The effect of insulin on net lipid oxidation predicts worsening of insulin resistance and development of type 2 diabetes mellitus

Suppression of lipid oxidation (L(ox)) by insulin is impaired in obesity and type 2 diabetes mellitus (T2DM). Here we tested whether high L(ox) represents a primary or acquired characteristic in the pathogenesis of T2DM. Hood-indirect calorimetry was performed under postabsorptive conditions and during a two-step hyperinsulinemic euglycemic clamp (insulin infusion rates in mU.m(-2).min(-1): 40 low and 400 high) in 465 Pima Indians: 317 with normal glucose tolerance (NGT), 117 with impaired glucose tolerance (IGT), and 31 with T2DM. The predictive effect of net lipid oxidation (L(ox)) on development of T2DM was assessed in 296 subjects (51 of whom developed T2DM), whereas the predictive effect of L(ox) on followup changes in insulin-mediated glucose disposal (M) and acute insulin response (AIR) was studied in 190 subjects with NGT at baseline. Cross-sectionally, after adjustment for age, sex, body fat (BF), and M low, L(ox) low was increased in T2DM compared with NGT and IGT subjects (P < 0.05). Prospectively, after adjustment for followup duration, age, sex, BF, M, and AIR, increased clamp L(ox) predicted T2DM [hazard rate ratios (95% CI): L(ox) low, 1.5 (1.1, 2.0), P < 0.01; L(ox) high, 1.3 (1.0, 1.8), P = 0.05]. High L(ox) low at baseline was also associated with subsequent worsening of M low (P = 0.04). These data indicate that the inability of insulin to suppress L(ox) may represent an early risk marker for insulin resistance and T2DM that is independent of adiposity, acute insulin secretion, and insulin action on glucose uptake.     

Familiality of physical and metabolic characteristics that predict the development of non-insulin-dependent diabetes mellitus in Pima Indians.

Susceptibility to non-insulin-dependent diabetes mellitus (NIDDM) is largely genetically determined. In Pima Indians, obesity, insulin resistance, and a low acute insulin response (AIR) to an intravenous glucose infusion are each predictors of the disease. To ascertain whether these phenotypes are genetically determined, we estimated their familiality in nondiabetic Pima Indians with a maximum-likelihood method. Percentage body fat (PFAT) was highly familial (h2 =.76), whereas waist/ thigh circumference ratio (W/T ratio) was not significantly familial after controlling for PFAT (h2 = .16). AIR was also highly familial (h2 = .80 at 10 min), even after controlling for PFAT and insulin action (h2 = .70). Insulin action at physiologic plasma insulin concentrations was familial (h2 = .61) but less so after controlling for PFAT and W/T ratio (h2 = .38). At maximally stimulating insulin concentrations, insulin action was familial (h2 = .45) and was less influenced by controlling for PFAT and W/T ratio (h2 = .49). We conclude that in Pima Indians (1) PFAT and AIR are highly familial traits, (2) central distribution of fat is not a familial trait when controlled for PFAT, (3) 38%-49% of the variance in insulin action, independent of the effect of obesity, is familial, and (4) PFAT, AIR, and insulin action are useful traits to study genetic susceptibility to NIDDM. Because genetic parameter estimates are applicable only to the populations from which they were estimated, it is important to determine whether these estimates of familialities in Pima Indians can be confirmed in other populations before the utility of these traits in searching for NIDDM susceptibility genes in those populations can be fully advocated.     

The relationship between fasting hyperglycemia and insulin secretion in subjects with normal or impaired glucose tolerance

