Relationship between fatty liver and glucose metabolism: A cross-sectional study in 571 obese children

BACKGROUND AND AIMS: Early onset type 2 diabetes mellitus (T2DM) is associated with obesity, insulin resistance and impaired beta-cell function. Non-alcoholic fatty liver disease (NAFLD) may be an independent risk factor for T2DM. We investigated the relationship between NAFLD and glucose metabolism in a large sample of obese children. METHODS AND RESULTS: A total of 571 obese children (57% males and 43% females) aged 8-18 years were consecutively studied at a tertiary care centre specialised in paediatric obesity. Liver ultrasonography was used to diagnose NAFLD after exclusion of hepatitis B and C and alcohol consumption. Oral-glucose tolerance testing (OGTT) was performed; insulin sensitivity was evaluated by using the insulin sensitivity index (ISI) and beta-cell function by using the ratio between the incremental areas under the curve (AUC) of insulin and glucose (incAUCins/incAUCglu). A total of 41% of the obese children had NAFLD. Impaired glucose tolerance or T2DM was present in 25% of the children with NAFLD versus 8% of those without it (p<0.001). Children with NAFLD had higher body mass index (BMI), fasting glucose, 120-min OGTT glucose, incAUCins/incAUCglu and lower ISI as compared with children without NAFLD (p</=0.002). At bootstrapped multivariable median regression analysis controlling for gender, age, pubertal status and BMI, NAFLD was an independent predictor of 120-min OGTT glucose and ISI, but not of incAUCins/incAUCglu. Similar findings were obtained using continuous liver steatosis as the predictor, instead of dichotomous NAFLD. CONCLUSION: NAFLD was present in 41% of our obese children and was associated with higher insulin resistance, but not with impaired beta-cell function

Elevated Concentrations of Liver Enzymes and Ferritin Identify a New Phenotype of Insulin Resistance: Effect of Weight Loss After Gastric Banding

BACKGROUND: Several studies have associated elevated liver enzymes (LFTs), obesity, and type 2 diabetes (T2DM), and a link has been established between insulin resistance (IR) and elevated ferritin concentrations. We examined the relationship between LFTs, ferritin, and IR in morbid obese subjects and the effect of weight loss after bariatric surgery. METHODS: We measured liver enzymes, ferritin, insulin resistance, and glucose tolerance (by OGTT) in 159 morbid obese subjects (BMI = 44.4 +/- 0.4 kg/m(2)) at baseline, 6 months and 1 year after laparoscopic-adjustable-gastric banding (LAGB). Subjects were divided in two groups: increased LFTs (ALT > 30; AST/ALT < 1) vs. normal LFTs. RESULTS: A large proportion of morbid obese subjects had increased LFTs (44%) which were associated with increased IR and ferritin, suggesting potential liver disease. A majority of the morbidly obese with increased LFTs, IGT, and T2DM, were male and had almost double ferritin concentrations, strongly correlated with ALT (r = 0.43, p < 0.0001). Both ferritin and ALT correlated with waist circumference and IR. One year after, LAGB glucose tolerance improved, LFTs and IR were reduced; ferritin did not change significantly, but was still correlated with IR. CONCLUSIONS: Ferritin may be an additional useful marker for more severe hepatic IR

Biodiversity of grapevines (Vitis vinifera L.) grown in the Province of Verona

PCR-based DNA microsatellite analysis has been applied to define the genetic relationships among 7 most representative grapevine cultivars grown in the province of Verona, 5 ancient grapevine and two varieties grown in different regions of Italy. For each variety three different clones or accessions were investigated to assess genotypical uniformity; in 5 cases we found out intravarietal dissimilarity. SSR data were used to create a distance matrix and then a polylogenetic tree. Results show a polygenetic relationship among some cultivated (Corvina, Rondinella, Molinara, Trebbiano di Soave-Verdicchio) and ancient (Dindarella-Pelara, Oseleta, Rossetta di montagna) varieties all grown in the Valpolicella hills, suggesting the possibility that their evolution occurred in the same area and with few common anchestors. Two situations of synonyms that had already described between Trebbiano di Soave and Verdicchio, and between Dindarella and Pelara, were confirmed by a molecular method as SSR analysis. Amplification of Trebbiano di Soave/Verdicchio locus VVMD36 yielded a fragment of 500 bp, this allele provides a fast and reliable tool to differentiate among Trebbiano grapevines.

