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.     

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.     

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.     

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.     

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.     

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.     

Circulating Betatrophin Correlates with Triglycerides and Postprandial Glucose among Different Glucose Tolerance Statuses—A Case-Control Study

Purpose

Previous researches of betatrophin on glucose and lipids metabolism under insulin-resistant condition have reached controversial conclusions. To further identify the possible impact of betatrophin, we measured the circulating betatrophin levels in newly diagnosed type 2 diabetes (T2DM) patients, and in subjects with both impaired glucose tolerance (IGT) and normal glucose tolerance (NGT) and investigated the relationship between serum betatrophin and other clinical parameters in these patients with different glucose tolerance statuses.

Methods

A total of 460 permanent residents of the Fengxian District, aged 40–60 years, were enrolled. Based on the results of a 75 g oral glucose tolerance test, we selected newly diagnosed T2DM (n = 50) patients and subjects with IGT (n = 51) and NGT (n = 50) according to their age, gender and body mass index (18–28 kg/m²). Anthropometric parameters, glycosylated haemoglobin, blood lipids and fasting insulin were measured. Serum betatrophin concentrations were determined via ELISA.

Results

Serum betatrophin levels in T2DM patients were increased significantly compared with IGT and NGT groups, and decreased in subjects with better islet beta cell function. Serum betatrophin was positively correlated with triglyceride, 2-hour postprandial glucose, alanine aminotransferase and aspartate transaminase after adjusting for age, sex and body mass index in all subjects. Multiple regression analysis showed that 2-hour postprandial glucose was independently associated with serum betatrophin significantly.

Conclusions

Circulating betatrophin is increased in newly-diagnosed T2DM patients and positively correlated with the triglycerides and postprandial glucose levels. The results suggest that betatrophin may participate in glucose and triglycerides metabolism.     

Serum oxidized low density lipoprotein, paraoxonase 1 and lipid peroxidation levels during oral glucose tolerance test.

Increasing evidence suggests that the postprandial state is a contributing factor to the development of atherosclerosis. To evaluate the effects of acute hyperglycemia on the oxidative stress, concentrations of serum-oxidized low density lipoprotein (oxLDL), paraoxonase 1 (PON1), and thiobarbituric acid reactive substances (TBARS) were measured in subjects with normal glucose tolerance (NGT) (n=35), impaired glucose tolerance (IGT) (n=25), and diabetic glucose tolerance (DGT) (n=20). In NGT group, the 2 hours' TBARS and oxLDL levels were not statistically different when compared to baseline, and 2 hours' PON1 activities were higher when compared to baseline (p<0.01). Subjects with IGT and DGT have higher 2 hours' serum TBARS and oxLDL levels than their baseline levels (p<0.01, for each). Baseline oxLDL levels of both IGT and DGT groups were higher than NGT group (p<0.01 and p<0.01, respectively). While there were not any significant differences in 2 hours' versus baseline PON1 activities in the IGT group, the 2 hours' versus baseline PON1 activities in the DGT group were significantly lower (p<0.01). The postchallenge 2 hours' PON1 activities of both IGT and DGT groups were lower than NGT group (p<0.01 and p<0.01, respectively). Baseline oxLDL was positively correlated with 2 hours' glucose (r=0.613, p<0.01) in IGT and DGT groups. PON1 activities were correlated with HDL-cholesterol, total cholesterol, and fasting glucose (r=0.680, r=0.698 and r=0.431, respectively, for each p<0.01) in NGT. In conclusion, oxidative stress occurs at an early stage in diabetes, and protective effects of HDL against atherosclerosis may be dependent on the PON1 activities.     

Elevated plasma nonesterified fatty acids are associated with deterioration of acute insulin response in IGT but not NGT

