Search

In the attempt to understand the origin of autoantibody (AAb) production in patients with and at-risk for T1D, multiple studies have analyzed and reported alterations in follicular helper T cells (Tfh) in presymptomatic AAb-positive subjects and patients with T1D. Yet, it is still not clear whether the regulatory counterpart of Tfh cells, represented by follicular regulatory T cells (Tfr), is similarly altered. To address this question, we performed analyses in peripheral blood, spleen and pancreatic lymph nodes (PLN) of organ donor subjects with T1D. Blood analyses were also performed in living AAb-negative and -positive subjects. While negligible differences in the frequency and phenotype of blood Tfr cells were observed between T1D, AAb-negative and AAb-positive adult subjects, the frequency of Tfr cells was significantly reduced in spleen and PLN of T1D as compared to non-diabetic controls. Furthermore, adoptive transfer of Tfr cells delayed disease development in a mouse model of T1D, a finding that could indicate that Tfr cells play an important role in peripheral tolerance and regulation of autoreactive Tfh cells. Together, our findings provide evidence of Tfr cell alterations within disease-relevant tissues in patients with T1D suggesting a role for Tfr cells in defective humoral tolerance and disease pathogenesis.

Autoantibodies (AAbs) are a hallmark of Type 1 diabetes (T1D). Alterations in the frequency and phenotype of follicular helper (Tfh) T cells have been previously documented in patients with type 1 diabetes (T1D), but the contribution of follicular regulatory T (Treg) cells, which are responsible for suppressing AAb development, is less clear. Here, we investigated the frequency and activation status of follicular (CXCR5

BACKGROUND. Neutrophils and their inflammatory mediators are key pathogenic components in multiple autoimmune diseases, while their role in human type 1 diabetes (T1D), a disease that progresses sequentially through identifiable stages prior to the clinical onset, is not well understood. We previously reported that the number of circulating neutrophils is reduced in patients with T1D and in presymptomatic at-risk subjects. The aim of the present work was to identify possible changes in circulating and pancreas-residing neutrophils throughout the disease course to better elucidate neutrophil involvement in human T1D. METHODS. Data collected from 389 subjects at risk of developing T1D, and enrolled in 4 distinct studies performed by TrialNet, were analyzed with comprehensive statistical approaches to determine whether the number of circulating neutrophils correlates with pancreas function. To obtain a broad analysis of pancreas-infiltrating neutrophils throughout all disease stages, pancreas sections collected worldwide from 4 different cohorts (i.e., nPOD, DiViD, Siena, and Exeter) were analyzed by immunohistochemistry and immunofluorescence. Finally, circulating neutrophils were purified from unrelated nondiabetic subjects and donors at various T1D stages and their transcriptomic signature was determined by RNA sequencing. RESULTS. Here, we show that the decline in β cell function is greatest in individuals with the lowest peripheral neutrophil numbers. Neutrophils infiltrate the pancreas prior to the onset of symptoms and they continue to do so as the disease progresses. Of interest, a fraction of these pancreas-infiltrating neutrophils also extrudes neutrophil extracellular traps (NETs), suggesting a tissue-specific pathogenic role. Whole-transcriptome analysis of purified blood neutrophils revealed a unique molecular signature that is distinguished by an overabundance of IFN-associated genes; despite being healthy, said signature is already present in T1D-autoantibody-negative at-risk subjects. CONCLUSIONS. These results reveal an unexpected abnormality in neutrophil disposition both in the circulation and in the pancreas of presymptomatic and symptomatic T1D subjects, implying that targeting neutrophils might represent a previously unrecognized therapeutic modality. FUNDING. Juvenile Diabetes Research Foundation (JDRF), NIH, Diabetes UK.

