Effects of short-term very low-calorie diet on intramyocellular lipid and insulin sensitivity in nondiabetic and type 2 diabetic subjects.

The study aimed to analyze the effects of a short-term very low-calorie diet (VLCD) on intramyocellular lipid (IMCL), total body fat, and insulin sensitivity in a group of obese nondiabetic and type 2 diabetic subjects. Seven untreated type 2 diabetic and 5 obese nondiabetic individuals were studied before and after a 6-day VLCD using proton magnetic resonance spectroscopy to quantify IMCL, dual-energy x-ray absorptiometry to assess body fat, and hyperinsulinemic-euglycemic clamps to measure peripheral insulin sensitivity. In both groups, decrements in total body fat mass and body mass index were small but statistically significant. In contrast, the diet resulted in a pronounced reduction in IMCL compared with baseline values in nondiabetic subjects (56% decrease) and type 2 diabetic subjects (40% decrease) (P < .05), and this was accompanied by an overall 9.3% increase in maximally stimulated glucose disposal rate (P < .01). Intramyocellular lipid was significantly correlated with insulin sensitivity (r = -0.69, P < .01) and waist circumference (r = 0.72 and 0.83, baseline and postdiet, respectively; both P < .01), but neither IMCL nor insulin sensitivity was related to measures of general adiposity such as body mass index, percentage of body fat, or total body fat (P = not significant). In conclusion, short-term VLCD is accompanied by small decrements in general adiposity, marked decrease in IMCL, and an increase in insulin sensitivity in nondiabetic and type 2 diabetic subjects. Therefore, rapid amelioration of insulin resistance by VLCD can be partially explained by loss of IMCL both in nondiabetic and type 2 diabetic subjects in the absence of substantial changes in total body fat. These observations are consistent with the idea that insulin resistance is more directly related to IMCL rather than to body fat per se.

Adiponectin multimeric complexes and the metabolic syndrome trait cluster.

Adiponectin circulates in human plasma mainly as a 180-kDa low molecular weight (LMW) hexamer and a high molecular weight (HMW) multimer of approximately 360 kDa. We comprehensively examined the relationships between circulating levels of total adiponectin, adiponectin multimers, and the relative distribution (i.e., ratio) of multimeric forms with key features of the metabolic syndrome. Total adiponectin (r = 0.45), HMW (r = 0.47), LMW (r = 0.31), and HMW-to-total adiponectin ratio (r = 0.29) were significantly correlated with insulin-stimulated glucose disposal rate. Similarly, total (r = -0.30), HMW (r = -0.38), and HMW-to-total adiponectin ratio (r = -0.34) were correlated with central fat distribution but not with total fat mass or BMI. Regarding energy metabolism, although there were no effects on resting metabolic rate, total (r = 0.41) and HMW (r = 0.44) were associated with increasing rates of fat oxidation. HMW-to-total adiponectin ratio increased as a function of total adiponectin, and it was HMW quantity (not total or HMW-to-total adiponectin ratio or LMW) that was primarily responsible for all of these relationships. Impact on nuclear magnetic resonance lipoprotein subclasses was assessed. HMW and total adiponectin were correlated with decreases in large VLDL (r = -0.44 and -0.41); decreases in small LDL (r = -0.41 and -0.36) and increases in large LDL (r = 0.36 and 0.30) particle concentrations accompanied by increased LDL particle size (r = 0.47 and 0.39); and increases in large HDL (r = 0.45 and 0.37) and HDL particle size (r = 0.53 and 0.47). Most of these correlations persisted after adjustment for metabolic covariables. In conclusion, first, serum adiponectin is associated with increased insulin sensitivity, reduced abdominal fat, and high basal lipid oxidation; however, it is HMW quantity, not total or HMW-to-total adiponectin ratio, that is primarily responsible for these relationships. Second, reduced quantities of HMW independently recapitulate the lipoprotein subclass profile associated with insulin resistance after correcting for glucose disposal rate and BMI. Finally, HMW adiponectin is an important factor in explaining the metabolic syndrome.

Estimation of resting energy expenditure considering effects of race and diabetes status.

