Albert Lecube

Proinflammatory Cytokines, Insulin Resistance, and Insulin Secretion in Chronic Hepatitis C Patients: A Case-Control Study

OBJECTIVE—The purpose of this study was to explore the initial pathogenic mechanisms of diabetes associated with hepatitis C virus (HCV) infection. RESEARCH DESIGN AND METHODS—Insulin resistance, proinflammatory cytokines, and β-cell function were evaluated in a case-control study. A total of 28 consecutive nondiabetic patients with chronic hepatitis C were included in the study (anti-HCV+). Fourteen patients with chronic hepatitis other than HCV infection served as the control group (anti-HCV−). Both groups were closely matched by the main clinical variables associated with insulin resistance and the degree of liver fibrosis. In addition, there were no differences between groups regarding hepatic insulin extraction measured by calculating the ratio between C-peptide and insulin. Serum levels of proinflammatory cytokines (tumor necrosis factor [TNF]-α, soluble TNF receptor [sTNFR] 1, soluble TNFR2, and interleukin-6) were measured by enzyme-linked immunosorbent assay. Insulin resistance (homeostasis model assessment [HOMA] of insulin resistance [HOMA-IR]) and insulin secretion at baseline (HOMA-β) and after various stimulus (oral glucose tolerance test, standard food intake, and intravenous glucagon) were determined by previously validated mathematic indexes. RESULTS—HOMA-IR was higher in anti-HCV+ than in anti-HCV− patients (4.35 ± 2.27 vs. 2.58 ± 1.74; P = 0.01). All the proinflammatory cytokines analyzed were significantly higher in anti-HCV+ patients than in anti-HCV− patients. In addition, sTNFR1 and sTNFR2 were directly correlated to HOMA-IR. HOMA-β as well as insulin and C-peptide responses after the intravenous glucagon test were significantly higher in anti-HCV+ patients than in anti-HC− patients. CONCLUSIONS—Insulin resistance mediated by proinflammatory cytokines, but not a deficit in insulin secretion, could be the primary pathogenic mechanism involved in the development of diabetes associated with HCV infection.

Iron Deficiency in Obese Postmenopausal Women

Objective: This study evaluates whether the iron deficiency suggested in children and adolescents with overweight is also present with increasing age.

Glucose Abnormalities in Patients with Hepatitis C Virus Infection Epidemiology and pathogenesis

Hepatitis C virus (HCV) infection is a major cause of chronic liver disease, affecting ∼3% of the world’s population (1,2). The disease is characterized by silent onset in most infected individuals (3), and recent studies indicate that the rate of progression to advanced liver disease might be lower than previously assumed (4–6). If we consider that most HCV-infected persons are <50 years of age, the burden of disease associated with HCV infection is likely to increase during the next 10–20 years as this cohort reaches the age at which complications of chronic liver disease typically occur (7). The prevalence of type 2 diabetes in people living in the developed world ranges from 2.0 to 9.4% (8), rising to 12.3% in U.S. adults between 40 and 74 years of age (9). The decline in mortality of people with diabetes, together with the rapidly increasing frequency of obesity and the sedentary lifestyle of the population portends a dramatic increase in the prevalence rates of type 2 diabetes (10–11). Therefore, both HCV liver disease and type 2 diabetes are two already prevalent diseases that will probably continue to increase in the next decades. HCV mainly affects the liver, but also several tissues outside the liver have been reported to be involved, resulting in a wide spectrum of extrahepatic manifestations (12–14). During the last decade, it has been hypothesized that diabetes could be one more of these extrahepatic conditions attributable to HCV infection. This raises the intriguing question of whether the rise in HCV infection is contributing to the increasing prevalence of type 2 diabetes. In this review, the available information concerning the epidemiological association between HCV infection and diabetes is summarized. In addition, the physiopathological mechanisms related to the association between HCV and diabetes …

Free insulin growth factor-I and vascular endothelial growth factor in the vitreous fluid of patients with proliferative diabetic retinopathy