Visceral fat and beta cell function in non-diabetic humans

n/

Insulin resistance in non-diabetic patients with non-alcoholic fatty liver disease: sites and mechanisms

n/

Macropinocytotic uptake and infection of human epithelial cells with species B2 adenovirus type 35

The human adenovirus serotype 35 (HAdV-35, short Ad35) causes kidney and urinary tract infections, and infects respiratory organs of immunocompromised individuals. Unlike other adenoviruses, Ad35 has a low seroprevalence which makes Ad35-based vectors promising candidates for gene therapy. Ad35 utilizes CD46 and integrins as receptors for infection of epithelial and hematopoietic cells. Here, we show that infectious entry of Ad35 into HeLa, human kidney HK-2 cells and normal human lung fibroblasts strongly depended on CD46 and integrins but not heparan sulfate, and variably required the large GTPase dynamin. Ad35 infections were independent of expression of the carboxy-terminal domain of AP180 which effectively blocks clathrin-mediated uptake. Ad35 infections were inhibited by small chemicals against the serine/threonine kinase Pak1 (p21-activated kinase), protein kinase C (PKC), sodium-proton exchangers, actin and acidic organelles. Remarkably, the F-actin inhibitor jasplakinolide, the Pak1 inhibitor IPA-3 or the sodium-proton exchange inhibitor EIPA blocked the endocytic uptake of Ad35. Dominant-negative proteins or small interfering RNAs against factors driving macropinocytosis, including the small GTPase Rac1, Pak1 or the Pak1 effector C-terminal binding protein 1 (CtBP1) potently inhibited Ad35 infection. Confocal laser scanning microscopy, electron microscopy and live cell imaging showed that Ad35 colocalized with fluid phase markers in large endocytic structures that were positive for CD46, alpha v integrins and also CtBP1. Our results extend earlier observations with HAdV-3 (Ad3), and establish macropinocytosis as an infectious pathway for species B human adenoviruses in epithelial and hematopoietic cells

Baseline phenotypes with preserved β-cell function and high insulin concentrations have the best improvements in glucose tolerance after weight loss: results from the prospective DEXLIFE and EGIR-RISC studies

\ua9 2024 The AuthorsBackground: Weight loss and lifestyle intervention improve glucose tolerance delaying the onset of type 2 diabetes (T2D), but individual responses are highly variable. Determining the predictive factors linked to the beneficial effects of weight loss on glucose tolerance could provide tools for individualized prevention plans. Thus, the aim was to investigate the relationship between pre-intervention values of insulin sensitivity and secretion and the improvement in glucose metabolism after weight loss. Methods: In the DEXLIFE cohort (373 individuals at high risk of T2D, assigned 3:1 to a 12-week lifestyle intervention or a control arm, Trial Registration: ISRCTN66987085), K-means clustering and logistic regression analysis were performed based on pre-intervention indices of insulin sensitivity, insulin secretion (AUC-I), and glucose-stimulated insulin response (ratio of incremental areas of insulin and glucose, iAUC I/G). The response to the intervention was evaluated in terms of reduction of OGTT-glucose concentration. Clusters\u27 validation was done in the prospective EGIR-RISC cohort (n = 1538). Results: Four replicable clusters with different glycemic and metabolomic profiles were identified. Individuals had similar weight loss, but improvement in glycemic profile and β-cell function was different among clusters, highly depending on pre-intervention insulin response to OGTT. Pre-intervention high insulin response was associated with the best improvement in AUC-G, while clusters with low AUC-I and iAUC I/G showed no beneficial effect of weight loss on glucose control, as also confirmed by the logistic regression model. Conclusions: Individuals with preserved β-cell function and high insulin concentrations at baseline have the best improvement in glucose tolerance after weight loss

Liver Enzymes Are Associated With Hepatic Insulin Resistance, Insulin Secretion, and Glucagon Concentration in Healthy Men and Women

International audienceOBJECTIVE: The pathophysiological mechanisms to explain the association between risk of type 2 diabetes and elevated concentrations of γ-glutamyltransferase (GGT) and alanineaminotransferase (ALT) remain poorly characterized. We explored the association of liver enzymes with peripheral and hepatic insulin resistance, insulin secretion, insulin clearance, and glucagon concentration. RESEARCH DESIGN AND METHODS: We studied 1,309 nondiabetic individuals from the Relationship between Insulin Sensitivity and Cardiovascular disease (RISC) study; all had a euglycemic-hyperinsulinemic clamp and an oral glucose tolerance test (OGTT) with assessment of insulin secretion and hepatic insulin extraction. The hepatic insulin resistance index was calculated in 393 individuals. RESULTS: In both men and women, plasma concentrations of GGT and ALT were inversely related with insulin sensitivity (M/I) (all P < 0.01). Likewise, the hepatic insulin resistance index was positively correlated with both GGT (r = 0.37, P < 0.0001, men; r = 0.36, P < 0.0001, women) and ALT (r = 0.25, P = 0.0005, men; r = 0.18, P = 0.01, women). These associations persisted in multivariable models. Increased GGT and ALT were significantly associated with higher insulin secretion rates and with both reduced endogenous clearance of insulin and hepatic insulin extraction during the OGTT (P = 0.0005 in men; P = 0.003 in women). Plasma fasting glucagon levels increased over ALT quartiles (men, quartile 4 vs. quartile 1 11.2 ± 5.1 vs. 9.3 ± 3.8 pmol/L, respectively, P = 0.0002; women, 9.0 ± 4.3 vs. 7.6 ± 3.1, P = 0.001). CONCLUSIONS: In healthy individuals, increased GGT and ALT were biomarkers of both systemic and hepatic insulin resistance with concomitant increased insulin secretion and decreased hepatic insulin clearance. The novel finding of a positive correlation between ALT and fasting glucagon level concentrations warrants confirmation in type 2 diabetes