Elevated fasting plasma C-peptide occurs in non-diabetic individuals with fatty liver, irrespective of insulin resistance.

AIMS: Studies have pointed to insulin resistance as a pathogenic factor in fatty liver. Although pancreatic B-cell function is believed to be involved, its role is unclear. This study was undertaken to test whether fasting C-peptide, an index of fasting B-cell function, was related to intra-hepatic fat (IHF) content in non-diabetic humans. METHODS: We assessed, retrospectively, fasting plasma C-peptide concentration in 31 patients with fatty liver and 62 individuals without fatty liver. The IHF content was measured by proton magnetic resonance spectroscopy ((1)H-MRS), while insulin sensitivity was estimated based on fasting plasma glucose and insulin with the homestasis model assessment (HOMA) 2 method. RESULTS: Age, sex and body mass index (BMI) were not different between groups. Patients with fatty liver had higher fasting insulin (P < 0.01), C-peptide (P < 0.005) and lower insulin sensitivity (HOMA2-%S). Fasting insulin alone explained 14% of the IHF content variability (P < 0.001); inclusion of fasting C-peptide in multivariate regression explained up to 32% (P < 0.001). A subgroup analysis was performed by matching 1 : 1 for HOMA2-%S. These data were analysed by conditional logistic regression which showed that, when HOMA2-%S was matched between groups, fasting C-peptide remained the only significant predictor of fatty liver. CONCLUSIONS: Non-diabetic individuals with fatty liver are characterized by increased fasting plasma C-peptide concentration, irrespective of their insulin resistant state.

Left ventricular function and energy metabolism in middle-aged men undergoing long-lasting sustained aerobic oxidative training.

OBJECTIVE: Ageing of the human heart is characterised by morphological, functional and metabolic changes. Short-term interventions and cross-sectional studies in older individuals questioned the possibility that physical exercise may reverse these alterations. In this study we aimed to assess whether in middle-aged men involved in regular and long lasting physical activity these alterations were attenuated. DESIGN: Left ventricular (LV) magnetic resonance imaging (MRI) and three-dimensional image selected in-vivo spectroscopy (3D-ISIS) (31)P magnetic resonance spectroscopy (MRS) were performed using a 1.5T scanner in 20 healthy, young and 25 healthy middle-aged non-obese men with a sedentary lifestyle (11 young and 14 middle-aged) or undergoing regular aerobic oxidative training (9 young and 11 middle-aged). Insulin sensitivity was estimated by the homeostatic model assessment 2 (HOMA-2) model. RESULTS: Sedentary young and middle-aged men were not different with respect to LV morphological parameters and systolic function. The phosphocreatine/ATP (PCr/ATP) ratio (marker of high energy phosphates metabolism) and the LV E-peak filling rate/A-peak filling rate ratio (E/A ratio) were lower in sedentary middle-aged than physically active subjects. Parameters of LV systolic function and the PCr/ATP ratio were not different in the middle-aged compared with the young trained men; the E/A peak flow ratio was higher in the middle-aged trained men than in the middle-aged sedentary men. Within the entire population, the PCr/ATP ratio and the E/A peak flow ratio were associated with insulin sensitivity. CONCLUSIONS: Trained middle-aged subjects showed a better pattern of LV energy metabolism and of diastolic function than their sedentary counterparts. At this age the exercise-related cardiac benefits were detectable when physical exercise was performed regularly and for a long period of time.

Increased serum resistin in elite endurance athletes with high insulin sensitivity.