PURPOSE To investigate the relationship between insulin-like growth factor-I (IGF-I) and vascular endothelial growth factor (VEGF) in the vitreous fluid of diabetic patients with proliferative diabetic retinopathy (PDR). DESIGN Observational case-control study. METHODS In a prospective study, 37 consecutive diabetic patients with PDR (14 type I and 23 type II diabetes mellitus) in whom a vitrectomy was performed were compared with 21 nondiabetic patients with other conditions requiring vitrectomy (control group). Free IGF-I and VEGF were measured by ELISA. RESULTS Vitreal levels of both free IGF-1 and VEGF were higher in diabetic patients with PDR than in control subjects (P <.01, and P <.0001, respectively). After adjusting for total intravitreous protein concentration, VEGF (ng/mg of proteins) remained significantly higher in diabetic patients with PDR than in the control group (P <.0001), whereas free IGF-I (ng/mg of proteins) was lower in diabetic patients than in control subjects (P <.0001). The vitreous concentrations of VEGF were higher in patients with active PDR than in patients with quiescent PDR (P <.005), whereas vitreous free IGF-I was not related to PDR activity. Finally, we did not observe a correlation between the vitreal levels of free IGF-I and VEGF. CONCLUSIONS We conclude that free IGF-I and VEGF are both increased, but not related, within the vitreous fluid of diabetic patients with PDR. In addition, our results support the current concept that VEGF is directly involved in the pathogenesis of PDR, whereas the precise role of free IGF-I remains to be established.

Iron in obesity. An ancient micronutrient for a modern disease.

Iron is a necessary constituent of several macromolecules involved in cell metabolism, but, at the same time, it could be a potentially dangerous element. For this reason iron balance must be finely regulated. At present, obesity has been recognized as a worldwide public health problem. Excess body fat is associated with increased all‐cause mortality and increased risk for several medical morbidities. Many studies have shown that obesity might increase the risk of iron deficiency but, at the same time, obese subjects exhibit high serum ferritin levels. Recent studies seem to indicate that obesity is associated with iron deficiency although the aetiology appears to be multifactorial and includes (i) A decrease in iron food intake; (ii) An impairment of intestinal iron uptake and iron release from stores because of an overexpression of hepcidin and (iii) Inadequate iron bioavailability because of inflammation. In addition, abnormal ferritin concentrations can be explained by chronic inflammation rather than by iron overload. The aim of the present article is to review current knowledge of iron and obesity.

Lower Zinc-α2-Glycoprotein Production by Adipose Tissue and Liver in Obese Patients Unrelated to Insulin Resistance

CONTEXT Zinc-alpha2 glycoprotein (ZAG) has been proposed as a new candidate in the pathogenesis of obesity, but most of the information stems from studies performed in rodents and in vitro assays. OBJECTIVE The main aim of the study was to compare serum levels of ZAG and its expression (mRNA levels and protein) in adipose tissue and the liver between obese and nonobese subjects. The relationship between ZAG and insulin resistance was also explored. DESIGN This was a case-control study. SETTING The study was conducted at a university referral center. PATIENTS AND METHODS Samples of serum, sc adipose tissue (SAT), visceral adipose tissue (VAT), and liver were obtained from 20 obese subjects during bariatric surgery. Samples from 10 nonobese patients matched by age and gender were used as a control group. Serum ZAG levels were determined by ELISA. ZAG mRNA levels were measured by real-time PCR and protein content by Western blot. The effect of insulin on liver production of ZAG was assessed using HepG2 cultures. RESULTS Serum concentration of ZAG (micrograms per milliliter) was significantly lower in obese subjects (40.87 +/- 10.45 vs. 63.26 +/- 16.40; P = 0.002). ZAG expression was significantly lower in the adipose tissue (SAT and VAT) and liver of obese patients than in control subjects. Significant negative correlations between body mass index and circulating ZAG (r = -0.65, P < 0.001) as well as between body mass index and mRNA ZAG levels in SAT (r = -0.68, P < 0.001) and VAT were detected (r = -0.64, P < 0.001). No relationship was found between ZAG and homeostasis model assessment for insulin resistance and insulin had no effect on ZAG production in vitro. CONCLUSION A down-regulation of ZAG in SAT, VAT, and liver exists in obese patients but seems unrelated to insulin resistance.

Phagocytic Activity Is Impaired in Type 2 Diabetes Mellitus and Increases after Metabolic Improvement

Objective 1) To evaluate whether peripheral blood mononuclear cells (PBMCs) from type 2 diabetic patients present an impairment of phagocytic activity; 2) To determine whether the eventual impairment in phagocytic activity is related to glycemic control and can be reversed by improving blood glucose levels. Methods 21 type 2 diabetic patients and 21 healthy volunteers were prospectively recruited for a case-control study. In addition, those patients in whom HbA1c was higher than 8% (n = 12) were hospitalized in order to complete a 5-day intensification treatment of blood glucose. Phagocytic activity was assessed by using a modified flow cytometry procedure developed in our laboratory based on DNA/RNA viable staining to discriminate erythrocytes and debris. This method is simple, highly sensitive and reproducible and it takes advantage of classic methods that are widely used in flow cytometry. Results Type 2 diabetic patients showed a lower percentage of activated macrophages in comparison with non-diabetic subjects (54.00±18.93 vs 68.53±12.77%; p = 0.006) Significant negative correlations between phagocytic activity and fasting glucose (r = −0.619, p = 0.004) and HbA1c (r = −0.506, p = 0.019) were detected. In addition, multiple linear regression analyses showed that either fasting plasma glucose or HbA1c were independently associated with phagocytic activity. Furthermore, in the subset of patients who underwent metabolic optimization a significant increase in phagocytic activity was observed (p = 0.029). Conclusions Glycemic control is related to phagocytic activity in type 2 diabetes. Our results suggest that improvement in phagocytic activity can be added to the beneficial effects of metabolic optimization.