High concentrations of nonesterified fatty acids (NEFA) are a risk factor for developing type 2 diabetes in Pima Indians. In vitro and in vivo, chronic elevation of NEFA decreases glucose-stimulated insulin secretion. We hypothesized that high fasting plasma NEFA would increase the risk of type 2 diabetes by inducing a worsening of glucose-stimulated insulin secretion in Pima Indians. To test this hypothesis, fasting plasma NEFA concentrations, body composition, insulin action (M), acute insulin response (AIR, 25-g IVGTT), and glucose tolerance (75-g OGTT) were measured in 151 Pima Indians [107 normal glucose tolerant (NGT), 44 impaired glucose tolerant (IGT)] at the initial visit. These subjects, participants in ongoing studies of the pathogenesis of obesity and type 2 diabetes, had follow-up measurements of body composition, glucose tolerance, M, and AIR. In NGT individuals, cross-sectionally, high fasting plasma NEFA concentrations at the initial visit were negatively associated with AIR after adjustment for age, sex, percent body fat, and M (P = 0.03). Longitudinally, high fasting plasma NEFA concentrations at the initial visit were not associated with change in AIR. In individuals with IGT, cross-sectionally, high fasting plasma NEFA concentrations at the initial visit were not associated with AIR. Longitudinally, high fasting plasma NEFA concentrations at the initial visit were associated with a decrease in AIR before (P < 0.0001) and after adjustment for sex, age at follow-up, time of follow-up, change in percent body fat and insulin sensitivity, and AIR at the initial visit (P = 0.0006). In conclusion, findings in people with NGT indicate that fasting plasma NEFA concentrations are not a primary etiologic factor for beta-cell failure. However, in subjects who have progressed to a state of IGT, chronically elevated NEFA seem to have a deleterious effect on insulin-secretory capacity.     

Effects of glucose ingestion on postprandial lipemia and triglyceride clearance in humans

To determine whether the metabolism of diet-derived triglycerides (TG) is acutely regulated by the consumption of insulinogenic carbohydrates, we measured the effects of glucose ingestion on oral and intravenous fat tolerance, and on serum triglyceride concentrations obtained during duodenal fat perfusion. Postprandial lipemia was diminished by the ingestion of 50 g (148 +/- 121 mg.dl-1 x 7 h-1 vs 192 +/- 124 mg.dl-1 x 7 h-1, P less than 0.05) and 100 g (104 +/- 106 mg.dl-1 x 7 h-1 vs 171 +/- 104 mg.dl-1 x 7 h-1, P less than 0.05) glucose. Peak postprandial TG concentrations occurred later after meals containing glucose and fat than after meals containing fat alone. This effect could be reproduced when an iso-osmotic quantity of urea was substituted for glucose in the test meal. Starch ingestion had no discernible effect on postprandial lipemia. Intravenous fat tolerance was similar before (4.9 +/- 1.2%.min-1) and 2 h (4.4 +/- 1.3%.min-1) and 4 h (4.8 +/- 1.5%.min-1) after 50 g glucose ingestion. During duodenal fat perfusion, glucose ingestion caused a progressive decrease in plasma triglyceride concentrations. These data suggest that glucose ingestion diminishes postprandial lipemia in a dose-dependent manner, but that this effect is not due to increased clearance of triglyceride from the circulation. The hypotriglyceridemic effects of glucose appear to reflect delayed gastric emptying and decreased hepatic secretion of triglyceride.     

Reversal of the sex difference in plasma leptin levels in obese children with impaired glucose tolerance

INTRODUCTION: Basal leptin level has been demonstrated to correlate positively with many indices of obesity, as well as insulin resistance. However, to date, little is known about regulation of leptin in obese children with incipient glucose metabolic disorders. OBJECTIVE: The aim of this study was to define the precise influence of the glucose tolerance status on plasma leptin in obese boys and girls separately. MATERIAL AND METHODS: 70 obese children with impaired glucose tolerance (IGT) and well-matched 70 normal glucose-tolerant (NGT) subjects were examined. Fasting and 2-h post glucose load plasma glucose and insulin levels as well as fasting leptin levels were determined, apart from anthropometric measurements. RESULTS: Leptin levels were significantly lower in girls with IGT compared to NGT girl (17.7+/-6.5 microg/L vs. 23.1+/-7.7 microg/L; p<.001). No such difference was observed in boys. In a multiple regression analysis adjusting for age and adiposity, in the female group plasma glucose and insulin levels 2-h after glucose load were the best predictors of fasting plasma leptin (r=-0.49, p<.005 and r=0.34, p<.05; respectively). In boys, plasma insulin level 2-h after glucose load was the independent determinant of leptin (r=0.36, p<.05). CONCLUSION: The differences between regulation of leptin synthesis in girls and boys with simple obesity were found. The stimulatory effect of insulin on leptin synthesis was greater in girls with normoglycemia than in girls with impaired glucose tolerance.     

