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Background: All previous studies that investigated the association between abdominal fat distribution and insulin resistance evaluated subcutaneous and visceral fat area and/or volume, but these values were not related to the body type of each subject. In the present study we have examined the association between abdominal fat distribution and peripheral (muscle)/hepatic sensitivity to insulin using the visceral to abdominal subcutaneous fat area ratio (VF/SF ratio) in male patients with type 2 diabetes mellitus. This ratio defines the predominancy of visceral or subcutaneous abdominal adiposity, independent of the body type of each individual., Methods: Thirty-six type 2 diabetic male patients underwent a euglycemic insulin clamp (insulin infusion rate = 40 mU/m2 x min) with 3-3H-glucose to measure insulin-mediated total body (primarily reflects muscle) glucose disposal (TGD) and suppression of endogenous (primarily reflects liver) glucose production (EGP) in response to a physiologic increase in plasma insulin concentration. Abdominal subcutaneous (SF) and intraabdominal visceral fat (VF) areas were quantitated with magnetic resonance imaging (MRI) at the level of L4-5., Results: TGD and TGD divided by steady state plasma insulin concentration during the insulin clamp (TGD/SSPI) correlated inversely with body mass index (BMI), total fat mass (FM) measured by 3H2O, SF and VF areas, while VF/SF ratio displayed no significant relationship with TGD or TGD/SSPI. In contrast, EGP and the product of EGP and SSPI during the insulin clamp (an index hepatic insulin resistance) correlated positively with VF/SF ratio, but not with BMI, FM, VF or SF., Conclusion: We conclude that, independent of the individual's body type, visceral fat dominant accumulation as opposed to subcutaneous fat accumulation is associated with hepatic insulin resistance, whereas peripheral (muscle) insulin resistance is more closely related to general obesity (i.e. higher BMI and total FM, and increased abdominal SF and VF) in male patients with type 2 diabetes.

We examined insulin action/secretion and cardiovascular disease risk factors in Japanese subjects with impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT) who were not taking any medications known to affect glucose tolerance, blood pressure (BP) or plasma lipids (PLs). A total of 1,399 subjects received measurements of anthropometry, BP, PLs, and plasma glucose/insulin concentrations during 75 g-oral glucose tolerance test (OGTT). According to 2003 American Diabetes Association criteria, subjects were classified as having normal fasting glucose (NFG)/normal glucose tolerance (NGT) (n = 1,173), IFG (n = 128), IGT (n = 55), and IFG/IGT (n = 43). Insulin action was calculated using the HOMA-R (index of hepatic insulin resistance) and Matsuda index (reflects whole body insulin sensitivity). The ratio of the incremental area under the curve of insulin to that of glucose during OGTT (delta AUC(PI)/delta AUC(PG)) was used as an index of beta-cell function. HOMA-R was higher in IFG (2.3 +/- 0.1) and IFG/IGT (2.5 +/- 0.2) than in NFG/NGT (1.8 +/- 0.03). The Matsuda index was lower in IFG (6.5 +/- 0.3), IGT (5.4 +/- 0.4) and IFG/IGT (5.1 +/- 0.5) than in NFG/NGT (9.6 +/- 0.2). Delta AUC(PI)/delta AUC(PG) was lower in IGT (0.6 +/- 0.05) and IFG/IGT (0.5 +/- 0.05) than in IFG (1.4 +/- 0.12) or NFG/NGT (1.2 +/- 0.03). Mean BP was higher in IGT (100 +/- 1.7 mmHg) than in NFG/NGT (91 +/- 0.3) or IFG (95 +/- 1.1). The plasma triglyceride level was higher in IGT (155 +/- 14 mg/dL) and IGT/IFG (173 +/- 12) than in IFG (132 +/- 7) or NFG/NGT (122 +/- 2). In conclusion, 1) whole body insulin sensitivity is decreased in IFG and IGT, with a greater reduction in IGT, 2) hepatic insulin resistance and preserved beta-cell function are characteristics of IFG, and 3) higher BP and triglyceride levels are observed in IGT. IGT is more closely associated with risk factors for cardiovascular disease than is IFG.