Type 2 diabetes is associated with risk of cancer. Hyperinsulinemia and insulin resistance may be the link with cancer, but whether this is independent of the diabetes status, obesity/visceral obesity and metabolic syndrome is uncertain and the present study wanted to address this issue. Fifteen-year all-cause, CVD and cancer mortality data were obtained through the Regional Health Registry in 2,011 out of 2,074 Caucasian middle-aged individuals of the Cremona Study, a population study on the prevalence of diabetes mellitus in Italy in which anthropometric and metabolic characteristics were collected. During the 15-year observation period, 495 deaths were registered: 221 CVD related and 180 cancer related. Age and sex were independently associated with all-cause, cancer and CVD mortality rates. Age- and sex-adjusted analysis showed that HOMA-IR, cigarette smoking and diabetes were independently associated with all-cause mortality; HOMA-IR, systolic blood pressure and fibrinogen were independently associated with CVD mortality; HOMA-IR and smoking habit were independently associated with cancer mortality. Individuals in the highest quintile of serum insulin had a 62% higher risk of cancer mortality (HR = 1.62 95% CI: 1.19-2.20; P

A fatty liver, which is a common feature in insulin-resistant states, can lead to chronic liver disease. It has been hypothesized that a fatty liver can also increase the rates of non-hepatic-related morbidity and mortality. Therefore, we wanted to determine whether the fatty liver index (FLI), a surrogate marker and a validated algorithm derived from the serum triglyceride level, body mass index, waist circumference, and γ-glutamyltransferase level, was associated with the prognosis in a population study. The 15-year all-cause, hepatic-related, cardiovascular disease (CVD), and cancer mortality rates were obtained through the Regional Health Registry in 2011 for 2074 Caucasian middle-aged individuals in the Cremona study, a population study examining the prevalence of diabetes mellitus in Italy. During the 15-year observation period, 495 deaths were registered: 34 were hepatic-related, 221 were CVD-related, 180 were cancer-related, and 60 were attributed to other causes. FLI was independently associated with the hepatic-related deaths (hazard ratio = 1.04, 95% confidence interval = 1.02-1.05, P < 0.0001). Age, sex, FLI, cigarette smoking, and diabetes were independently associated with all-cause mortality. Age, sex, FLI, systolic blood pressure, and fibrinogen were independently associated with CVD mortality; meanwhile, age, sex, FLI, and smoking were independently associated with cancer mortality. FLI correlated with the homeostasis model assessment of insulin resistance (HOMA-IR), a surrogate marker of insulin resistance (Spearman's ρ = 0.57, P < 0.0001), and when HOMA-IR was included in the multivariate analyses, FLI retained its association with hepatic-related mortality but not with all-cause, CVD, and cancer-related mortality. Conclusion: FLI is independently associated with hepatic-related mortality. It is also associated with all-cause, CVD, and cancer mortality rates, but these associations appear to be tightly interconnected with the risk conferred by the correlated insulin-resistant state. © 2011 American Association for the Study of Liver Diseases

"\"Objective Trimetazidine may have beneficial effects on left ventricular (LV) function in patients with systolic heart failure. The authors assessed whether long-term addition of trimetazidine to conventional treatment could improve, along with LV function, resting whole body energy metabolism in patients with chronic systolic heart failure. Design Single blind randomised study. Setting University Hospital. Patients 44 patients with systolic heart failure receiving full medical treatment. Interventions Indirect calorimetry and two-dimensional echocardiography at baseline and after 3 months. Main outcome measures Whole body resting energy expenditure (REE), percentage of predicted REE, LV ejection fraction (EF), NYHA class, quality of life. Results Trimetazidine increased EF compared with conventional therapy alone (from 35 +\\\/- 8% to 42 +\\\/- 11% vs from 35 +\\\/- 7% to 36 +\\\/- 6%; p=0.02, analysis of variance for repeated measures). NYHA class and quality of life also improved compared with conventional therapy (p