AIMS/HYPOTHESIS: Resistin is an adipokine associated with obesity and type 2 diabetes in animal models, but in humans its role remains uncertain. This study was undertaken to test whether serum resistin is related to insulin resistance and markers of low-grade inflammation in elite athletes taken as a model of extreme insulin sensitivity. SUBJECTS MATERIALS AND METHODS: In 23 elite athletes (sprinters, middle-distance and marathon runners) and in 72 sedentary men including lean and obese individuals with NGT, and obese individuals with IGT or new-onset type 2 diabetes, we assessed insulin sensitivity using a whole-body insulin-sensitivity index (WBISI) derived from a 3-h OGTT; energy homeostasis was also assessed by means of indirect calorimetry, along with circulating adipokines and low-grade pro-inflammatory cyto-chemokines. RESULTS: Professional athletes had increased WBISIs (p<0.001) and lipid oxidation (p<0.03); they also showed higher serum resistin concentrations (p<0.001), although the pro-inflammatory chemokines were not increased in comparison with the other study groups. Resistin was independently associated only with fasting plasma NEFA. Increased resistin was detected in the middle-distance and marathon runners, but not in the sprinters when compared with the lean, young, sedentary individuals. CONCLUSIONS/INTERPRETATION: Serum resistin concentration is increased in elite athletes, providing evidence against the notion that resistin levels reflect insulin resistance in humans, as seen in animal studies. Increased resistin was observed in aerobic-endurance, but not sustained-power athletes and this feature appeared to be independently associated with parameters of fatty acid metabolism.

Reduced whole-body lipid oxidation is associated with insulin resistance, but not with intramyocellular lipid content in offspring of type 2 diabetic patients.

AIMS/HYPOTHESIS: Intramyocellular lipid accumulation and insulin resistance are thought to be due to reduced lipid oxidation in a human model of high risk of developing type 2 diabetes. METHODS: We studied 32 offspring of type 2 diabetic parents and 32 control individuals by means of DXA, indirect calorimetry, insulin clamp and 1H MRS of the calf muscles, and differences between and within study groups were analysed before and after segregation by quartiles of fasting lipid oxidation. RESULTS: In comparison with control subjects, the offspring showed impaired insulin sensitivity, which was associated with higher fasting intramyocellular lipid content (Spearman's rho -0.35; p=0.04), but fasting lipid oxidation did not differ between groups (1.21+/-0.46 vs. 1.25+/-0.37 mg.kg(-1) lean body mass per min; p=0.70). Nevertheless, offspring in the lowest quartile of lipid oxidation had the most severe impairment of insulin sensitivity and a strong association was shown between lipid oxidation and insulin sensitivity within quartiles (Spearman's rho 0.47; p=0.01); this was not observed within the control group (Spearman's rho 0.13; p=0.47). Intramyocellular lipid content was not significantly different within quartiles of lipid oxidation in either of the groups. CONCLUSIONS/INTERPRETATION: Insulin sensitivity improved across increasing quartiles of fasting lipid oxidation in the offspring group, but remained constant in the control group, supporting the hypothesis that impaired fat oxidation is a primary pathogenic factor of insulin resistance in people with a genetic background for type 2 diabetes. Despite their association with impaired insulin sensitivity, soleus and tibialis anterior intramyocellular lipid content remained constant across increasing quartiles of fasting lipid oxidation within both groups.

Functional characterization of 4 polymorphisms in promoter region of hepatic lipase gene.

Hepatic lipase (HL) is a lipolytic enzyme involved in the metabolism of plasma lipoproteins, especially high density lipoproteins. Association studies have provided strong evidence for relations of common mutations in the promoter region of the HL gene to postheparin plasma HL activity and the plasma high density lipoprotein cholesterol concentration, but the functional relevance of these polymorphisms has not been evaluated to date. We analyzed the physiological significance of 4 common polymorphisms (-250G/A, -514C/T, -710T/C, and -763A/G, all in strong linkage disequilibrium) in the promoter of the HL gene by use of electrophoretic mobility shift assays and transient transfection studies in HepG2 cells. No consistent evidence was found for a significant contribution of any of these polymorphisms to the basal rate of transcription of the HL gene. These data suggest that the 4 polymorphisms in the promoter region of the HL gene are in linkage disequilibrium with >/=1 as-yet-unknown functional polymorphisms in the HL gene locus with a significant effect on HL metabolism and/or enzymatic activity.

Smaller, denser LDL particles are not a risk factor for cardiovascular disease in healthy nonagenarian women of the Cremona Population Study.