Background and Aims: Abdominal fat accumulation (visceral/hepatic) has been associated with hepatic insulin resistance (IR) in obesity and type 2 diabetes (T2DM). We examined the relationship between visceral/hepatic fat accumulation and hepatic IR/accelerated gluconeogenesis (GNG)., Methods: In 14 normal glucose tolerant (NGT) (body mass index [BMI] = 25 +/- 1 kg/m(2)) and 43 T2DM (24 nonobese, BMI = 26 +/- 1; 19 obese, BMI = 32 +/- 1 kg/m(2)) subjects, we measured endogenous (hepatic) glucose production (3-(3)H-glucose) and GNG ((2)H(2)O) in the basal state and during 240 pmol/m(2)/min euglycemic-hyperinsulinemic clamp, and liver (LF) subcutaneous (SAT)/visceral (VAT) fat content by magnetic resonance spectroscopy/magnetic resonance imaging., Results: LF was increased in lean T2DM compared with lean NGT (18% +/- 3% vs 9% +/- 2%, P < .03), but was similar in lean T2DM and obese T2DM (18% +/- 3% vs 22% +/- 3%; P = NS). Both VAT and SAT increased progressively from lean NGT to lean T2DM to obese T2DM. T2DM had increased basal endogenous glucose production (EGP) (NGT, 15.1 +/- 0.5; lean T2DM, 16.3 +/- 0.4; obese T2DM, 17.2 +/- 0.6 micromol/min/kg(ffm); P = .02) and basal GNG flux (NGT, 8.6 +/- 0.4; lean T2DM, 9.6 +/- 0.4; obese T2DM, 11.1 +/- 0.6 micromol/min/kg(ffm); P = .02). Basal hepatic IR index (EGP x fasting plasma insulin) was increased in T2DM (NGT, 816 +/- 54; lean T2DM, 1252 +/- 164; obese T2DM, 1810 +/- 210; P = .007). In T2DM, after accounting for age, sex, and BMI, both LF and VAT, but not SAT, were correlated significantly (P < .05) with basal hepatic IR and residual EGP during insulin clamp. Basal percentage of GNG and GNG flux were correlated positively with VAT (P < .05), but not with LF. LF, but not VAT, was correlated with fasting insulin, insulin-stimulated glucose disposal, and impaired FFA suppression by insulin (all P < .05)., Conclusions: Abdominal adiposity significantly affects both lipid (FFA) and glucose metabolism. Excess VAT primarily increases GNG flux. Both VAT and LF are associated with hepatic IR.

Circulating level of adiponectin, an adipocyte-derived protein, is reduced in states of insulin resistance such as obesity and type 2 diabetes. We have previously shown that hypoadiponectinemia is related to insulin resistance in essential hypertension. Recent studies have shown that normotensive subjects with a positive family history of essential hypertension (FH+) have decreased insulin sensitivity compared to subjects with a negative family history of essential hypertension (FH-). We here examined the association between adiponectin concentration and insulin sensitivity in FH+ and FH-. Thirty young, non-obese and normotensive men without a family history of diabetes mellitus were enrolled. A total of 15 subjects were FH+, and the remaining 15 subjects were FH-. Insulin sensitivity index (ISI) was evaluated by the euglycemic hyperinsulinemic glucose clamp technique. Concentrations of adiponectin and other metabolic variables were measured. The FH+ group had significantly lower levels of ISI and adiponectin than did the FH- group. In all of the subjects, ISI was positively correlated with adiponectin concentration and high-density lipoprotein (HDL) cholesterol level and was negatively correlated with insulin level. Adiponectin concentration was the only independent determinant of ISI in a multiple regression analysis. Our results showed that adiponectin level was significantly decreased and that this was accompanied by reduced insulin sensitivity in young, nonobese and normotensive men with a family history of essential hypertension. Phenotype of reduced adiponectin level as an earlier penetrance may be especially useful in genetic analyses of insulin resistance and essential hypertension.

