevation caused marked increases in EGP during somatostatin-insulin clamps (12,15), but not after an overnight fast (15,16). Similarly, inhibition of lipolysis by nicotinic acid or its derivative, acipimox, decreased basal EGP in some (17,18) but not other (19,20) studies. These apparent discrepancies could result from FFA-induced insulin secretion counterbalancing the stimulatory effect of FFAs on EGP (15) or from hepatic autoregulation preventing an increase in EGP under conditions that might favor hepatic gluconeogenesis (GNG) (16). Of note, increased GNG was documented in type 2 diabetes from a variety of precursors (21,22), whereas contradictory effects of FFAs on the contribution of GNG to EGP have been reported during lipid/ heparin infusion or acipimox studies (16,18,20,23).In most studies, glycerol was not infused during control experiments to match the lipid-i...

Insulin resistance is frequently associated with increased lipid content in muscle and liver. Insulin excess stimulates tissue lipid accumulation. To examine the effects of insulin and improved glycemia on insulin sensitivity and intracellular lipids, we performed stepped (1, 2, and 4 mU ⅐ min ؊1 ⅐ kg ؊1 ) hyperinsulinemiceuglycemic clamps in eight type 2 diabetic and six nondiabetic control subjects at baseline and after 12 and 67 h of insulin-mediated near-normoglycemia (118 ؎ 7 mg/dl). Intrahepatocellular lipids (IHCLs) and intramyocellular lipids (IMCLs) of soleus (IMCL-S) and tibialis anterior muscle (IMCL-TA) were measured with 1 H nuclear magnetic resonance spectroscopy. At baseline, nondiabetic subjects had an approximate twofold higher insulin sensitivity (P < 0.02) and lower IHCLs than diabetic patients (5.8 ؎ 1.2 vs. 18.3 ؎ 4.2%, P < 0.03), in whom IMCL-TA negatively correlated with insulin sensitivity (r ‫؍‬ ؊0.969, P < 0.001). After a 67-h insulin infusion in diabetic patients, IMCL-S and IHCLs were increased (P < 0.05) by ϳ36 and ϳ18%, respectively, and correlated positively with insulin sensitivity (IMCL-S: r ‫؍‬ 0.982, P < 0.0005; IHCL: r ‫؍‬ 0.865, P < 0.03), whereas fasting glucose production, measured with D-[6,6-2 H 2 ]glucose, decreased by ϳ10% (P < 0.04). In conclusion, these results indicate that IMCLs relate to insulin resistance in type 2 diabetic patients at baseline and that insulin-mediated near-normoglycemia for ϳ3 days reduces fasting glucose production but stimulates lipid accumulation in liver and muscle without affecting insulin sensitivity. Diabetes 51:3025-3032, 2002

The initial effects of free fatty acids (FFAs) on glucose transport/phosphorylation were studied in seven healthy men in the presence of elevated (1.44 +/- 0.16 mmol/l), basal (0.35 +/- 0.06 mmol/l), and low (<0.01 mmol/l; control) plasma FFA concentrations (P < 0.05 between all groups) during euglycemic-hyperinsulinemic clamps. Concentrations of glucose-6-phosphate (G-6-P), inorganic phosphate (Pi), phosphocreatine, ADP, and pH in calf muscle were measured every 3.2 min for 180 min by using 31P nuclear magnetic resonance spectroscopy. Rates of whole-body glucose uptake increased similarly until 140 min but thereafter declined by approximately 20% in the presence of basal and high FFAs (42.8 +/- 3.6 and 41.6 +/- 3.3 vs. control: 52.7 +/- 3.3 micromol x kg(-1) x min(-1), P < 0.05). The rise of intramuscular G-6-P concentrations was already blunted at 45 min of high FFA exposure (184 +/- 17 vs. control: 238 +/- 17 micromol/l, P = 0.008). At 180 min, G-6-P was lower in the presence of both high and basal FFAs (197 +/- 21 and 213 +/- 18 vs. control: 286 +/- 19 micromol/l, P < 0.05). Intramuscular pH decreased by -0.013 +/- 0.001 (P < 0.005) during control but increased by +0.008 +/- 0.002 (P < 0.05) during high FFA exposure, while Pi rose by approximately 0.39 mmol/l (P < 0.005) within 70 min and then slowly decreased in all studies. In conclusion, the lack of an initial peak and the early decline of muscle G-6-P concentrations suggest that even at physiological concentrations, FFAs primarily inhibit glucose transport/phosphorylation, preceding the reduction of whole-body glucose disposal by up to 120 min in humans.

Women with previous gestational diabetes (pGDM) are frequently insulin-resistant, which could relate to intramyocellular lipid content (IMCL). IMCL were measured with 1 H nuclear magnetic resonance spectroscopy in soleus (IMCL-S) and tibialis-anterior muscles (IMCL-T) of 39 pGDM (32 ؎ 2 years, waist-to-hip ratio 0.81 ؎ 0.01) and 22 women with normal glucose tolerance (NGT; 31 ؎ 1 years, 0.76 ؎ 0.02) at 4 -6 months after delivery. Body fat mass (BFM) was assessed from bioimpedance analysis, insulin sensitivity index (S I ), and glucose effectiveness (S G ) from insulin-modified frequently sampled glucose tolerance tests. pGDM exhibited 45% increased BFM, 35% reduced S I and S G (P < 0.05), and 40% (P < 0.05) and 55% (P < 0.005) higher IMCL-S and IMCL-T, respectively. IMCL related to body fat (BFM P < 0.005, leptin P < 0.03), but only IMCL-T correlated (P < 0.03) with S I and glucose tolerance index independent of BMI. Insulin-resistant pGDM (n ‫؍‬ 17) had higher IMCL-S (؉66%) and IMCL-T (؉86%) than NGT and insulin-sensitive pGDM (؉28%). IMCL were also higher (P < 0.005, P ‫؍‬ 0.05) in insulinsensitive pGDM requiring insulin treatment during pregnancy and inversely related to the gestational week of GDM diagnosis. Thus, IMCL-T reflects insulin sensitivity, whereas IMCL-S relates to obesity. IMCL could serve as an additional parameter of increased diabetes risk because it identifies insulin-resistant pGDM and those who were diagnosed earlier and/or required insulin during pregnancy. Diabetes 52:244 -251, 2003

Fetuin-A is markedly increased in patients with MO. The reduction of Fetuin-A after weight loss could play an important role in the beneficial effects of gastric bypass surgery.