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Insulin resistance is the best prediction factor for the clinical onset of type 2 diabetes. It was suggested that intramuscular triglyceride store may be a primary pathogenic factor for its development. To test this hypothesis, 14 young lean offspring of type 2 diabetic parents, a model of in vivo insulin resistance with increased risk to develop diabetes, and 14 healthy subjects matched for anthropomorphic parameters and life habits were studied with 1) euglycemic-hyperinsulinemic clamp to assess whole body insulin sensitivity, 2) localized 1H nuclear magnetic resonance (NMR) spectroscopy of the soleus (higher content of fiber type I, insulin sensitive) and tibialis anterior (higher content of fiber type IIb, less insulin sensitive) muscles to assess intramyocellular triglyceride content, 3) 13C NMR of the calf subcutaneous adipose tissue to assess composition in saturated/unsaturated carbons of triglyceride fatty acid chains, and 4) dual X-ray energy absorption to assess body composition. Offspring of diabetic parents, notwithstanding normal fat content and distribution, were characterized by insulin resistance and increased intramyocellular triglyceride content in the soleus (P < 0.01) but not in the tibialis anterior (P = 0.19), but showed a normal content of saturated/unsaturated carbons in the fatty acid chain of subcutaneous adipocytes. Stepwise regression analysis selected intramyocellular triglyceride soleus content and plasma free fatty acid levels as the main predictors of whole body insulin sensitivity. In conclusion, 1H and 13C NMR spectroscopy revealed intramyocellular abnormalities of lipid metabolism associated with whole body insulin resistance in subjects at high risk of developing diabetes, and might be useful tools for noninvasively monitoring these alterations in diabetes and prediabetic states. [ABSTRACT FROM AUTHOR] more...

Studies have pointed to insulin resistance as pathogenic factor in fatty liver; the role of beta-cell function, even if generally accepted, is unexplored. This study was undertaken to test whether fasting indexes of beta-cell function were related to the intra-hepatic fat (IHF) content in non-diabetic humans. IHF content was measured by means of ¹H-Magnetic Resonance Spectroscopy (MRS), and insulin sensitivity and beta-cell function were estimated based on fasting plasma glucose, insulin and C-peptide in 31 patients with fatty liver and 62 individuals with matched anthropometric features (age: 36±8 vs. 36±7 years, BMI: 27.4±3.8 vs. 26.7±3.2 kg/m²). Patients with fatty liver had higher fasting glucose (P<0.05), insulin (P<0.01), c-peptide (P<0.005) and insulin resistance (HOMA2-%S: 56±24% vs. 77±38%; P=0.008). Fasting insulin secretion (383±168 vs. 284±107 pmol/L; P=0.007) and the beta-cell insulin sensitivity (HOMA2-%B: 171 ± 41% vs. 152±43%; P=0.04) were also increased in patients with fatty liver. A subgroup analysis, performed matching also for HOMA2-%S (including only those <70%; n=25 and n=30 in subjects with and without fatty liver: 47±12% vs. 49±12; P=0.56), confirmed increased insulin secretion (408±178 vs. 266±107 pmol/L; P=0.002) and HOMA2-%B (174±62% ys. 136±56%; P=0.02) in the individuals with fatty liver. In univariate analysis including the entire population fasting insulin explained 14% of the IHF content variability (P<0.000); in multivariate analysis the inclusion of fasting C-peptide increased it more than two-fold (to 32%; P<0.000); inclusion of age, sex, BMI and glucose in this model was not useful. Logistic regression showed that the insulin*C-peptide product was associated with the likelihood of having fatty liver (P<0.001). In conclusion, nondiabetic individuals with fatty liver are characterized not only by reduced insulin sensitivity but also by features of enhanced fasting beta-cell function, which is an independent meaningful factor. [ABSTRACT FROM AUTHOR] more...

Fatty liver is characterized by metabolic abnormalities at the liver site but also at the level of the skeletal muscle and adipose tissue. In patients with overt type 2 diabetes fatty liver is associated with impaired insulin-stimulated myocardial glucose uptake and reduced coronary functional capacity. To ascertain whether fatty liver is associated with alterations of cardiac energy metabolism also before the development of overt diabetes, we studied 21 young, non-diabetic men with fatty liver and 21 healthy men matched for anthropometric features (age: 35±7 vs. 36±7 years, BMI: 27.5±3.6 vs. 27.1±1.3 kg/m²) in the resting state by means of cardiac Magnetic Resonance Imaging (MRI), ³P spectroscopy (MRS) and hepatic ¹H-MRS to assess respectively the cardiac morphology and function, the left ventricular (LV) energy metabolism and the IHF content as a continuous variable. Insulin sensitivity (HOMA2-%S) and B-cell insulin sensitivity (HOMA2-%B) were determined by the updated HOMA computer model. Individuals with fatty liver showed reduced insulin sensitivity (HOMA2-%S: 51±19% vs. 63±18%; P<0.05), abnormal serum triglycerides (1.85±1.20 vs. 1.00±0.49 mmol/L; P<0.02), FFA (711 ± 194 vs. 559±184 mmol/L; P<0.01) and adipokines concentrations (lower plasma adiponectin and resistin concentrations) and higher blood pressure. Parameters of LV morphology (mass and volumes), systolic function (ejection fraction, stroke volume) and diastolic function (early/atrial peak filling rates and deceleration time) were not different between groups. The LV phosphocreatine (PCr)/ATP ratio, which is a recognized marker of cardiac high energy phosphates metabolism, was significantly reduced in patients with fatty liver (defined as IHF content >5% wet weight) in comparison with normals (1.85±0.35 vs. 2.11± 0.31 mean ± SD; P<0.016) and was proportionally linked with diastolic blood pressure (Spearman's rho: r=0.41, P<0.02). In conclusion, despite of normal LV morphologic features and systolic and diastolic functions, abnormal LV energy metabolism may be detected in non-diabetic patients with fatty liver. Even if within the normal range, higher blood pressure may be contributing to this cardiac metabolic alteration. [ABSTRACT FROM AUTHOR] more...