The effect of pioglitazone (PIO) on plasma adiponectin concentration, endogenous glucose production (EGP), and hepatic fat content (HFC) was studied in 11 type 2 diabetic patients (age, 52 +/- 2 yr; body mass index, 29.6 +/- 1.1 kg/m(2); HbA(1c), 7.8 +/- 0.4%). HFC (magnetic resonance spectroscopy) and basal plasma adiponectin concentration were quantitated before and after PIO (45 mg/d) for 16 wk. Subjects received a 3-h euglycemic insulin (100 mU/m(2).min) clamp combined with 3-[(3)H] glucose infusion to determine rates of EGP and tissue glucose disappearance (Rd) before and after PIO. PIO reduced fasting plasma glucose (10.0 +/- 0.7 to 7.2 +/- 0.6 mmol/liter, P < 0.01) and HbA(1c) (7.8 +/- 0.4 to 6.5 +/- 0.3%, P < 0.01) despite increased body weight (83.0 +/- 3.0 to 86.4 +/- 3.0 kg, P < 0.01). PIO improved Rd (6.6 +/- 0.6 vs. 5.2 +/- 0.5 mg/kg.min, P < 0.005) and reduced EGP (0.23 +/- 0.04 to 0.05 +/- 0.02 mg/kg.min, P < 0.01) during the 3-h insulin clamp. After PIO treatment, HFC decreased from 21.3 +/- 4.2 to 11.0 +/- 2.4% (P < 0.01), and plasma adiponectin increased from 7 +/- 1 to 21 +/- 2 micro g/ml (P < 0.0001). Plasma adiponectin concentration correlated negatively with HFC (r = -0.60, P < 0.05) and EGP (r = -0.80, P < 0.004) and positively with Rd before (r = 0.68, P < 0.02) pioglitazone treatment; similar correlations were observed between plasma adiponectin levels and HFC (r = -0.65, P < 0.03) and Rd after (r = 0.70, P = 0.01) pioglitazone treatment. EGP was almost completely suppressed after pioglitazone treatment; taken collectively, plasma adiponectin concentration, before and after pioglitazone treatment, still correlated negatively with EGP during the insulin clamp (r = -0.65, P < 0.001). In conclusion, PIO treatment in type 2 diabetes causes a 3-fold increase in plasma adiponectin concentration. The increase in plasma adiponectin is strongly associated with a decrease in hepatic fat content and improvements in hepatic and peripheral insulin sensitivity. The increase in plasma adiponectin concentration after thiazolidinedione therapy may play an important role in reversing the abnormality in hepatic fat mobilization and the hepatic/muscle insulin resistance in patients with type 2 diabetes.

Type 2 diabetes mellitus (DM) is characterized by insulin resistance and pancreatic beta cell dysfunction. In high-risk subjects, the earliest detectable abnormality is insulin resistance in skeletal muscle. Impaired insulin-mediated signaling, gene expression, glycogen synthesis, and accumulation of intramyocellular triglycerides have all been linked with insulin resistance, but no specific defect responsible for insulin resistance and DM has been identified in humans. To identify genes potentially important in the pathogenesis of DM, we analyzed gene expression in skeletal muscle from healthy metabolically characterized nondiabetic (family history negative and positive for DM) and diabetic Mexican-American subjects. We demonstrate that insulin resistance and DM associate with reduced expression of multiple nuclear respiratory factor-1 (NRF-1)-dependent genes encoding key enzymes in oxidative metabolism and mitochondrial function. Although NRF-1 expression is decreased only in diabetic subjects, expression of both PPAR gamma coactivator 1-alpha and-beta (PGC1-alpha/PPARGC1 and PGC1-beta/PERC), coactivators of NRF-1 and PPAR gamma-dependent transcription, is decreased in both diabetic subjects and family history-positive nondiabetic subjects. Decreased PGC1 expression may be responsible for decreased expression of NRF-dependent genes, leading to the metabolic disturbances characteristic of insulin resistance and DM.