To assess the relationship between the fasting plasma glucose (FPG) concentration and insulin secretion in normal glucose tolerance (NGT) and impaired glucose tolerance (IGT) subjects, 531 nondiabetic subjects with NGT (n = 293) and IGT (n = 238; 310 Japanese and 232 Mexican Americans) received an oral glucose tolerance test (OGTT) with measurement of plasma glucose, insulin, and C-peptide every 30 min. The insulin secretion rate was determined by plasma C-peptide deconvolution. Insulin sensitivity (Matsuda index) was measured from plasma insulin and glucose concentrations. The insulin secretion/insulin resistance (IS/IR) or disposition index was calculated as DeltaISR/DeltaG / IR. As FPG increased in NGT subjects, the IS/IR index declined exponentially over the range of FPG from 70 to 125 mg/dl. The relationship between the IS/IR index and FPG was best fit with the equation: 28.8 exp(-0.036 FPG). For every 28 mg/dl increase in FPG, the IS/IR index declined by 63%. A similar relationship between IS/IR index and FPG was observed in IGT. However, the decay constant was lower than in NGT. The IS/IR index for early-phase insulin secretion (0-30 min) was correlated with the increase in FPG in both NGT and IGT (r = -0.43, P < 0.0001 and r = -0.20, P = 0.001, respectively). However, the correlation between late-phase insulin secretion (60-120 min) and FPG was not significant. In conclusion, small increments in FPG, within the "normal" range, are associated with a marked decline in glucose-stimulated insulin secretion and the decrease in insulin secretion with increasing FPG is greater in subjects with NGT than IGT and primarily is due to a decline in early-phase insulin secretion.     

Effects of an Ala54Thr polymorphism in the intestinal fatty acid-binding protein on responses to dietary fat in humans

A polymorphism in FABP2 that results in an alanine-to-threonine substitution at amino acid 54 of the intestinal fatty acid-binding protein (IFABP) is associated with insulin resistance in Pima Indians. In vitro, the threonine form (Thr54) has a higher binding affinity for long-chain fatty acids than does the alanine form (Ala54). We tested whether this polymorphism affected metabolic responses to dietary fat, in vivo. Eighteen healthy Pima Indians, half homozygous for the Thr54 form of IFABP and half homozygous for the Ala54 form, were studied. The groups were matched for sex, age, and body mass index. Plasma triglyceride, nonesterified fatty acid (NEFA), glucose, and insulin responses were measured after a mixed meal (35% of daily energy requirements, 50 g of fat) and after a high fat challenge (1362 kcal, 129 g of fat). NEFA concentrations were approximately 15% higher after the mixed meal and peaked earlier and were approximately 20% higher at 7 h in response to the high fat test meal in Thr54 homozygotes compared with Ala54 homozygotes. Insulin responses to the test meals tended to be higher in Thr54 homozygotes, but glucose and triglyceride responses were not different.The results of this study suggest that the Thr54 form of IFABP is associated with higher and prolonged NEFA responses to dietary fat in vivo. Higher NEFA concentrations may contribute to insulin resistance and hyperinsulinemia in individuals with this allele.     

Circulating Interleukin‐6 in Relation to Adiposity,Insulin Action,and Insulin Secretion

Objective: Plasma concentrations of interleukin‐6 (IL‐6), a proinflammatory cytokine produced and released in part by adipose tissue, are elevated in people with obesity and type 2 diabetes. Because recent studies suggest that markers of inflammation predict the development of type 2 diabetes, we examined whether circulating plasma IL‐6 concentrations were related to direct measures of insulin resistance and insulin secretory dysfunction in Pima Indians, a population with high rates of obesity and type 2 diabetes. Research Methods and Procedures: Fasting plasma IL‐6 concentrations (enzyme‐linked immunosorbent assay), body composition (DXA), insulin action (M; hyperinsulinemic euglycemic clamp), and acute insulin secretory responses to glucose (25 g intravenous glucose tolerance test) were measured in 58 Pima Indians without diabetes (24 women, 34 men). Results: Fasting plasma IL‐6 concentrations were positively correlated with percentage of body fat (r = 0.26, p = 0.049) and negatively correlated with M (r = ?0.28, p = 0.031), but were not related to acute insulin response (r = 0.13, p = 0.339). After adjusting for percentage of body fat, plasma IL‐6 was not related to M (partial r = ?0.23, p = 0.089). Discussion: Fasting plasma IL‐6 concentrations are positively related to adiposity and negatively related to insulin action in Pima Indians. The relationship between IL‐6 and insulin action seems to be mediated through adiposity.     