ApoE is a polymorphic protein involved in the metabolism of plasma lipoproteins; the e4 allele was shown to be associated with coronary and aortic atherosclerosis in age-dependent fashion mediated by unknown mechanisms. This study was undertaken to assess whether the apoE isoforms in humans were associated with normal glucose tolerance and with metabolic and inflammatory risk factors of CVD. ApoE genotype was assessed in 365 individuals. Of those, 309 were studied in the postabsorptive conditions and 142 of them also underwent a 3h-OGTT; 56 additional subjects were studied by means of the insulin clamp in combination with [6,6-2H2] glucose infusion. ApoE genotype frequencies were similar to those previously reported and were not influenced by age and BMI. Fasting plasma glucose, insulin, FFA, the lipid profile, surrogate markers (HOMA-IR, OGTT-derived index) as well as the clamp-derived parameters or insulin sensitivity and insulin secretion were not different by apoE genotypes. Serum adipokines concentrations (leptin, adiponectin, resistin) and markers of inflammation (serum fasting hsCRP and MCP1/CCL2) were also not different by apoE genotypes. In the subgroup of young e4 carriers which underwent the clamp procedure, a higher fasting endogenous glucose production was detected. ApoE genotype was not associated with insulin resistance or altered insulin secretion, and no abnormalities in the typical circulating endocrine, metabolic, and inflammatory features of the insulin resistance syndrome were detected. © Springer-Verlag 2011

OBJECTIVE Some obese individuals have normal insulin sensitivity. It is controversial whether this phenotype is associated with increased all-cause mortality risk. RESEARCH DESIGN AND METHODS Fifteen-year all-cause mortality data were obtained through the Regional Health Registry for 2,011 of 2,074 Caucasian middle-aged individuals of the Cremona Study, a population study on the prevalence of diabetes in Italy. Individuals were divided in four categories according to BMI (nonobese: RESULTS Obese insulin-sensitive subjects represented 11% (95% CI 8.1–14.5) of the obese population. This phenotype had similar BMI but lower waist circumference, blood pressure, fasting glucose, triglycerides, and fibrinogen and higher HDL cholesterol than obese insulin-resistant subjects. In the 15-year follow-up, 495 deaths (cardiovascular disease [CVD]: n = 221; cancer: n = 180) occurred. All-cause mortality adjusted for age and sex was higher in the obese insulin-resistant subjects (hazard ratio 1.40 [95% CI 1.08–1.81], P = 0.01) but not in the obese insulin-sensitive subjects (0.99 [0.46–2.11], P = 0.97) when compared with nonobese insulin-sensitive subjects. Also, mortality for CVD and cancer was higher in the obese insulin-resistant subjects but not in the obese insulin-sensitive subjects when compared with nonobese insulin-sensitive subjects. CONCLUSIONS In contrast to obese insulin-resistant subjects, metabolically healthy obese individuals are less common than previously thought and do not show increased all-cause, cancer, and CVD mortality risks in a 15-year follow-up study.

ObjectiveExercise training may cause changes in thyroid function. This thyroid response may be due to exercise-induced modulation of energy metabolism but also of the adipocytes endocrine function. In particular, the role of leptin and of circulating soluble leptin receptor (sOB-R) was unexplored. The aim of this study was to assess the relationships between thyroid function, whole body energy metabolism, and adipokines – mainly leptin and its receptor, sOB-R.MethodsWe measured serum TSH, free tri-iodothyronine (FT3), free thyroxine, leptin, and sOB-R and assessed energy homeostasis by means of indirect calorimetry, in 27 highly trained athletes and 27 sedentary, healthy men.ResultsTSH–FT3 ratio was lower in athletes (Pn=13) or marathon runners (n=14). Whole body respiratory quotient was lower in athletes. Fasting serum sOB-R was higher and leptin lower in athletes than controls. Also serum adiponectin, resistin, and retinol binding protein-4 concentrations were different in athletes than in controls. The ratio between leptin and sOB-R, the free leptin index (FLI), was lower in athletes than in controls (0.025±0.014 vs 0.085±0.049; P3 ratio.ConclusionMale, elite athletes had lower TSH–FT3 ratio and FLI than controls while FLI was independently associated with TSH–FT3 ratio supporting the hypothesis that the level of biologically active leptin is involved in the adaptive response of thyroid function in professional athletes.