Both ethnicity and familial diabetes (FHD) confer risk for type 2 diabetes [diabetes mellitus (DM)], but their relative influence has not been established. To analyze the separate impact of ethnicity, Mexican-American vs. Caucasian, and FHD on the physiological determinants of glucose tolerance, we measured insulin sensitivity of glucose uptake (IS(GU)) (by the clamp technique), endogenous glucose production (by 3-[(3)H]glucose infusion), and insulin secretory response (to oral glucose) in 172 Mexican-Americans and 60 Caucasians with normal glucose tolerance (NGT) or DM. IS(GU) was markedly reduced in diabetics vs. NGT (3.9 +/- 0.2 vs. 8.4 +/- 0.5 ml.min(-1).kg(ffm)(-1), P < 0.0001), and lower in Mexican-Americans than in Caucasians (5.3 +/- 0.3 vs. 7.3 +/- 0.7 ml.min(-1).kg(ffm)(-1), P < 0.003; ffm, fat-free mass). In a multivariate analysis including both ethnicity and FHD (and adjusting for body mass index, age, and diabetes), ethnicity was still a significant (P = 0.02) independent correlate of IS(GU). Insulin resistance of glucose production was increased in diabetics (14 +/- 1 mmol.min(-1).[ micro U/ml], P < 0.0001 vs. 9 +/- 1 of NGT), whereas the 30' insulin/glucose ratio was decreased (16 +/- 1 micro U/mg, P < 0.0001 vs. 60 +/- 5). In multivariate models, neither ethnicity nor FHD were significant independent correlates of glucose production and early insulin response. We conclude that the primary physiological target of the propensity to diabetes of Mexican-Americans is insulin resistance of glucose uptake.

We examined the relationship between peripheral/hepatic insulin sensitivity and abdominal superficial/deep subcutaneous fat (SSF/DSF) and intra-abdominal visceral fat (VF) in patients with type 2 diabetes mellitus (T2DM). Sixty-two T2DM patients (36 males and 26 females, age = 55 +/- 3 yr, body mass index = 30 +/- 1 kg/m2) underwent a two-step euglycemic insulin clamp (40 and 160 mU. m(-2). min(-1)) with [3-3H]glucose. SSF, DSF, and VF areas were quantitated with magnetic resonance imaging at the L(4-5) level. Basal endogenous glucose production (EGP), hepatic insulin resistance index (basal EGP x FPI), and total glucose disposal (TGD) during the first and second insulin clamp steps were similar in male and female subjects. VF (159 +/- 9 vs. 143 +/- 9 cm2) and DSF (199 +/- 14 vs. 200 +/- 15 cm(2)) were not different in male and female subjects. SSF (104 +/- 8 vs. 223 +/- 15 cm2) was greater (P < 0.0001) in female vs. male subjects despite similar body mass index (31 +/- 1 vs. 30 +/- 1 kg/m2) and total body fat mass (31 +/- 2 vs. 33 +/- 2 kg). In male T2DM, TGD during the first insulin clamp step (1st TGD) correlated inversely with VF (r = -0.45, P < 0.01), DSF (r = -0.46, P < 0.01), and SSF (r = -0.39, P < 0.05). In males, VF (r = 0.37, P < 0.05), DSF (r = 0.49, P < 0.01), and SSF (r = 0.33, P < 0.05) were correlated positively with hepatic insulin resistance. In females, the first TGD (r = -0.45, P < 0.05) and hepatic insulin resistance (r = 0.49, P < 0.05) correlated with VF but not with DSF, SSF, or total subcutaneous fat area. We conclude that visceral adiposity is associated with both peripheral and hepatic insulin resistance, independent of gender, in T2DM. In male but not female T2DM, deep subcutaneous adipose tissue also is associated with peripheral and hepatic insulin resistance.