Effect of Glucose Tolerance Status on PAI‐1 Plasma Levels in Overweight and Obese Subjects

Objective: The aim of our study was to examine whether plasminogen activator inhibitor‐1 (PAI‐1) plasma levels varied as a function of differences in glucose tolerance status independently of body fatness, body‐fat distribution, and insulin sensitivity. Research Methods and Procedures: Plasma PAI‐1 antigen levels, along with insulin resistance [measured by homeostatic model assessment (HOMA_IR)], central fat accumulation, body composition, blood pressure, and fasting concentrations of glucose, insulin, and lipids, were measured in 229 overweight and obese [body mass index (BMI) ≥25 kg/m²) subjects with normal glucose tolerance (NGT) and in 44 age‐ and BMI‐matched subjects with impaired glucose tolerance (IGT). Results: Plasma PAI‐1 antigen levels were significantly higher in IGT than in NGT subjects. Log PAI‐1 was positively correlated with BMI, HOMA_IR, and log insulin, and inversely associated with high‐density lipoprotein‐cholesterol both in IGT and in NGT individuals. On the other hand, log PAI‐1 was positively correlated with waist circumference, fat mass (FM), fat‐free mass, systolic and diastolic blood pressure, and log triglycerides only in the NGT group. After multivariate analyses, the strongest determinants of PAI‐1 levels were BMI, FM, waist circumference, and high‐density lipoprotein cholesterol in the NGT group and only HOMA_IR in the IGT cohort. Discussion: This study demonstrates that PAI‐1 concentrations are higher in IGT than in NGT subjects. Furthermore, we suggest that the influences of total adiposity, central fat, and insulin resistance, main determinants of PAI‐1 concentrations, are different according to the degree of glucose tolerance.     

Decreased Insulin Clearance in Individuals with Elevated 1-h Post-Load Plasma Glucose Levels

Reduced insulin clearance has been shown to predict the development of type 2 diabetes. Recently, it has been suggested that plasma glucose concentrations ≥8.6 mmol/l (155 mg/dl) at 1 h during an oral glucose tolerance test (OGTT) can identify individuals at high risk for type 2 diabetes among those who have normal glucose tolerance (NGT 1 h-high). The aim of this study was to examine whether NGT 1 h-high have a decrease in insulin clearance, as compared with NGT individuals with 1-h post-load glucose <8.6 mmol/l (l (155 mg/dl, NGT 1 h-low). To this end, 438 non-diabetic White individuals were subjected to OGTT and euglycemic-hyperinsulinemic clamp to evaluate insulin clearance and insulin sensitivity. As compared with NGT 1 h-low individuals, NGT 1 h-high had significantly higher 1-h and 2-h post-load plasma glucose and 2-h insulin levels as well as higher fasting glucose and insulin levels. NGT 1 h-high exhibited also a significant decrease in both insulin sensitivity (P<0.0001) and insulin clearance (P = 0.006) after adjusting for age, gender, adiposity measures, and insulin sensitivity. The differences in insulin clearance remained significant after adjustment for fasting glucose (P = 0.02) in addition to gender, age, and BMI. In univariate analyses adjusted for gender and age, insulin clearance was inversely correlated with body weight, body mass index, waist, fat mass, 1-h and 2-h post-load glucose levels, fasting, 1-h and 2-h post-load insulin levels, and insulin-stimulated glucose disposal. In conclusion, our data show that NGT 1 h-high have a reduction in insulin clearance as compared with NGT 1 h-low individuals; this suggests that impaired insulin clearance may contribute to sustained fasting and post-meal hyperinsulinemia.     