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. 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.

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.

Fatty liver is characterized by metabolic abnormalities at the liver, but also at skeletal muscle and adipose tissue sites. It is hypothesized that the heart may be suffering metabolic alterations, and this study was undertaken to ascertain whether individuals with fatty liver have left ventricular (LV) alterations of energy metabolism, structure, and function and abnormal amounts of epicardial fat as a specific marker of visceral fat accumulation. To this end we studied young, nondiabetic men matched for anthropometric features with (n = 21) or without (n = 21) fatty liver by means of (1) cardiac magnetic resonance imaging (MRI); (2) cardiac 31P-MR spectroscopy (MRS); and (3) hepatic 1H-MRS to assess quantitatively the intrahepatic fat (IHF) content. Insulin sensitivity was determined by the updated HOMA-2 computer model. Individuals with fatty liver showed reduced insulin sensitivity, increased serum free fatty acid (FFA), and E-selectin, abnormal adipokine concentrations, and higher blood pressure. LV morphology and systolic and diastolic functions were not different; however, in the scanned intrathoracic region, the intrapericardial (7.8 ± 3.1 versus 5.9 ± 2.5 cm2; P < 0.05) and extrapericardial (11.7 ± 6.1 versus 7.8 ± 3.2 cm2; P < 0.03) fat was increased in men with fatty liver compared with those without fatty liver. 1The phosphocreatine (PCr)/adenosine triphosphate (ATP) ratio, a recognized in vivo marker of myocardial energy metabolism, was reduced in men with fatty liver in comparison with normals (1.85 ± 0.35 versus 2.11 ± 0.31; P < 0.016). In conclusion, in newly found individuals with fatty liver, fat was accumulated in the epicardial area and despite normal LV morphological features and systolic and diastolic functions, they had abnormal LV energy metabolism. Copyright © 2007 by the American Association for the Study of Liver Diseases

OBJECTIVE—Perturbations in cardiac energy metabolism might represent early alterations in diabetes preceding functional and pathological changes. We evaluated left ventricular (LV) structure/geometry and function in relation to energy metabolism and cardiovascular risk factors in overweight/obese men using magnetic resonance techniques. RESEARCH DESIGN AND METHODS—We studied 81 healthy men (aged 22–55 years, with BMI between 19 and 35 kg/m2) by means of cardiac magnetic resonance imaging and 31P-magnetic resonance spectroscopy in the resting and fasted conditions and stratified them in quartiles of BMI (cut offs: 23.2, 25.5 and 29.0 kg/m2). RESULTS—LV mass increased across quartiles of BMI; meanwhile, the volumes did not differ. Parameters of LV systolic and diastolic function were not different among quartiles. The phosphocreatine-to-ATP ratio was reduced across increasing quartiles of mean ± SD BMI (2.25 ± 0.52, 1.89 ± 0.26, 1.99 ± 0.38, and 1.79 ± 0.29; P < 0.006) in association with insulin sensitivity (computer homeostasis model assessment 2 model); this relation was independent of age, BMI, blood pressure, wall mass, HDL cholesterol, triglycerides, smoking habits, and metabolic syndrome. CONCLUSIONS—Abnormal LV energy metabolism was detectable in obese men in the presence of normal function, supporting the hypothesis that metabolic remodeling in insulin resistant states precedes functional and structural/geometrical remodeling of the heart regardless of the onset of overt hyperglycemia.

We evaluated LDL particle size and its relation with other established risk factors for cardiovascular disease in a group of healthy nonagenarian (≥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.

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.

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.

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.