Reversal of the sex difference in plasma leptin levels in obese children with impaired glucose tolerance

INTRODUCTION: Basal leptin level has been demonstrated to correlate positively with many indices of obesity, as well as insulin resistance. However, to date, little is known about regulation of leptin in obese children with incipient glucose metabolic disorders. OBJECTIVE: The aim of this study was to define the precise influence of the glucose tolerance status on plasma leptin in obese boys and girls separately. MATERIAL AND METHODS: 70 obese children with impaired glucose tolerance (IGT) and well-matched 70 normal glucose-tolerant (NGT) subjects were examined. Fasting and 2-h post glucose load plasma glucose and insulin levels as well as fasting leptin levels were determined, apart from anthropometric measurements. RESULTS: Leptin levels were significantly lower in girls with IGT compared to NGT girl (17.7+/-6.5 microg/L vs. 23.1+/-7.7 microg/L; p<.001). No such difference was observed in boys. In a multiple regression analysis adjusting for age and adiposity, in the female group plasma glucose and insulin levels 2-h after glucose load were the best predictors of fasting plasma leptin (r=-0.49, p<.005 and r=0.34, p<.05; respectively). In boys, plasma insulin level 2-h after glucose load was the independent determinant of leptin (r=0.36, p<.05). CONCLUSION: The differences between regulation of leptin synthesis in girls and boys with simple obesity were found. The stimulatory effect of insulin on leptin synthesis was greater in girls with normoglycemia than in girls with impaired glucose tolerance.     

Rosiglitazone Improves Glucose Metabolism in Obese Adolescents With Impaired Glucose Tolerance: A Pilot Study

Impaired glucose tolerance (IGT) is a prediabetic state fueling the rising prevalence of type 2 diabetes mellitus (T2DM) in adolescents with marked obesity. Given the importance of insulin resistance, the poor β‐cell compensation and the altered fat partitioning as underlying defects associated with this condition, it is crucial to determine the extent to which these underlying abnormalities can be reversed in obese adolescents. We tested, in a pilot study, whether rosiglitazone (ROSI) restores normal glucose tolerance (NGT) in obese adolescents with IGT by improving insulin sensitivity and β‐cell function. In a small randomized, double‐blind, placebo (PLA)‐controlled study, lasting 4 months, 21 obese adolescents with IGT received either ROSI (8 mg daily) (n = 12, 5M/7F, BMI z‐score 2.44 ± 0.11) or PLA (n = 9, 4M/5F, BMI z‐score 2.41 ± 0.09). Before and after treatment, all subjects underwent oral glucose tolerance test (OGTT), hyperinsulinemic‐euglycemic clamp, magnetic resonance imaging, and ¹H NMR assessment. After ROSI treatment, 58% of the subjects converted to NGT compared to 44% in the PLA group (P = 0.528). Restoration of NGT was associated with a significant increase in insulin sensitivity (P < 0.04) and a doubling in the disposition index (DI) (P < 0.04), whereas in the PLA group, these changes were not significant. The short‐term use of ROSI appears to be safe in obese adolescents with IGT. ROSI restores NGT by increasing peripheral insulin sensitivity and β‐cell function, two principal pathophysiological abnormalities of IGT.     

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.     

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.     

Postprandial dyslipidemia in men with visceral obesity: an effect of reduced LDL receptor expression?

Postprandial lipemia after an oral fat challenge was studied in middle-aged men with visceral obesity. The two groups had similar plasma cholesterol levels, but obese subjects had higher levels of plasma triglyceride and reduced amounts of high-density cholesterol. Fasting plasma insulin was fourfold greater in obese subjects because of concomitant insulin resistance, with a calculated HOMA score of 3.1 +/- 0.6 vs. 0.8 +/- 0.2, respectively. Plasma apolipoprotein B(48) (apoB(48)) and retinyl palmitate (RP) after an oral fat challenge were used to monitor chylomicron metabolism. Compared with lean subjects, the fasting concentration of apoB(48) was more than twofold greater in obese individuals, suggestive of an accumulation of posthydrolyzed particles. After the oral lipid load, the incremental areas under the apoB(48) and RP curves (IAUC) were both significantly greater in obese subjects (apoB(48): 97 +/- 17 vs. 44 +/- 12 microg.ml(-1). h; RP: 3,120 +/- 511 vs. 1,308 +/- 177 U. ml(-1). h, respectively). A delay in the conversion of chylomicrons to remnants probably contributed to postprandial dyslipidemia in viscerally obese subjects. The triglyceride IAUC was 68% greater in obese subjects (4.7 +/- 0.6 vs. 2.8 +/- 0.8 mM. h, P < 0.06). Moreover, peak postprandial triglyceride was delayed by approximately 2 h in obese subjects. The reduction in triglyceride lipolysis in vivo did not appear to reflect changes in hydrolytic enzyme activities. Postheparin plasma lipase rates were found to be similar for lean and obese subjects. In this study, low-density lipoprotein (LDL) receptor expression on monunuclear cells was used as a surrogate marker of hepatic activity. We found that, in obese subjects, the binding of LDL was reduced by one-half compared with lean controls (70.9 +/- 15.07 vs. 38.9 +/- 4.6 ng LDL bound/microg cell protein, P = 0.02). Because the LDL receptor is involved in the removal of proatherogenic chylomicron remnants, we suggest that the hepatic clearance of these particles might be compromised in insulin-resistant obese subjects. Premature and accelerated atherogenesis in viscerally obese, insulin-resistant subjects may in part reflect delayed clearance of postprandial lipoprotein remnants.     