The homeostatic model assessment (HOMA) method for the measurement of insulin sensitivity and beta-cell function has gained widespread use in large-scale studies thanks to it simplicity and good performance. Two versions of the HOMA method are currently available. The classical HOMA1 which is based On simple formulas, and the updated HOMA2 which is the authentic output of the computer model and must be calculated using specific software. Aim of this study was to gain experimental evidence of the notion that HOMA2 is more reliable than HOMA1. We examined OGTT studies performed in 305 subjects spanning a broad range of glucose tolerance (n=138 nondiabetic nonobese subjects, n=133 nondiabetic obese subjects, and n=34 newly diagnosed diabetic patients). OGTT data were used to derive validated indexes of insulin sensitivity (ISI according to Matsuda-DeFronzo), beta-cell function (2nd Phase according to Stumvoll et al.), and glucose tolerance (1/AUC 120 i.e., reciprocal of the 120-min area under the glucose curve). Such reference indexes were compared by correlation analysis with the HOMA1 and HOMA2 couterparts evaluated from fasting pre-load samples. To determine whether HOMA2 was more reliable than HOMA1, the statistical significance of the difference between the correlation coefficients obtained with the HOMA1 and HOMA2 methods was tested. We found that the HOMA1 and HOMA2 indexes of insulin sensitivity gave similar performance (correlation coefficients vs. ISI were 0.92 and 0.91 for HOMA1 and HOMA2, respectively, p=N.S.). In contrast, HOMA2 was significantly better than HOMA1 at predicting beta-cell function (correlation coefficients vs. 2nd Phase were 0.59 and 0.72 for HOMA1 and HOMA2, respectively, p< 0.05). Finally, the HOMA2 disposition index (obtained multiplying insulin sensitivity and beta-cell function together) was more strongly associated to oral glucose tolerance than the HOMA1 disposition index (correlation coefficients vs. 1/AUC120 were 0.56 and 0.70 for HOMA1 and HOMA2, respectively, p< 0.05). In conclusion, HOMA2 was distinctly better than HOMA1 in predicting OGTT-based indexes of beta-cell function and glucose tolerance. These findings corroborate the notion that it is advisable to switch to HOMA2. [ABSTRACT FROM AUTHOR] more...

This study examined the impact of L-acetylcamitine therapy in patients with lipodystrophy syndrome consequent to the effect of antiretroviral therapy in human immunodeficiency virus (HIV) on insulin sensitivity and body composition. Seven HIV-1 patients with lipodystrophy syndrome (3 females/4 males, age = 40 ± 4 yr, HIV duration = 8 ± 2 yr, BMI = 23.7 ± 3.2 kg/m², on protease inhibitors and nucleoside analog reverse transcriptase inhibitors) were studied. In all patients, the following parameters were evaluated before and after 32 weeks of therapy with L-acetylcarnitine (2g/day): fasting glucose and insulin levels (to calculate HOMA-IS and QUICKI), lipid profile, lipid oxidation (indirect calorimetry), body composition (DEXA) and intramyocellular triglyceride (IMCL) content of the calf muscles (¹H-NMR spectroscopy). After treatment with L-acetylcarnitine insulin sensitivity improved (HOMA-IS from 0.56±0.30 to 0.97±0.45 and QUICKI from 3.40±0.13 to 3.86±0.16; both p<0.05). L-acetylcarnitine, caused a decrease of IMCL content of the soleus muscle (from 206 ± 99 to 80 ± 43 AU; P = 0.005), meanwhile it was unaffected at the level of tibialis anterior (from 28 ± 11 to 31 ± 10 AU, P = ns). L-acetylcarnitine treatment increased the percentage of fat in the legs (from 13.5% to 14.7%; p=0.005). The percentage fat in the mink and in the arms did not change (respectively from 25±2 to 24±1%, P = 0.08 and from 21±4 to 21±3%, P= 0.7). In parallel plasma FFA (0.78±0.29 vs 0.65±0.23 mmol/l; p< 0.05) and Respiratory Quotient (0.82±0.16 vs 0.74±0.15; p<0.05) decreased. Treatment with L-acetylcarnitine for 32 weeks in HIV-1 infected patients with lipodystrophy syndrome caused improvement of insulin sensitivity and of FFA metabolism. Most interestingly, the short-term treatment with L-acetylcarnitine determined an improvement of body fat distribution both at orthotopic and ectopic sites. [ABSTRACT FROM AUTHOR] more...