糖尿病不同发展阶段胰岛功能的变化趋势*

目的:研究糖尿病不同发展阶段胰岛素敏感性及胰岛素分泌功能的改变,指导2型糖尿病的早期诊断。方法:57例行OGTT体检者,分为NGT、IGT、IFG+IGT、新诊断T2DM四组,并行IVGTT,采用HOMA-IR评估胰岛素敏感性,采用葡萄糖处置指数[DI1=HOMA-β/HOMA-IR,DI2=ΔI30/ΔG30/HOMA-IR,DI3=MBCI×IAI,DI4=AIR0-10/HOMA-IR]及AUCINS/HOMA-IR评估胰岛素分泌功能。结果:IGT、IFG+IGT、新诊断T2DM组HOMA-IR无统计学差异(P>0.05),均显著高于NGT组(P<0.05)。IGT、IFG+IGT、新诊断T2DM组DI1逐步降低(P<0.05);NGT、IGT组DI1无统计学差异(P>0.05)。NGT、IGT、IFG+IGT、新诊断T2DM组DI2、DI3、DI4逐步降低(P<0.05)。IFG+IGT、新诊断T2DM组OGTTAUCINS/HOMA-IR逐步降低(P<0.05),且显著低于NGT组(P<0.05);NGT、IGT组OGTTAUCINS/HOMA-IR无统计学差异(P>0.05)。结论:(1)IGT阶段胰岛素抵抗及胰岛素1相、早期相分泌功能的下降同时存在。IFG+IGT阶段胰岛素1相、早期相分泌进一步下降,并出现基础相、2相分泌的减少,胰岛素抵抗加重不明显。新诊断T2DM阶段胰岛素各相分泌进一步减少,胰岛素抵抗加重不明显。(2)在T2DM发生过程中,胰岛素分泌功能下降较胰岛素敏感性下降更为明显。(3)胰岛素抵抗及胰岛素1相、早期相分泌功能的下降是T2DM的预测因子。(4)IFG+IGT阶段应积极干预。     

Plasma Adiponectin Levels in High Risk African‐Americans with Normal Glucose Tolerance,Impaired Glucose Tolerance,and Type 2 Diabetes**

Objective: We studied plasma adiponectin, insulin sensitivity, and insulin secretion before and after oral glucose challenge in normal glucose tolerant, impaired glucose tolerant, and type 2 diabetic first degree relatives of African‐American patients with type 2 diabetes. Research Methods and Procedures: We studied 19 subjects with normal glucose tolerance (NGT), 8 with impaired glucose tolerance (IGT), and 14 with type 2 diabetes. Serum glucose, insulin, C‐peptide, and plasma adiponectin levels were measured before and 2 hours after oral glucose tolerance test. Homeostasis model assessment‐insulin resistance index (HOMA‐IR) and HOMA‐β cell function were calculated in each subject using HOMA. We empirically defined insulin sensitivity as HOMA‐IR < 2.68 and insulin resistance as HOMA‐IR > 2.68. Results: Subjects with IGT and type 2 diabetes were more insulin resistant (as assessed by HOMA‐IR) when compared with NGT subjects. Mean plasma fasting adiponectin levels were significantly lower in the type 2 diabetes group when compared with NGT and IGT groups. Plasma adiponectin levels were 2‐fold greater (11.09 ± 4.98 vs. 6.42 ± 3.3811 μg/mL) in insulin‐sensitive (HOMA‐IR, 1.74 ± 0.65) than in insulin‐resistant (HOMA‐IR, 5.12 ± 2.14) NGT subjects. Mean plasma adiponectin levels were significantly lower in the glucose tolerant, insulin‐resistant subjects than in the insulin sensitive NGT subjects and were comparable with those of the patients with newly diagnosed type 2 diabetes. We found significant inverse relationships of adiponectin with HOMA‐IR (r = ?0.502, p = 0.046) and with HOMA‐β cell function (r = ?0.498, p = 0.042) but not with the percentage body fat (r = ?0.368, p = 0.063), serum glucose, BMI, age, and glycosylated hemoglobin A1C (%A1C). Discussion: In summary, we found that plasma adiponectin levels were significantly lower in insulin‐resistant, non‐diabetic first degree relatives of African‐American patients with type 2 diabetes and in those with newly diagnosed type 2 diabetes. We conclude that a decreased plasma adiponectin and insulin resistance coexist in a genetically prone subset of first degree African‐American relatives before development of IGT and type 2 diabetes.     

Relation of the White Blood Cell Count to Obesity and Insulin Resistance: Effect of Race and Gender