Impaired glucose tolerance: its relevance to early endothelial dysfunction.

We studied the effects of acute glycemia on plasma nitric oxide (NO; nitrite plus nitrate) levels, Cu-Zn Superoxide dismutase (Cu-Zn SOD) activity and thiobarbituric acid-reactive substances (TBARS) levels in age-matched female subjects before and two hours after glucose loading. According to the results of glucose loading, subjects were divided in the three groups as normal (n = 13, NGT), impaired (n = 11, IGT) and diabetic glucose tolerance (n = 10, DGT). Plasma NO levels were significantly higher in subjects with DGT than in subjects with NGT (p< 0.001) and IGT (p< 0.05) at baseline. Two hours after glucose loading, plasma NO levels were significantly decreased in subjects with IGT and DGT (p< 0.001 and p< 0.001). Although plasma TBARS levels in subject with NGT did not change from the baseline levels after glucose loading, TBARS levels were significantly elevated in subjects with DGT and IGT (p< 0.001 and p< 0.001). Plasma Cu-Zn SOD activities were within a similar range in all subjects at baseline. Cu-Zn SOD activities were significantly increased in subjects with NGT, and were significantly decreased in subjects with IGT and DGT (p< 0.001 and p< 0.001) after glucose loading. There was a positive correlation between NO and glucose in subjects with NGT (r = 0.34, p< 0.01) and a negative correlation between NO and TBARS in IGT sum DGT during glucose tolerance (r= -0.38, p< 0.01). We suggest that NO availability was decreased when the blood glucose levels were only moderately elevated above normal levels. This might be related with the enhanced oxidative stress.     

Impaired fasting glucose with or without impaired glucose tolerance: progressive or parallel states of prediabetes?

Our objective was to determine whether defects underlying impaired fasting glucose (IFG) are maintained and additive when combined with impaired glucose tolerance (IGT) (representing a progressive form of prediabetes) or are distinct in IFG/IGT (reflecting a parallel form of prediabetes). Volunteers with IFG (n = 10), IFG/IGT (n = 14), or normal glucose tolerance (NGT; n = 15) were matched for demographics and anthropometry. Insulin secretion was assessed using the glucose step-up protocol and insulin action through the use of a two-stage hyperinsulinemic euglycemic clamp with infusion of [6,6-(2)H(2)]glucose. Modeling of insulin secretory parameters revealed similar basal (Phi(b)) but diminished dynamic (Phi(d)) components in both IFG and IFG/IGT (P = 0.05 vs. NGT for both). Basal glucose rate of appearance (R(a)) was higher in IFG compared with NGT (P < 0.01) and also, surprisingly, with IFG/IGT (P < 0.04). Moreover, glucose R(a) suppressed more during the low-dose insulin clamp in IFG (P < 0.01 vs. NGT, P = 0.08 vs. IFG/IGT). Insulin-stimulated glucose uptake [glucose rate of disappearance (R(d))] was similar in IFG, IFG/IGT, and NGT throughout the clamp. We conclude that nuances of beta-cell dysfunction observed in IFG were also noted in IFG/IGT. A trend for additional insulin secretory defects was observed in IFG/IGT, possibly suggesting progression in beta-cell failure in this group. In contrast, basal glucose R(a) and its suppressability with insulin were higher in IFG, but not IFG/IGT, compared with NGT. Together, these data indicate that IFG/IGT may be a distinct prediabetic syndrome rather than progression from IFG.     

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.     

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。