Visceral fat (VF) excess has been associated with decreased peripheral insulin sensitivity and has been suggested to contribute to hepatic insulin resistance. However, the mechanisms by which VF impacts on hepatic glucose metabolism and the quantitative role of VF in glycemic control have not been investigated. In the present study 63 type 2 diabetic subjects (age, 55 +/- 1 yr; fasting plasma glucose, 5.5-14.4 mmol/liter; hemoglobin A(1c), 6.1-11.7%) underwent measurement of 1) fat-free mass ((3)H(2)O technique), 2) sc and visceral abdominal fat area (magnetic resonance imaging), 3) insulin sensitivity (euglycemic insulin clamp), 4) endogenous glucose output ([(3)H]glucose infusion technique), and 5) gluconeogenesis ((2)H(2)O method). After adjustment for sex, age, body mass index, diabetes duration, ethnicity, and sc fat area, VF area was positively related to fasting hyperglycemia (partial r = 0.46; P = 0.001) as well as to hemoglobin A(1c) (partial r = 0.50; P = 0.0003). Insulin sensitivity was reciprocally related to VF independently of body mass index (partial r = 0.33; P = 0.01). In contrast, the relation of basal endogenous glucose output to VF was not statistically significant. This lack of association was explained by the fact that VF was positively associated with gluconeogenesis flux (confounder-adjusted, partial r = 0.45; P = 0.003), but was reciprocally associated with glycogenolysis (partial r = 0.31; P < 0.05). We conclude that in patients with established type 2 diabetes, VF accumulation has a significant negative impact on glycemic control through a decrease in peripheral insulin sensitivity and an enhancement of gluconeogenesis.

We examined the effect of pioglitazone on abdominal fat distribution to elucidate the mechanisms via which pioglitazone improves insulin resistance in patients with type 2 diabetes mellitus. Thirteen type 2 diabetic patients (nine men and four women; age, 52 +/- 3 yr; body mass index, 29.0 +/- 1.1 kg/m(2)), who were being treated with a stable dose of sulfonylurea (n = 7) or with diet alone (n = 6), received pioglitazone (45 mg/d) for 16 wk. Before and after pioglitazone treatment, subjects underwent a 75-g oral glucose tolerance test (OGTT) and two-step euglycemic insulin clamp (insulin infusion rates, 40 and 160 mU/m(2).min) with [(3)H]glucose. Abdominal fat distribution was evaluated using magnetic resonance imaging at L4-5. After 16 wk of pioglitazone treatment, fasting plasma glucose (179 +/- 10 to 140 +/- 10 mg/dl; P < 0.01), mean plasma glucose during OGTT (295 +/- 13 to 233 +/- 14 mg/dl; P < 0.01), and hemoglobin A(1c) (8.6 +/- 0.4% to 7.2 +/- 0.5%; P < 0.01) decreased without a change in fasting or post-OGTT insulin levels. Fasting plasma FFA (674 +/- 38 to 569 +/- 31 microEq/liter; P < 0.05) and mean plasma FFA (539 +/- 20 to 396 +/- 29 microEq/liter; P < 0.01) during OGTT decreased after pioglitazone. In the postabsorptive state, hepatic insulin resistance [basal endogenous glucose production (EGP) x basal plasma insulin concentration] decreased from 41 +/- 7 to 25 +/- 3 mg/kg fat-free mass (FFM).min x microU/ml; P < 0.05) and suppression of EGP during the first insulin clamp step (1.1 +/- 0.1 to 0.6 +/- 0.2 mg/kg FFM.min; P < 0.05) improved after pioglitazone treatment. The total body glucose MCR during the first and second insulin clamp steps increased after pioglitazone treatment [first MCR, 3.5 +/- 0.5 to 4.4 +/- 0.4 ml/kg FFM.min (P < 0.05); second MCR, 8.7 +/- 1.0 to 11.3 +/- 1.1 ml/kg FFM(.)min (P < 0.01)]. The improvement in hepatic and peripheral tissue insulin sensitivity occurred despite increases in body weight (82 +/- 4 to 85 +/- 4 kg; P < 0.05) and fat mass (27 +/- 2 to 30 +/- 3 kg; P < 0.05). After pioglitazone treatment, sc fat area at L4-5 (301 +/- 44 to 342 +/- 44 cm(2); P < 0.01) increased, whereas visceral fat area at L4-5 (144 +/- 13 to 131 +/- 16 cm(2); P < 0.05) and the ratio of visceral to sc fat (0.59 +/- 0.08 to 0.44 +/- 0.06; P < 0.01) decreased. In the postabsorptive state hepatic insulin resistance (basal EGP x basal immunoreactive insulin) correlated positively with visceral fat area (r = 0.55; P < 0.01). The glucose MCRs during the first (r = -0.45; P < 0.05) and second (r = -0.44; P < 0.05) insulin clamp steps were negatively correlated with the visceral fat area. These results demonstrate that a shift of fat distribution from visceral to sc adipose depots after pioglitazone treatment is associated with improvements in hepatic and peripheral tissue sensitivity to insulin.