Based on the "lipotoxic" hypothesis, the free fatty acid flux from the excessive amount of adipose tissue toward the peripheral tissues would induce the development of insulin resistance especially when the triglyceride storage or the concentration of intermediate fat metabolites (diacylglycerides, ceramides) within the cytoplasm of these cells become excessive. Nonalcoholic fatty liver disease (NAFLD) includes a wide spectrum of liver damage, ranging from simple steatosis to steatohepatitis and advanced fibrosis. NAFLD is associated with general and intra-abdominal obesity and with a reduced ability of insulin to stimulate metabolic pathways in the liver itself and in other tissues. There are animal models and models in human diseases sustaining the hypothesis that a primary hepatic disease may determine the development of type 2 diabetes (T2DM). Epidemiologic data generated on surrogate markers of NAFLD (transaminases and γ-glutamyltransferase), semiquantitative assessment of fatty liver (ultrasound), and surrogate algorithms of NAFLD also support a causative effect of NAFLD on the risk to develop T2DM. In spite of the presence of these indirect associations, a clear-cut link between NAFLD and abnormal β-cell function is yet to be reported. Therefore, more data are warranted to prove what is considered a likely causative relationship between NAFLD and T2DM. © 2011 Springer Science+Business Media, LLC

Background: This study was performed to assess left ventricular (LV) energy metabolism and function in patients with type 1 diabetes with or without overt microvascular complications. Methods: We performed cardiac Magnetic Resonance Imaging (MRI) and 31P spectroscopy (MRS) in 24 patients with overt microvascular complications and in 15 carefully selected patients without complications in spite of a long duration of the disease (> 20 years) and matched for anthropometric features. 31 healthy subjects served as a control group. Results: Systolic function was preserved in all study subjects. Patients with overt complications showed a higher LV wall mass/end diastolic volume ratio and altered parameters of diastolic function when compared to patients without complications and to controls. They were also characterized by lower PCr/ATP ratio (a recognized marker of energy metabolism). No effect of HbA1c was detected within groups. Conclusions: In patients with type 1 diabetes 1) overt microvascular complications were associated with altered LV geometry, diastolic function and energy metabolism 2) in patients without complications and duration of disease > 20 years no association with these alterations were found despite poor glycemic control. The features of this highly selected subgroup of patients demonstrated that long lasting chronic hyperglycemia per se is not sufficient to induce abnormality of cardiac energy metabolism and that additional yet to be identified (metabolic or genetic) factors must be important contributing factors. © 2010 Elsevier Ireland Ltd. All rights reserved

OBJECTIVE - Monocyte chemoattractant protein-1 (MCP-1/CCL2) is a chemokine involved into the pathogenesis of atherosclerosis and has prognostic value in the acute and chronic phases in patients with acute coronary syndromes. RESEARCH DESIGN AND METHODS - MCP-1/CCL2 concentration was measured in plasma fractions of 363 middle-aged overweight/obese individuals (aged 61 12 years BMI 30.1 +/- 6.6 kg/m(2), 15% with type 2 diabetes, and 12% with impaired glucose tolerance) of a population survey carried out in 1990-1991 in Lombardy, Italy (Cremona Study), and cardiovascular disease (CVD) mortality was assessed in 2006 through Regional Health Registry files. RESULTS - At baseline MCP-1/CCL2 was increased in individuals with type 2 diabetes (p < 0.05) and showed significant correlations with biochemical risk markers of atherosclerosis. After 15 years, among the 363 subjects, there were 82 deaths due to CVD. In univariate analysis age, sex, fasting glucose and insulin, fibrinogen, glucose tolerance status, smoking habit, and MCP-1/CCL2 were associated with CVD mortality. Age, sex, fasting serum glucose, MCP-1/CCL2, and smoking habit maintained an independent association with CVD mortality in multiple regression analysis. In a subgroup of 113 subjects in whom data for C-reactive protein (CRP) were available, its level was not predictive of CVD mortality. CONCLUSIONS - In middle-aged overweight/obese individuals MCP-1/CCL2 was independently associated with CVD mortality. Further studies will be necessary to establish its role as a surrogate biomarker and as a potential therapeutic target. OBJECTIVE Monocyte chemoattractant protein-1 (MCP-1/CCL2) is a chemokine involved into the pathogenesis of atherosclerosis and has prognostic value in the acute and chronic phases in patients with acute coronary syndromes. RESEARCH DESIGN AND METHODS MCP-1/CCL2 concentration was measured in plasma fractions of 363 middle-aged overweight/obese individuals (aged 61 ± 12 years, BMI 30.1 ± 6.6 kg/m2, 15% with type 2 diabetes, and 12% with impaired glucose tolerance) of a population survey carried out in 1990–1991 in Lombardy, Italy (Cremona Study), and cardiovascular disease (CVD) mortality was assessed in 2006 through Regional Health Registry files. RESULTS At baseline MCP-1/CCL2 was increased in individuals with type 2 diabetes (P < 0.05) and showed significant correlations with biochemical risk markers of atherosclerosis. After 15 years, among the 363 subjects, there were 82 deaths due to CVD. In univariate analysis age, sex, fasting glucose and insulin, fibrinogen, glucose tolerance status, smoking habit, and MCP-1/CCL2 were associated with CVD mortality. Age, sex, fasting serum glucose, MCP-1/CCL2, and smoking habit maintained an independent association with CVD mortality in multiple regression analysis. In a subgroup of 113 subjects in whom data for C-reactive protein (CRP) were available, its level was not predictive of CVD mortality. CONCLUSIONS In middle-aged overweight/obese individuals MCP-1/CCL2 was independently associated with CVD mortality. Further studies will be necessary to establish its role as a surrogate biomarker and as a potential therapeutic target.