Diabetes Is the Main Factor Accounting for Hypomagnesemia in Obese Subjects

Objective Type 2 diabetes (T2DM) and obesity are associated with magnesium deficiency. We aimed to determine whether the presence of type 2 diabetes and the degree of metabolic control are related to low serum magnesium levels in obese individuals. Methods A) Case-control study: 200 obese subjects [50 with T2DM (cases) and 150 without diabetes (controls)] prospectively recruited. B) Interventional study: the effect of bariatric surgery on serum magnesium levels was examined in a subset of 120 obese subjects (40 with type 2 diabetes and 80 without diabetes). Results Type 2 diabetic patients showed lower serum magnesium levels [0.75±0.07 vs. 0.81±0.06 mmol/L; mean difference −0.06 (95% CI −0.09 to −0.04); p<0.001] than non-diabetic patients. Forty-eight percent of diabetic subjects, but only 15% of non-diabetic subjects showed a serum magnesium concentration lower than 0.75 mmol/L. Significant negative correlations between magnesium and fasting plasma glucose, HbA1c, HOMA-IR, and BMI were detected. Multiple linear regression analysis showed that fasting plasma glucose and HbA1c independently predicted serum magnesium. After bariatric surgery serum magnesium increased only in those patients in whom diabetes was resolved, but remain unchanged in those who not, without difference in loss weight between groups. Changes in serum magnesium negatively correlated with changes in fasting plasma glucose and HbA1c. Absolute changes in HbA1c independently predicted magnesium changes in the multiple linear regression analysis. Conclusions Our results provide evidence that the presence of diabetes and the degree of metabolic control are essential in accounting for the lower levels of magnesium that exist in obese subjects.

A nontargeted proteomic approach to the study of visceral and subcutaneous adipose tissue in human obesity

Subcutaneous (SAT) and visceral adipose tissue (VAT) differ in biochemical and metabolic properties, especially when obesity is present. We submitted paired SAT and VAT samples from six morbidly obese patients and six non-obese persons to two-dimensional differential gel electrophoresis and matrix-assisted laser desorption/ionization-time-of-flight/time-of-flight mass spectrometry. Compared with non-obese subjects, obese patients presented with increased carboxylesterase-1, zinc finger protein 324A, annexin A5, ubiquitin carboxyl-terminal hydrolase, α-crystallin B chain, osteoglycin, retinal dehydrogenase-1 and 14-3-3 protein γ, and decreased transferrin, complement C3, fibrinogen γ chain, albumin, α1-antitrypsin and peroxiredoxin-6, irrespective of the adipose tissue depot studied. SAT and VAT differed in protein species of fibrinogen and osteoglycin, whereas adipose tissue depot and obesity interacted on the protein abundance of actin, α-actinin 1, one protein species of carboxylesterase-1, retinal dehydrogenase-1 and 14-3-3 protein γ. Our nontargeted proteomic approach identified novel protein species that may be involved in the development of obesity in humans.

Potential Role of Tumor Necrosis Factor-α in Downregulating Sex Hormone–Binding Globulin

Low plasma sex hormone–binding globulin (SHBG) levels are associated with obesity and predict the development of type 2 diabetes. The reason why obese individuals have low circulating SHBG has been attributed to hyperinsulinemia, but no mechanistic evidence has been described. The aim of the current study is to explore whether tumor necrosis factor-α (TNF-α) rather than insulin could be the main factor accounting for low SHBG levels in obesity. We performed in vitro and in vivo studies using human HepG2 cells and human SHBG transgenic mice. In addition, a cross-sectional study to explore the relationship between TNF-α and SHBG in obese patients and an interventional study to examine the effect of insulin administration on circulating SHBG in type 2 diabetic patients were performed. We provide evidence that TNF-α, but not insulin, is the main factor by which SHBG is reduced in obesity. Plasma SHBG was significantly increased rather than decreased after insulin treatment in diabetic patients. TNF-α–induced reduction of SHBG expression was mediated by downregulating HNF4A. Finally, a negative and independent correlation was found between plasma TNF-α receptor 1 and SHBG levels in obese patients. Our results suggest that TNF-α plays an important role downregulating SHBG in chronic low-grade inflammatory diseases such as obesity and type 2 diabetes.