PRATLEY, RICHARD E, CHARLTON WILSON AND CLIFTON BOGARDUS. Relation of the white blood cell count to obesity and insulin resistance: effect of race and gender. Obes Res. Recent reports suggest that the white blood cell (WBC) count is related to plasma insulin concentrations and insulin resistance in healthy individuals. The present study examines whether these relations are independent of obesity and the pattern of body fat distribution and tests whether race and gender affect these relations. WBC counts, insulin responses to a 75 gram oral glucose tolerance test (OGTT) and glucose disposal during a two-step hyperinsulinemic euglycemic clamp were measured in 300 men and women (149 Pima Indians, 100 whites, and 51 blacks) with a wide range of obesity. WBC counts were lower in blacks than Pima Indians or whites and tended to be higher in women than men. The subgroups were comparable in age and body weight, but percent body fat and plasma insulin concentrations were higher and glucose disposal during the glucose clamp was lower in Pima Indians than in blacks or whites. In the group as a whole, the WBC count correlated with obesity (body mass index and percent body fat), the waist to thigh ratio (an index of the pattern of body fat distribution), and plasma insulin concentrations and was negatively related to age and glucose disposal during the clamp. In multiple regression analyses, only age, race and obesity were significantly associated with the WBC count. When the analyses were restricted to Pima men, in whom correlations between the WBC count and the metabolic variables appeared the strongest, the WBC count remained significantly associated with plasma insulin concentrations, but not glucose disposal, after controlling for age and obesity. The results of this study indicate that age, race, and obesity are significantly associated with the WBC count in healthy individuals. Plasma insulin concentrations, but not insulin resistance per se, may also be weakly associated with the WBC count, but this may be population specific.     

Comparison of tests for glycated haemoglobin and fasting and two hour plasma glucose concentrations as diagnostic methods for diabetes.

OBJECTIVE--To compare the ability of tests measuring two hour plasma glucose, fasting plasma glucose, and glycated haemoglobin concentrations in predicting the specific microvascular complications of non-insulin dependent diabetes mellitus. DESIGN--Cross sectional and longitudinal analysis of the relation between complications and concomitant results of the three tests. SETTING--Gila River Indian Community, Arizona. SUBJECTS--Pima Indians (cross sectional, n = 960), aged 25 years or above who were not receiving insulin or oral hypoglycaemic treatment at the baseline examination. MAIN OUTCOME MEASURES--Development of retinopathy and nephropathy. RESULTS--Cross sectionally, frequency distributions of logarithms of the three sets of results were bimodal, with the prevalence of retinopathy and nephropathy being, respectively, 12.0-26.7 and 3.9-4.2 times as high above as below cut off points which minimised overlap (two hour plasma glucose concentration 12.6 mmol/l; fasting plasma glucose concentration 9.3 mmol/l; glycated haemoglobin (HbA1c) concentration 7.8%). Longitudinally, each of the three measures of glycaemia significantly predicted the development of retinopathy (P < 0.0001) and nephropathy (P < 0.05). Receiver operating characteristic curves showed that two hour plasma glucose concentration was superior to fasting plasma glucose concentration (P < 0.05) for prevalent cases of retinopathy, but otherwise no variable had a significant advantage for detecting incident or prevalent cases of either complication. CONCLUSIONS--These findings suggest that determination of glycated haemoglobin or fasting plasma glucose concentrations alone may be acceptable alternatives to measuring glucose concentration two hours after challenge with 75 g glucose for the diagnosis of diabetes.     

Relationship between serum concentrations of interleukin-6 and tumor necrosis factor alpha in female Turkish subjects with normal and impaired glucose tolerance.

Serum interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNFalpha) concentrations were measured in subjects during two-hour glucose loading in order to investigate the effects of glucose on serum IL-6 and TNFalpha concentrations. Twenty-six female subjects (mean age 60 +/- 10 years) had normal glucose tolerance (NGT) and nineteen female subjects (mean age: 63 +/- 9 years) had impaired glucose tolerance (IGT) according to WHO criteria. Serum IL-6 and TNFalpha concentrations were measured by chemiluminescent immunometric assay. Subjects with IGT have higher fasting serum TNFalpha levels than subjects with NGT (p < 0.01). Serum IL-6 and TNFalpha concentrations were elevated during glucose loading (for each comparison, p < 0.01). The increase in serum TNFalpha concentrations in IGT was greater than in NGT (p < 0.01). Serum IL-6 and TNFalpha concentration significantly correlated with insulin and glucose in IGT group (for each comparison, p < 0.01). The correlation between serum glucose and cytokines concentrations was significant in IGT (for each comparison, p < 0.01). There was also a positive correlation between serum IL-6 and TNFalpha in NGT and IGT (for each comparison, p < 0.01). In conclusion, hyperglycemia is associated with increased circulating cytokine concentrations and fasting TNFalpha concentrations seem to be more associated with IGT than IL-6.     