Abstract: AMP-activated protein kinase (AMPK) mediates metabolic responses of muscle to exercise and is involved in improvement of insulin resistance by endurance exercise. Recent studies have suggested that the renin-angiotensin system (RAS) might negatively modulate insulin-mediated actions, but there has been little investigation of the correlation between RAS and AMPK. To determine the correlations between insulin resistance, the RAS, and AMPK, we performed glucose clamp studies using both insulin and 5-aminoimidazole-4-carboxamide 1-beta-D-ribofuranoside (AICAR) to investigate the effects of various hypotonics on insulin and AMPK sensitivities. Six-week-old male Sprague-Dawley rats were divided into two groups: those fed a standard chow (SD) and those fed a fructose-rich chow (fructose-fed rats [FFRs]) for 6 weeks. FFRs were treated either with a vehicle or with valsartan or hydralazine for the last 2 weeks. We also performed Western blotting for AMPK, phospho-AMPK, and stimulating glucose transporter (GLUT)-4 proteins in each group. The glucose infusion rate for insulin (GIRI) was significantly lower in FFRs (10.5 ± 1.8 mg/kg/min) than in SD (15.5 ± 0.4 mg/kg/min), and GIRI was improved by valsartan (13.0 ± 1.0 mg/kg/min) but not by hydralazine (8.3 ± 1.6 mg/kg/min). The glucose infusion rate for AICAR (GIRA) in FFRs (11.1 ± 2.2 mg/kg/min) was significantly lower than that in SD (15.5 ± 2.8 mg/kg/min), and GIRA was improved by valsartan (17.5 ± 3.1 mg/kg/min) but not by hydralazine in FFRs (11.8 ± 1.5 mg/kg/min). Serum triglyceride level was significantly higher in FFRs; however, no difference was observed in serum triglyceride level after AICAR infusion among the groups. The amounts of AMPKα protein and the amounts of phospho-AMPK protein in the soleus muscle in basal conditions were not different among SD, FFRs, and FFRs treated with valsartan. There was no difference in the levels of phosphorylation of AMPK in the soleus muscle by AICAR among these three groups. No difference was observed in acetyl-CoA carboxylase (ACC) protein or phospho-ACC in both the basal condition and after AICAR infusion between SD and FFRs. Treatment with valsartan significantly increased GLUT-4 content of the soleus muscle compared with that in FFRs. These results suggest that the RAS has a significant role in the AMPK system and that impairment of response to AICAR in FFRs could be downstream of AMPK or ACC phosphorylation. [Copyright &y& Elsevier]

Abstract: Adenosine monophosphate-activated protein kinase (AMPK) mediates metabolic responses of muscle to exercise and is involved in improvement of insulin resistance by endurance exercise. Recent studies have suggested that the renin-angiotensin system might negatively modulate insulin-mediated actions, but there has been little investigation of the correlation between the renin-angiotensin system and AMPK. To determine this correlation, we performed studies with glucose clamp in vivo, and glucose uptake by skeletal muscle ex vivo using 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR). Six-week-old male Sprague-Dawley rats were fed standard chow (standard-diet rats; SD) or fructose-rich chow (fructose-fed rats; FFR) for 6 weeks. At the age of 12 weeks, SD and FFR were treated by oral gavage, either with angiotensin II (Ang II) receptor blockade (ARB; valsartan 30 mg/kg) or vehicle. Thirty minutes after the treatment, we performed glucose