OBJECTIVE: To evaluate the impact of diabetes status and race, in addition to other covariables, on the estimation of resting energy expenditure (REE). RESEARCH DESIGN AND METHODS: Demographic, anthropometric, and clinical parameters were assessed in 166 adults of varying weights. Subjects were categorized by race (white versus black) and into three subgroups based on glucose tolerance (normoglycemia, impaired glucose tolerance, and type 2 diabetes), termed the diabetes status index (DSI). REE was measured by indirect calorimetry. A multiple regression model was established for optimal prediction of REE based on covariables. RESULTS: An average decrease in REE of 135 kcal/day independent of all other variables was observed in blacks (P < 0.001). DSI was found to be a significant covariable (P = 0.002) in predicting REE, which was observed to be higher in diabetic women. Therefore, race and DSI entered the multiple regression equation to predict REE as significant independent variables, together with lean body mass (LBM) and age x BMI interaction (P < 0.001). Overall, REE prediction resulted in an R(2) of 0.79 and a root mean square error of 136 kcal/day. These values indicate that the resultant equations could offer advantages over other key published prediction equations. The equations are: 1) REE(female) = 803.8 + 0.3505 x age x (BMI - 34.524) - 135.0 x race + 15.866 x LBM + 50.90 x DSI; and 2) REE(male) = 909.4 + 0.3505 x age x (BMI -34.524) -135.0 x race + 15.866 x LBM -9.10 x DSI. The predictive value of the equations did not diminish substantially when fat-free mass estimated by skinfold calipers was substituted for dual-energy X-ray absorptiometry scan measurements of LBM. CONCLUSIONS: Race and diabetes status are important when predicting REE, coupled with LBM, age, BMI, and sex. Race and DSI have not been considered in equations commonly used to predict REE. Their inclusion could improve individualization of dietary prescriptions for type 2 diabetic subjects and heterogeneous populations.

Critical evaluation of adult treatment panel III criteria in identifying insulin resistance with dyslipidemia.

OBJECTIVE: The goal of this study was to evaluate the efficacy of the Third Report of the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (ATP III) in identifying insulin resistance. RESEARCH DESIGN AND METHODS: This study included 74 nondiabetic Caucasians who were evaluated for insulin resistance and risk factors associated with the metabolic syndrome. Glucose disposal rate (GDR) was measured by hyperinsulinemic-euglycemic clamp and was used to quantify insulin resistance. Sensitivity and specificity of ATP III criteria in detecting insulin resistance were calculated for various cutoffs of GDR. RESULTS: Insulin resistance was associated with increased waist circumference, fasting glucose, blood pressure, triglycerides, and decreased levels of HDL cholesterol. Only 12.2% of study subjects met ATP III criteria for metabolic syndrome, and ATP III criteria exhibited low sensitivity for detecting insulin resistance. Although high in specificities (>90%), the sensitivities of ATP III criteria ranged only between 20 and 50% when insulin resistance was defined as various GDR cutoff values below 10 to 12 mg.kg(-1).min(-1). The larger number of subjects who were insulin resistant but did not meet ATP III criteria were found to have an adverse cardiovascular disease risk profile, including higher BMI, waist circumference, fasting glucose, triglycerides, and an unfavorable lipoprotein subclass profile determined by nuclear magnetic resonance compared with insulin-sensitive individuals (i.e., increased large VLDL, increased small LDL, and decreased large HDL particle concentrations). CONCLUSIONS: ATP III criteria have low sensitivity for identifying insulin resistance with dyslipidemia in nondiabetic individuals who are at increased risk for cardiovascular disease and diabetes. More sensitive criteria should be developed for clinical assessment of metabolic and cardiovascular disease risk relevant to the metabolic syndrome.

Effects of insulin resistance and type 2 diabetes on lipoprotein subclass particle size and concentration determined by nuclear magnetic resonance.