Hormone replacement therapy decreases insulin resistance and lipid metabolism in Japanese postmenopausal women with impaired and normal glucose tolerance

OBJECTS: To investigate the effect of combined estrogen and progesterone therapy on insulin resistance (IR) and carbohydrate and lipid metabolism in postmenopausal women (PMW) with impaired (IGT) and normal glucose tolerance (NGT). METHODS: Sixteen Japanese PMW with IGT and 33 with NGT received daily oral hormone replacement therapy (HRT; 0.625 mg of conjugated equine estrogen plus 2.5 mg of medroxyprogesterone acetate) for 12 months. As controls, 13 Japanese PMW with IGT and 31 with NGT were enrolled and not treated by HRT. Fasting plasma glucose (FPG), fasting immunoreactive insulin (IRI), and IR were measured in each subject at study initiation and 12 months later. We used homeostasis model assessment (HOMA) to determine IR. RESULTS: FPG and HOMA IR were decreased in both HRT groups, and fasting IRI was reduced in the HRT-NGT group. In controls, FPG, fasting IRI, and HOMA IR were unaltered. Total and low-density lipoprotein cholesterol were decreased and high-density lipoprotein cholesterol was increased in both HRT groups, but triglyceride was unchanged. In controls, lipid metabolism was unaltered. CONCLUSION: HRT decreased IR and improved carbohydrate and lipid metabolism in Japanese PMW with IGT and NGT. These beneficial effects argue for the use of HRT in PMW with IGT as well as NGT.     

Glucose response to an oral glucose tolerance test predicts weight change in non-diabetic subjects

Objective: Glucose exerts a dual action in the regulation of energy balance, consisting of inhibition of energy intake and stimulation of energy expenditure. Whether blood glucose affects long‐term regulation of body weight in humans remains to be established. We sought to test the hypothesis that the post‐challenge glucose response is a predictor of weight change. Research Methods and Procedures: We performed a prospective analysis of the impact of glucose response to an oral glucose tolerance test (OGTT) and a mixed‐meal test (MT) on subsequent changes in body weight (BW) on 253 Pima Indians (166 men and 87 women) with normal glucose regulation at baseline and follow‐up (follow‐up: 7 ± 4 years). Main outcome measures included BW change (total, percent, and annual), plasma glucose and insulin concentrations during OGTT and MT [total and incremental areas under the curve (AUCs)], resting metabolic rate (RMR; indirect calorimetry), and insulin action (euglycemic‐hyperinsulinemic clamp). Results: Total and incremental glucose AUCs during the OGTT (but not the MT) were negatively associated with BW change (total, percent, and annual), both before and after adjusting for sex, age, initial BW, follow‐up time, insulin action, RMR, fasting plasma glucose and insulin concentrations, and insulin response. Total and incremental glucose AUCs during the OGTT were independent determinants of final BW with age, initial BW, follow‐up time, fasting plasma insulin concentrations, and RMR. Discussion: Higher post‐challenge glucose response protects against BW gain in subjects with normal glucose regulation. We propose that this action may be because of the effect of glucose on food intake and/or thermogenesis.     

Impaired glucose tolerance (IGT) is not associated with disturbed homocysteine metabolism

Summary. Elevated plasma total homocysteine (tHcy) has been suggested to be an additional risk factor for cardiovascular disease in subjects with impaired glucose tolerance (IGT) and Type 2 diabetes (T2D). In order to investigate whether an insulin resistant/chronic hyperinsulinemic situation in male diabetic and prediabetic subjects directly influences the tHcy metabolism, fasting tHcy and post-methionine load tHcy plasma levels (PML-tHcy) were determined in 15 men with IGT, 13 men with newly dia-gnosed T2D, and 16 normoglycemic controls (NGT). Fasting tHcy (IGT, 13.1 ± 4.6; T2D, 12.8 ± 4.0; NGT, 10.7 ± 4.4 μmol/L) and PML-tHcy (IGT, 46.5 ± 17.39; T2D, 41.1 ± 6.8; NGT, 38.0 ± 9.7 μmol/L) showed no differences between the groups. Fasting tHcy and PML-tHcy correlated with fasting proinsulin (r = 0.395, p < 0.05; r = 0.386, p< 0.05) and creatinine (r = 0.489, p < 0.01; r = 0.339, p < 0.05), resp. Multiple regression analysis showed only a relationship between fasting tHcy and creatinine. No relationships have been found between fasting tHcy and PML-tHcy, resp., and indicators of an insulin resistant state, e.g., insulin and proinsulin, as well as serum cobalamin and folate concentrations. In conclusion, our data suggest that the degree of glucose intolerance has no direct impact on the metabolism of homocysteine. However, tHcy levels tend to be elevated with the development of nephropathy, indicating an association between tHcy and renal function in these subjects. Received May 11, 1999     