clamp studies to measure glucose infusion rates during infusion of insulin (GIRI) and of AICAR (GIRA), which stimulates AMPK, and studied the effect of ARB on either GIRI or GIRA. In an ex vivo study, we used bilateral fresh soleus muscles from 3-week-old male Sprague-Dawley rats to examine the glucose uptake (measured by 3H-2-deoxyglucose uptake) of one side of soleus muscle incubated with AICAR with or without Ang II, or with tumor necrosis factor-α, in comparison with that of the other (untreated control) side of the muscle. Blood pressure of FFR was significantly higher than that of SD rats. GIRI was significantly lower in FFR than in SD, and treatment with ARB did not change GIRI. GIRA of FFR was significantly lower than that of SD, but GIRA of FFR treated with ARB was significantly increased compared with that of FFR treated with vehicle. In the ex vivo study, incubation with AICAR significantly increased glucose uptake of soleus muscles, Ang II significantly decreased AICAR-activated glucose uptake in a dose-dependent manner, and ARB canceled the effect of Ang II. The results suggest that acute inhibition of the angiotensin 1 receptor improves glucose metabolism via not insulin but AMPK pathway through the angiotensin 1 receptor in FFR. [Copyright &y& Elsevier]

The aim of this cross-sectional study was to examine insulin action and secretion, plasma lipids and BP in subjects with IFG and/or IGT in 1399 Japanese subjects (age=58.8±0.3 yrs; M/F=637/762) who were not taking any medications known to affect glucose tolerance, BP or plasma lipids. All subjects received measurements of anthropometry, BP, plasma lipids and plasma glucose and insulin levels during 75g-OGTT. According to 2003 ADA criteria, subjects were classified as NFG/NGT (N) (FlaG< 100mg/dl and 2-h PG< 140mg/dl, n=1173), IFG (FPG=100-125 and 2-h PG<140, n=128), IGT (FPG<100 and 2-h PG=140-199, n=55), and IFG/IGT (FPG = 100-125 and 2-h PG= 140-199, n=43). Insulin action was calculated from OGTT using HOMA-IR and Matsuda index (10,000/ [(FPGxFPI)x(meanPGxmeanPI)][sup ½]). The ratio of the incremental area under the curve (AUC) of insulin to the incremental AUC of glucose during OGTT (ΔI/ΔG) was used to evaluate β-cell function. Age and BMI were similar in all 4 groups. HOMA-IR (an index of hepatic insulin resistance) was higher in IFG (2.3±0.1) and IFG/IGT (2.5±0.2) compared with N (1.8±0.03) (p<0.01). Matsuda index (an index of whole body insulin sensitivity) was lower in IFG (6.5±0.3), IGT (5.4±-0.4) and IFG/IGT (5.1±0.5) compared with N (9.6±0.2) (p<0.01). ΔI/δG was lower in IGT (0.6±0.05) and IFG/IGT (0.5±0.05) compared with IFG (1.4±0.12) or N (1.2±0.03) (p<0.01). Mean BP was higher in IGT (100±1.7mmHg) versus N (91±0.3) and IFG (95±1.1) (p<0.05). Plasma triglyceride (TG) level was higher in IGT (155±14mg/dl) and IFG/IGT (173±12) versus N (122±2) (p<0.05), although total/HDL/LDL cholesterol levels were similar in the groups. These results indicate: (i) whole body insulin sensitivity is decreased in IFG and IGT, with a greater reduction in IGT, (ii) hepatic insulin resistance and preserved β-cell function are characteristics of IFG, (iii) higher levels of BP and TG are observed in IGT. Conclusion: Postprandial hyperglycemia, due to the impairments of whole body insulin sensitivity and β-cell function, is closely related to risk factors for the development of macrovascular disease. [ABSTRACT FROM AUTHOR]