The insulin resistance syndrome (IRS) is associated with dyslipidemia and increased cardiovascular disease risk. A novel method for detailed analyses of lipoprotein subclass sizes and particle concentrations that uses nuclear magnetic resonance (NMR) of whole sera has become available. To define the effects of insulin resistance, we measured dyslipidemia using both NMR lipoprotein subclass analysis and conventional lipid panel, and insulin sensitivity as the maximal glucose disposal rate (GDR) during hyperinsulinemic clamps in 56 insulin sensitive (IS; mean +/- SD: GDR 15.8 +/- 2.0 mg. kg(-1). min(-1), fasting blood glucose [FBG] 4.7 +/- 0.3 mmol/l, BMI 26 +/- 5), 46 insulin resistant (IR; GDR 10.2 +/- 1.9, FBG 4.9 +/- 0.5, BMI 29 +/- 5), and 46 untreated subjects with type 2 diabetes (GDR 7.4 +/- 2.8, FBG 10.8 +/- 3.7, BMI 30 +/- 5). In the group as a whole, regression analyses with GDR showed that progressive insulin resistance was associated with an increase in VLDL size (r = -0.40) and an increase in large VLDL particle concentrations (r = -0.42), a decrease in LDL size (r = 0.42) as a result of a marked increase in small LDL particles (r = -0.34) and reduced large LDL (r = 0.34), an overall increase in the number of LDL particles (r = -0.44), and a decrease in HDL size (r = 0.41) as a result of depletion of large HDL particles (r = 0.38) and a modest increase in small HDL (r = -0.21; all P < 0.01). These correlations were also evident when only normoglycemic individuals were included in the analyses (i.e., IS + IR but no diabetes), and persisted in multiple regression analyses adjusting for age, BMI, sex, and race. Discontinuous analyses were also performed. When compared with IS, the IR and diabetes subgroups exhibited a two- to threefold increase in large VLDL particle concentrations (no change in medium or small VLDL), which produced an increase in serum triglycerides; a decrease in LDL size as a result of an increase in small and a reduction in large LDL subclasses, plus an increase in overall LDL particle concentration, which together led to no difference (IS versus IR) or a minimal difference (IS versus diabetes) in LDL cholesterol; and a decrease in large cardioprotective HDL combined with an increase in the small HDL subclass such that there was no net significant difference in HDL cholesterol. We conclude that 1) insulin resistance had profound effects on lipoprotein size and subclass particle concentrations for VLDL, LDL, and HDL when measured by NMR; 2) in type 2 diabetes, the lipoprotein subclass alterations are moderately exacerbated but can be attributed primarily to the underlying insulin resistance; and 3) these insulin resistance-induced changes in the NMR lipoprotein subclass profile predictably increase risk of cardiovascular disease but were not fully apparent in the conventional lipid panel. It will be important to study whether NMR lipoprotein subclass parameters can be used to manage risk more effectively and prevent cardiovascular disease in patients with the IRS.

Effective use of thiazolidinediones for the treatment of glucocorticoid-induced diabetes.

We evaluated the efficacy of a thiazolidinedione in the treatment of diabetes induced by glucocorticoids. We examined the effectiveness of troglitazone in seven patients with long-standing steroid-induced diabetes. Five of the seven subjects were treated with insulin alone, one was treated with both insulin and oral therapy and one was treated with oral therapy alone. The mean insulin dose in six of the seven subjects was 0.66+/-0.09 units/kg per day. Diabetes status was assessed by measuring serum fructosamine, HgbA1c, oral glucose and meal tolerance tests (OGTT and MTT) at baseline and after treatment for 5-8 weeks with troglitazone 400 mg/day. Troglitazone caused a significant decrease in fructosamine (274+/-32 vs. 217+/-22 mmol/l; P<0.01) and HgbA1C (7.8+/-0.4 vs. 7.2+/-0.4%; P<0.01) as well as decrements in the areas under the OGTT 2,308+/-156 vs. 1,937+/-127 mmol/l; P<0.05) and MTT glucose curves (4694+/-449 vs. 4057+/-437 mmol/l; P<0.05). In addition, the area under the insulin curve for the oral glucose tolerance test showed a significant increase from 27,438+/-4,488 to 41,946+/-6,048 pmol/l (P<0.05). Total and LDL cholesterol were also significantly decreased (6.4+/-0.9 vs. 5.0+/-0.6 mmol/l and 3.8+/-0.7 vs. 2.7+/-0.4 mmol/l, respectively, P<0.05). Fasting leptin values decreased by 23% despite an increase in body weight. Troglitazone is effective in the treatment of glucocorticoid-induced diabetes as manifested by lower measures of glycemia, HgbA1c, and post-prandial glucose values, while the doses of other diabetes medications remained unchanged or were reduced. The insulin-sensitizing drug also produced a marked increase in endogenous insulin secretion in response to glucose, lower total and LDL cholesterol, and decreased fasting leptin despite weight gain. Thiazolidinediones may improve diabetes-related parameters by antagonizing pathways of glucocorticoid-induced insulin resistance and by reversing adverse effects of glucocorticoids on beta cell function.