Continuous glucose monitoring in cystic fibrosis patients according to the glucose tolerance.

Cystic fibrosis (CF) is associated with a long preclinical state of abnormal glucose tolerance. The aim of this study was (i) to evaluate the profile of glucose tolerance in young adults with CF and (ii) to compare these results with those obtained by a continuous subcutaneous glucose monitoring (CGMS). CF subjects with fasting glycemia inferior to 126 mg/dl were included in the study. An oral glucose tolerance test (OGTT) identified the subjects either with a normal glucose tolerance (NGT), or impaired glucose tolerance (IGT), or diabetes. CGMS (Medtronic) was performed during 3 days to analyze mean glucose level, high glucose excursions, and glucose area under the curve (AUC). Forty-nine patients were included in the study. NGT (n=22), IGT (n=17), and diabetes groups (n=10) were comparable except with regard to age and BMI (p<0.001). HbA1c values in diabetes group were significantly higher (p<0.001) than in NGT and IGT groups. CGMS revealed peaks of glucose values superior to 200 mg/dl at least once after a meal in 8 patients (36%) with NGT, in 9 patients (52%) with IGT, and in all patients with diabetes (p<0.01). Mean CGMS glucose and glucose AUC values increased in patients with diabetes compared to patients with NGT and IGT (p<0.05). Peak of CGMS glucose reached 182+/-60 mg/dl in NGT group despite the normal glucose profile at OGTT. In conclusion, CGMS revealed pathological glucose excursions not only in patients with impaired glucose tolerance at OGTT but also in patients with a normal glycemic profile. CGMS could be a useful tool for the early detection of hyperglycemia in patients with CF.     

Glucose Homeostatic Law: Insulin Clearance Predicts the Progression of Glucose Intolerance in Humans

Homeostatic control of blood glucose is regulated by a complex feedback loop between glucose and insulin, of which failure leads to diabetes mellitus. However, physiological and pathological nature of the feedback loop is not fully understood. We made a mathematical model of the feedback loop between glucose and insulin using time course of blood glucose and insulin during consecutive hyperglycemic and hyperinsulinemic-euglycemic clamps in 113 subjects with variety of glucose tolerance including normal glucose tolerance (NGT), impaired glucose tolerance (IGT) and type 2 diabetes mellitus (T2DM). We analyzed the correlation of the parameters in the model with the progression of glucose intolerance and the conserved relationship between parameters. The model parameters of insulin sensitivity and insulin secretion significantly declined from NGT to IGT, and from IGT to T2DM, respectively, consistent with previous clinical observations. Importantly, insulin clearance, an insulin degradation rate, significantly declined from NGT, IGT to T2DM along the progression of glucose intolerance in the mathematical model. Insulin clearance was positively correlated with a product of insulin sensitivity and secretion assessed by the clamp analysis or determined with the mathematical model. Insulin clearance was correlated negatively with postprandial glucose at 2h after oral glucose tolerance test. We also inferred a square-law between the rate constant of insulin clearance and a product of rate constants of insulin sensitivity and secretion in the model, which is also conserved among NGT, IGT and T2DM subjects. Insulin clearance shows a conserved relationship with the capacity of glucose disposal among the NGT, IGT and T2DM subjects. The decrease of insulin clearance predicts the progression of glucose intolerance.     