We evaluated LDL particle size and its relation with other established risk factors for cardiovascular disease in a group of healthy nonagenarian ( > or = 90 years) women participating in the Cremona Population Study. A group of younger healthy postmenopausal women (45-75 years) was used as control group. Nonagenarian women had significantly lower body mass index, systolic and diastolic blood pressure, and fasting insulin concentrations. Plasma total, LDL and HDL cholesterol, apo AI and apo B concentrations, and LpAI and LpAI:AII particles were significantly lower in the nonagenarian group as well. LDL particle size (262.7+/-0.9 vs. 270.1+/-1.1 A) was also lower in the nonagenarian group. The presence of the E4 isoform of apo E in the nonagenarian group resulted in significantly higher levels of plasma apo AI and LpAI:AII particles, and a trend toward larger LDL particles, and a lower diastolic blood pressure. In conclusion, smaller and denser LDL particles might not represent an important risk factor for cardiovascular disease in healthy nonagenarian women of the Cremona Population Study, characterised by a reduced number of LDL particles and other protective factors, like low systolic and diastolic blood pressure, body mass index, and plasma insulin levels.

Hypobetalipoproteinemia associated with apo B-48.4, a truncated protein only 14 amino acids longer than apo B-48.

Familial hypobetalipoproteinemia is an autosomal codominant trait that can be caused by mutations in the apo B gene. Here we report a novel apo B gene mutation causing hypobetalipoproteinemia, that is associated with the synthesis of a truncated apo B protein in a young healthy male subject and his mother. The mutation is an A deletion at position 6627 of the apo B cDNA leading to a truncated protein of 2166 amino acids (apo B-48.4). This truncated apo B was detected mainly in VLDL, LDL and in trace amounts in HDL, but not in the lipoprotein deficient plasma fraction. Affected family members present with elevated levels of HDL-cholesterol, mainly due to an increase in HDL2 particles. Postprandial triglycerides and retinyl esters in the d < 1.006 g/ml lipoprotein in the proband showed a normal response to an oral fat load compared to a group of eight matched healthy controls. In summary this novel mutation is associated with hypobetalipoproteinemia with a normal fat absorption as expected for a protein with a length similar to that of apo B-48.

Increased J774 macrophage cytotoxicity of late postprandial triglyceride-rich lipoproteins from normolipidemic young men expressing an apolipoprotein epsilon 4 allele.

It has been demonstrated that normolipidemic young men with apolipoprotein E4/3 phenotype have a prolonged postprandial clearance of triglyceride-rich lipoproteins following a high-fat diet. In the present study, we isolated fasting and postprandial (3 and 8 h) lipoprotein fraction from normolipidemic young men with E3/3 and E4/3 phenotypes and examined the in vitro cytotoxicity of these lipoproteins towards J774 macrophages. 8 h E4/3 very low density lipoprotein (VLDL) were significantly more cytotoxic than either 8 h E3/3 VLDL or fasting and 3 h E4/3 VLDL (lactate dehydrogenase (LDH) released: 161 +/- 21, 107 +/- 9, 88 +/- 16 and 101 +/- 12 I.U./l, respectively). Fasting E4/3 intermediate density lipoprotein (IDL) were also significantly more cytotoxic than either fasting E3/3 IDL or 3 h and 8 h E4/3 IDL (LDH released: 105 +/- 23, 60 +/- 9, 37 +/- 5 and 53 +/- 16 I.U./l, respectively), whereas either fasting or postprandial low density lipoprotein (LDL) and high density lipoprotein (HDL) samples did not show any difference in cytotoxicity between the two groups studied. 8 h E4/3 VLDL samples incubated with J774 macrophages had a lower esterified cholesterol (40 +/- 3 versus 52 +/- 3 micrograms), and higher triglyceride (783 +/- 133 versus 418 +/- 64 micrograms) and free fatty acid (FFA) (2.0 +/- 0.4 versus 0.9 +/- 0.1 microgram) content than fasting E4/3 VLDL. The increased macrophage cytotoxicity of late postprandial triglyceride-rich lipoproteins seems to be related to the FFA content of E4/3 VLDL.

Influence of breast- and formula-feeding on plasma cholesterol precursor sterols throughout the first year of life.