CONTEXT:Serum retinol-binding protein 4 (RBP-4), leptin, and adiponectin concentrations identify insulin resistance in varied conditions, but their relationships with insulin sensitivity and ectopic fat accumulation are unclear.OBJECTIVE:Our objective was to establish how these adipokines are related with intramyocellular lipid (IMCL) and intrahepatic lipid (IHL) content.DESIGN AND SETTING:We assessed retrospectively serum fasting RBP-4 concentrations in 1) 53 nondiabetic individuals in which insulin sensitivity and IMCL content were assessed by means of the insulin clamp and of 1H magnetic resonance spectroscopy of the calf muscles, and 2) 140 nondiabetic individuals in which insulin sensitivity and the IHL content were assessed by means of the updated homeostasis model assessment and of 1H magnetic resonance spectroscopy. In both experiments, serum leptin and adiponectin concentrations were measured.RESULTS:Fasting serum RBP-4, adiponectin, and leptin were associated with peripheral insulin sensitivity, were abnormal in the first-degree relatives of type 2 diabetic parents, and correlated with the soleus IMCL content and with the IHL content. The association of RBP-4 and adiponectin with insulin sensitivity was age, sex, and body mass index independent, but stepwise regression analysis suggested that RBP-4, but not adiponectin and leptin, was independently associated with insulin sensitivity. Adiponectin was independently associated with the IHL content, RBP-4, and leptin with the soleus IMCL content.CONCLUSION:Serum RBP-4 was a robust marker of insulin resistance. Serum RBP-4, leptin, and adiponectin concentrations reflected ectopic fat accumulation in humans CONTEXT:Serum retinol-binding protein 4 (RBP-4), leptin, and adiponectin concentrations identify insulin resistance in varied conditions, but their relationships with insulin sensitivity and ectopic fat accumulation are unclear.OBJECTIVE:Our objective was to establish how these adipokines are related with intramyocellular lipid (IMCL) and intrahepatic lipid (IHL) content.DESIGN AND SETTING:We assessed retrospectively serum fasting RBP-4 concentrations in 1) 53 nondiabetic individuals in which insulin sensitivity and IMCL content were assessed by means of the insulin clamp and of 1H magnetic resonance spectroscopy of the calf muscles, and 2) 140 nondiabetic individuals in which insulin sensitivity and the IHL content were assessed by means of the updated homeostasis model assessment and of 1H magnetic resonance spectroscopy. In both experiments, serum leptin and adiponectin concentrations were measured.RESULTS:Fasting serum RBP-4, adiponectin, and leptin were associated with peripheral insulin sensitivity, were abnormal in the first-degree relatives of type 2 diabetic parents, and correlated with the soleus IMCL content and with the IHL content. The association of RBP-4 and adiponectin with insulin sensitivity was age, sex, and body mass index independent, but stepwise regression analysis suggested that RBP-4, but not adiponectin and leptin, was independently associated with insulin sensitivity. Adiponectin was independently associated with the IHL content, RBP-4, and leptin with the soleus IMCL content.CONCLUSION:Serum RBP-4 was a robust marker of insulin resistance. Serum RBP-4, leptin, and adiponectin concentrations reflected ectopic fat accumulation in humans.