Troglitazone antagonizes metabolic effects of glucocorticoids in humans: effects on glucose tolerance, insulin sensitivity, suppression of free fatty acids, and leptin.

Glucocorticoids induce insulin resistance in humans, whereas thiazolidinediones enhance insulin sensitivity. Although the effects of glucocorticoids and thiazolidinediones have been assessed in isolation, interaction between these drugs, which both act as ligands for nuclear receptors, has been less well studied. Therefore, we examined the metabolic effects of dexamethasone and troglitazone, alone and in combination, for the first time in humans. A total of 10 healthy individuals with normal glucose tolerance (age 40 +/- 11 years, BMI 31 +/- 6.1 kg/m(2)) were sequentially studied at baseline, after 4 days of dexamethasone (4 mg/day), after 4-6 weeks on troglitazone alone (400 mg/day), and again after 4 days of dexamethasone added to troglitazone. Key metabolic variables included glucose tolerance assessed by blood glucose and insulin responses to an oral glucose tolerance test (OGTT), insulin sensitivity evaluated via hyperinsulinemic-euglycemic clamp, free fatty acids (FFAs) and FFA suppressibility by insulin during the clamp study, and fasting serum leptin. Dexamethasone drastically impaired glucose tolerance, with fasting and 2-h OGTT insulin values increasing by 2.3-fold (P < 0.001) and 4.4-fold (P < 0.001) over baseline values, respectively. The glucocorticoid also induced a profound state of insulin resistance, with a 34% reduction in maximal glucose disposal rates (GDRs; P < 0.001). Troglitazone alone increased GDRs by 20% over baseline (P = 0.007) and completely prevented the deleterious effects of dexamethasone on glucose tolerance and insulin sensitivity, as illustrated by a return of OGTT glucose and insulin values and maximal GDR to near-baseline levels. Insulin-mediated FFA suppressibility (FFA decline at 30 min during clamp/FFA at time 0) was also markedly reduced by dexamethasone (P = 0.002). Troglitazone had no effect per se, but it was able to normalize FFA suppressibility in subjects coadministered dexamethasone. Futhermore, the magnitudes of response of FFA suppressibility and GDR to dexamethasone were proportionate. The same was true for the reversal of dexamethasone-induced insulin resistance by troglitazone, but not in response to troglitazone alone. Leptin levels were increased 2.2-fold above baseline by dexamethasone. Again, troglitazone had no effect per se but blocked the dexamethasone-induced increase in leptin. Subjects experienced a 1.7-kg weight gain while taking troglitazone but no other untoward effects. We conclude that in healthy humans, thiazolidinediones antagonize the action of dexamethasone with respect to multiple metabolic effects. Specifically, troglitazone reverses both glucocorticoid-induced insulin resistance and impairment of glucose tolerance, prevents dexamethasone from impairing the antilipolytic action of insulin, and blocks the increase in leptin levels induced by dexamethasone. Even though changes in FFA suppressibility were correlated with dexamethasone-induced insulin resistance and its reversal by troglitazone, a cause-and-effect relationship cannot be established. However, the data suggest that glucocorticoids and thiazolidinediones exert fundamentally antagonistic effects on human metabolism in both adipose and muscle tissues. By preventing or reversing insulin resistance, troglitazone may prove to be a valuable therapeutic agent in the difficult clinical task of controlling diabetes in patients receiving glucocorticoids.