We evaluated endogenous cholesterol synthesis and plasma lipid profile longitudinally from birth to 1 year old in infants who were exclusively breast-fed (n = 19) or formula-fed (n = 19) for the first 4 months of life. At 1 and 4 months of age, breast-fed infants had higher plasma total and low-density lipoprotein cholesterol and apolipoprotein B levels than formula-fed infants, whereas plasma mevalonate and lanosterol levels were not different between the two study groups.

Lipoprotein profile after combined kidney-pancreas transplantation in insulin dependent diabetes mellitus.

In order to evaluate the effect of a combined kidney-pancreas (KP) transplantation in insulin-dependent diabetes mellitus (IDDM) patients on the lipid and lipoprotein profile, 15 KP patients were compared with 11 kidney (K)--transplanted IDDM patients, 19 IDDM patients on hemodialysis (HD), and 15 nondiabetic control subjects. Cholesterol, triglycerides, apo AI, and apo B were measured in total plasma and in VLDL, LDL, and HDL of all participants. VLDL cholesterol, VLDL-triglycerides, and VLDL-apo B were significantly lower in KP patients, but not in K patients, than in HD patients. In addition, patients in the K, but not in the KP, group showed high levels of apo B in LDL and an increased triglyceride/apo B ratio in VLDL, compared with patients in the HD group. The percentage of apo AI associated with HDL was significantly higher in both transplanted groups than in the HD group. However, compared with a nondiabetic control population, an increase in VLDL particles and in triglyceride content in LDL and HDL still persisted following combined KP transplantation. Insulin resistance (probably due to steroid therapy) associated with high peripheral and potentially low hepatic insulin levels (due to the systemic drainage of the transplanted pancreas) could be the main causes of the remaining lipoprotein abnormalities.

Normalization of lipoprotein composition by intraperitoneal insulin in IDDM. Role of increased hepatic lipase activity.

OBJECTIVE: To characterize the effects of intraperitoneal insulin pump therapy on lipoprotein composition and lipolytic enzyme activity in patients with insulin-dependent diabetes mellitus (IDDM). RESEARCH DESIGN AND METHODS: Ten IDDM patients were studied 3 times: when receiving conventional subcutaneous insulin therapy and at 3 and 9 months from the initiation of intraperitoneal insulin regimen. Ten nondiabetic subjects matched for age, sex, and body weight were studied as controls. Levels of cholesterol, triglycerides, apolipoprotein A-I (apoA-I) and B (apoB) were measured in total plasma and lipoprotein fractions (very-low-density lipoprotein [VLDL], intermediate-density lipoprotein [IDL], low-density lipoprotein [LDL], and high-density lipoprotein [HDL]: HDL2 and HDL3). Postheparin plasma lipoprotein lipase and hepatic lipase activities were determined by an immunochemical method. RESULTS: IDDM patients showed higher levels of HDL3 and lower levels of HDL2 particles during intraperitoneal insulin therapy in comparison with subcutaneous insulin therapy. Both cholesterol and apoA-I significantly increased in HDL3 and decreased in HDL2 during intraperitoneal treatment. Plasma total cholesterol significantly decreased in the diabetic patients at 3 months of intraperitoneal insulin therapy compared with both subcutaneous insulin regimen and control subjects. IDL triglyceride concentrations during intraperitoneal treatment were significantly lower than those seen with subcutaneous therapy. Furthermore, triglyceride:apoB ratio in VLDL and cholesterol:apoB ratio in LDL significantly decreased in IDDM patients treated by intraperitoneal insulin. A significant increase in the activity of hepatic lipase with intraperitoneal insulin therapy by 9 months compared with subcutaneous insulin therapy has been shown. CONCLUSIONS: The increased activity of hepatic lipase after intraperitoneal insulin administration in IDDM patients appears to be one of the main determinants of lipoprotein changes observed, resulting in the normalization of lipoprotein composition during this mode of therapy. The normal inverse relationship between VLDL triglycerides and HDL cholesterol, which was not present in IDDM patients with subcutaneous therapy, was restored with intraperitoneal insulin regimen.