OBJECTIVE—Fatty liver may be involved in the pathogenesis of type 2 diabetes. Physical exercise is a tool to improve insulin sensitivity, but little is known about its effect on intrahepatic fat (IHF) content. The purpose of this study was to examine the association of habitual physical activity, insulin resistance, and adiponectin with IHF content. RESEARCH DESIGN AND METHODS—Participants were 191 (77 female and 114 male) apparently healthy, nonalcoholic individuals (aged 19–62 years; BMI 17.0–35.5 kg/m2). IHF content was assessed in a quantitative fashion and noninvasively as a continuous variable by means of 1H magnetic resonance spectroscopy (MRS), and habitual physical activity was assessed by means of a questionnaire. Fatty liver was defined as IHF content of >5% wet weight, and insulin sensitivity was estimated using the computer homeostasis model assessment (HOMA)-2 indexes. RESULTS—A reduced prevalence of fatty liver in the quartile of the most physically active individuals (25, 11, 25, and 2% in quartile 1, 2, 3, and 4, respectively; χ2 = 15.63; P = 0.001) was found along with an inverse correlation between the physical activity index and the IHF content when plotted as continuous variables (Pearson’s r = −0.27; P < 0.000). This association was not attenuated when adjusted for age, sex, BMI, HOMA-2, and adiponectin (partial correlation r = −0.25; P < 0.001). CONCLUSIONS—This study demonstrated that a higher level of habitual physical activity is associated with a lower IHF content and suggested that this relationship may be due to the effect of exercise per se.

