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 ⅐ kg ؊1 ⅐ 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. Diabetes 52:453-462, ...

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 (Ͼ90%), 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 ⅐ kg Ϫ1 ⅐ min Ϫ1 . 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.

Mice null for adipocyte fatty acid binding protein ( A FABP) compensate by increasing expression of keratinocyte fatty acid binding protein (KFABP) (Hotamisligil et al. S c i e n c e 274:1377-1379, 1996). In the present s t u d y, AFABP knockout (KO) and wild-type (WT) mice became equally obese on a high-fat diet, as judged by fat pad weights, adipocyte size, and body composition analysis. High-fat feeding led to moderate insulin resistance in both WT and AFABP knockout mice, as indicated by an ~2-fold increase in plasma insulin. H o w e v e r, in the high fat-fed mice, plasma glucose levels were ~15% lower in the AFABP-KO mice. Adipocytes isolated from AFABP-KO and WT mice fed high-or low-fat diets exhibited similar rates of basal and norepinephrine-stimulated lipolysis and insulinstimulated rates of glucose conversion to fatty acids and glyceride-glycerol. However, basal glucose conversion to fatty acids was higher in adipocytes of AFA B P -KO mice. Adipocyte tumor necrosis factor-r e l e a s e was similarly increased by high-fat diet-induced obesity in both WT and AFABP-KO mice. As assessed by We s tern blot analysis, the level of KFABP protein in A FABP-KOs was ~40% of the level of AFABP in WT controls. The binding affinities of KFABP for longchain fatty acids were 2-to 4-fold higher than those of A FA B P, but the relative affinities for different fatty acids were similar. As for AFA B P, the rate of fatty acid transfer from KFABP to model phospholipid vesicles was increased with acceptor membrane concentration and by inclusion of acidic phospholipids, indicating a similar mechanism of transfer. We conclude KFABP can functionally compensate for the absence of AFA B P, resulting in no major alterations in adipocyte metabolism or fat accumulation in response to short-term feeding of high-fat diets that result in moderate hyperinsulinemia. D i a b e t e s 4 9 :9 0 4-911, 2000

Objective-To study 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 non-diabetic and Type 2 Diabetic (T2DM) patients.Research Methods and Procedures-Seven untreated T2DM and 5 obese non-diabetic individuals were studied before and after a 6-day VLCD using proton-magnetic resonance spectroscopy to quantify IMCL, DXA to assess body fat, and hyperinsulinemic-euglycemic clamps to measure peripheral insulin sensitivity.Results-In both groups, decrements in total body fat mass and BMI were small but statistically significant. In contrast, the diet resulted in a pronounced reduction in IMCL compared to baseline values in non-diabetics (56% decrease) and T2DM (40% decrease), P<0.05, and this was accompanied by an overall 9.3% increase in maximally-stimulated glucose disposal rate (P<0.01). IMCL was significantly correlated with insulin sensitivity, (r=−0.69; P<0.01) and waist circumference (r = 0.72 and 0.83, baseline and post-diet respectively, both P < 0.01), but neither IMCL nor insulin sensitivity was related to measures of general adiposity such as BMI, % body fat, or total body fat (P=NS).Conclusions-Short-term VLCD is accompanied by small decrements in general adiposity, marked decrease in IMCL, and an increase in insulin sensitivity in non-diabetic and T2DM subjects. Therefore, rapid amelioration of insulin resistance by VLCD can be partially explained by loss of IMCL in both non-diabetics and in T2DM in the absence of substantial changes in total body fat. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access Author ManuscriptMetabolism. Author manuscript; available in PMC 2009 January 1. Published in final edited form as:Metabolism. 2008 January ; 57(1): 1-8. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptThese observations are consistent with the idea that insulin resistance is more directly related to IMCL rather than body fat per se.