Differential effects of the C1431T and Pro12Ala PPARgamma gene variants on plasma lipids and diabetes risk in an Asian population

We investigated the association of C1431T and Pro12Ala polymorphisms at the peroxisome proliferator-activated receptor gamma (PPARgamma) locus with plasma lipids and insulin resistance-related variables, according to diabetes status, in a large and representative Asian population from Singapore consisting of 2,730 Chinese, 740 Malays, and 568 Indians. Moreover, we estimated the diabetes risk and examined gene-nutrient interactions between these variants and the ratio of polyunsaturated fatty acid to saturated fat (SFA) in determining body mass index (BMI) and fasting insulin. We found differential effects of these gene variants. The Pro12Ala polymorphism was more associated with plasma lipids and fasting glucose concentrations, whereas the C1431T polymorphism was related to the risk of diabetes. Carriers of the 12Ala allele had higher HDL-cholesterol than did Pro12Pro homozygotes (P < 0.05), and the effect of the 12Ala allele on fasting glucose was modified by diabetes status (P < 0.001). After controlling for confounders, carriers of the T allele had decreased risk of diabetes compared with CC homozygotes [odds ratio (OR) 0.73, 95% confidence interval (CI) 0.58-0.93; P = 0.011]; this effect was stronger in Indians (OR 0.38, 95% CI 0.15-0.92; P = 0.032). For both polymorphisms, normal subjects carrying the less prevalent allele had higher BMI (P < 0.05). The PUFA/SFA did not modify the effect of these polymorphisms on BMI or insulin.     

Impaired skeletal muscle substrate oxidation in glucose-intolerant men improves after weight loss

Objective: An impaired fatty acid handling in skeletal muscle may be involved in the development of insulin resistance and diabetes mellitus type 2 (DM2). We investigated muscle fatty acid metabolism in glucose‐intolerant men (impaired glucose tolerance (IGT)), a prediabetic state, relative to BMI‐matched control men (normal glucose tolerance (NGT)) during fasting and after a meal, because most people in the western society are in the fed state most of the day. Methods and Procedures: Skeletal muscle free fatty acid (FFA) uptake and oxidation were studied using the stable isotope tracer [2,2‐²H]‐palmitate and muscle indirect calorimetry in the forearm model during fasting and after a mixed meal (33 energy % (E%) carbohydrates, 61 E% fat). Intramyocellular triglycerides (IMTGs) were monitored with ¹H‐magnetic resonance spectroscopy. IGT men were re‐examined after weight loss (?15% of body weight (BW)). Results: The postprandial increase in forearm muscle respiratory quotient (RQ) was blunted in IGT compared to NGT, but improved after weight loss. Weight loss also improved fasting‐fat oxidation and tended to decrease IMTGs (P = 0.08). No differences were found in fasting and postprandial forearm muscle fatty acid uptake between NGT and IGT, or in IGT before and after weight loss. Discussion: The ability to switch from fat oxidation to carbohydrate oxidation after a meal is already impaired in the prediabetic state, suggesting this may be an early factor in the development toward DM2. This impaired ability to regulate fat oxidation during fasting and after a meal (impaired metabolic flexibility) can be (partly) reversed by weight loss.     

Impaired glucose tolerance without hypertriglyceridemia does not enhance postprandial lipemia.

Postprandial lipemia has been thought to be one of risk factors for coronary heart disease, and enhances in potential patients for atherosclerotic disease. Patients with impaired glucose tolerance (IGT) often show hypertriglyceride, which is caused by enhanced portprandial lipemia. Therefore, postprandial lipemia in patients with IGT and without hypertriglyceridemia has not been cleared. We have examined the levels of plasma triglyceride and chylomicron remnants after a high fat meal load (1250 kcal, 40% fat and 420 mg cholesterol) in 13 normotriglyceridemic subjects with IGT and 10 controls with normal glucose tolerance (NGT). Chylomicron remnants were evaluated as remnant-like particles (RLP) that were not bound to an immunoaffinity gel mixture containing apo A-I and apo B-100 monoclonal antibody. RLP cholesterol levels 4 hours after the fat load were significantly lower in IGT subjects than in NGT subjects. Increase of RLP cholesterol after the fat meal load only significantly correlated with increase of insulin during the first 30 min after a 75 g oral glucose tolerance test, but not fasting lipid, insulinogenic index and HOMA-R (homeostasis model) in all subjects. These results suggest that postprandial response does not enhance in IGT subjects, and may associate with early-phase insulin secretion and without insulin resistance in normotriglyceridemic men with IGT or NGT.