CONTEXT:Serum resistin concentration is increased in patients with nonalcoholic fatty liver disease in proportion with the histological severity of the disease, but the relevance of the contribution of fatty liver per se is undetermined.OBJECTIVE:The objective of the study was to assess the relationship between serum resistin and the degree of ectopic fat accumulation in vivo in humans.DESIGN AND SETTING:The hepatic fat (IHF) content, measured quantitatively by means of 1H magnetic resonance spectroscopy, serum resistin, and biochemical and hormonal metabolic correlates of fatty liver and insulin resistance were assessed in 28 affected patients, and 47 individuals with comparable anthropometric features served as controls. Insulin sensitivity was estimated using the computer homeostatic model assessment (HOMA)-2. A subset of volunteers (n = 18) also underwent 1H magnetic resonance spectroscopy of the calf muscles to assess the intramyocellular lipid content (IMCL).RESULTS:In patients with fatty liver, the IHF content (13 +/- 8 vs. 2 +/- 1% wet weight; P < 0.0001) and also the soleus IMCL content (P < 0.05) were increased in comparison with the controls. Patients with fatty liver had lower insulin sensitivity (HOMA2 insulin sensitivity: 59 +/- 24 vs. 72 +/- 29%; P < 0.04), serum resistin (3.4 +/- 0.8 vs. 3.9 +/- 1.0 ng/ml; P < 0.02), and adiponectin (P < 0.01) concentrations. Serum resistin was inversely correlated with the IHF content (r = -0.35; P < 0.003) and the soleus IMCL content (r = -0.51; P < 0.05) but not HOMA2 insulin sensitivity.CONCLUSION:This study demonstrates that excessive ectopic fat accumulation in the liver and skeletal muscle of insulin-resistant subjects is associated with lower serum resistin concentration and not with hyperresistinemia CONTEXT:Serum resistin concentration is increased in patients with nonalcoholic fatty liver disease in proportion with the histological severity of the disease, but the relevance of the contribution of fatty liver per se is undetermined.OBJECTIVE:The objective of the study was to assess the relationship between serum resistin and the degree of ectopic fat accumulation in vivo in humans.DESIGN AND SETTING:The hepatic fat (IHF) content, measured quantitatively by means of 1H magnetic resonance spectroscopy, serum resistin, and biochemical and hormonal metabolic correlates of fatty liver and insulin resistance were assessed in 28 affected patients, and 47 individuals with comparable anthropometric features served as controls. Insulin sensitivity was estimated using the computer homeostatic model assessment (HOMA)-2. A subset of volunteers (n = 18) also underwent 1H magnetic resonance spectroscopy of the calf muscles to assess the intramyocellular lipid content (IMCL).RESULTS:In patients with fatty liver, the IHF content (13 +/- 8 vs. 2 +/- 1% wet weight; P < 0.0001) and also the soleus IMCL content (P < 0.05) were increased in comparison with the controls. Patients with fatty liver had lower insulin sensitivity (HOMA2 insulin sensitivity: 59 +/- 24 vs. 72 +/- 29%; P < 0.04), serum resistin (3.4 +/- 0.8 vs. 3.9 +/- 1.0 ng/ml; P < 0.02), and adiponectin (P < 0.01) concentrations. Serum resistin was inversely correlated with the IHF content (r = -0.35; P < 0.003) and the soleus IMCL content (r = -0.51; P < 0.05) but not HOMA2 insulin sensitivity.CONCLUSION:This study demonstrates that excessive ectopic fat accumulation in the liver and skeletal muscle of insulin-resistant subjects is associated with lower serum resistin concentration and not with hyperresistinemia.

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

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. © Springer-Verlag 2005

OBJECTIVE—This study was performed to ascertain whether insulin resistance with respect to protein metabolism is an additional primary metabolic abnormality affecting insulin-resistant offspring of type 2 diabetic parents, along with insulin resistance with respect to glucose and lipid metabolism. RESEARCH DESIGN AND METHODS—We studied 18 young, nonobese offspring of type 2 diabetic parents and 27 healthy matched (by means of dual-energy X-ray absorption) individuals with the bolus plus continuous infusion of [6,6-2H2]glucose and [1-13C]leucine in combination with the insulin clamp (40 mU · m–2 · min−1). RESULTS—Fasting plasma leucine, phenylalanine, alanine, and glutamine concentrations, as well as the glucose and leucine turnover (reciprocal pool model: 155 ± 10 vs. 165 ± 5 μmol · kg lean body mass–1 · h−1 in offspring of type 2 diabetic patients and healthy matched individuals, respectively), were also not different. During the clamp, glucose turnover rates were significantly reduced in offspring of type 2 diabetic patients (7.1 ± 0.5) in comparison with healthy matched individuals (9.9 ± 0.6 mg · kg lean body mass–1 · min−1; P < 0.01). Also, the suppression of leucine turnover was impaired in offspring of type 2 diabetic patients (12 ± 1%) in comparison with healthy matched individuals (17 ± 1%; P = 0.04) and correlated with the degree of the impairment of insulin-stimulated glucose metabolism (R2 = 0.13; P = 0.02). CONCLUSIONS—Nonobese, nondiabetic, insulin-resistant offspring of type 2 diabetic patients were characterized by an impairment of insulin-dependent suppression of protein breakdown, which was proportional to the impairment of glucose metabolism. These results demonstrate that in humans, a primary in vivo impairment of insulin action affects glucose and fatty acid metabolism as previously shown and also protein/amino acid metabolism.

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 dB1.006 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. © 1998 Elsevier Science Ireland Ltd. All rights reserved.

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.

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.