Characterization of the IGF system in 15 patients with Alström syndrome

Background Alström syndrome (ALMS) is a rare recessively inherited progressive disease (OMIM 203800). Among its diverse spectrum of clinical features are phenotypes associated with deficiencies of the GH/IGF‐I axis, including short stature, obesity, insulin resistance, hypertriglyceridaemia and heart failure. Patients and measurements To characterize the IGF system in ALMS, we evaluated a subset of 15 young adults with ALMS for hepatic, renal and thyroid function. Glycaemic and hormone measurements such as insulin, GH, FSH, LH, testosterone and 17‐beta‐oestradiol were clinically assessed. In addition, we measured IGF‐I, IGF‐II, IGF binding‐protein‐3 (IGFBP‐3) and acid labile subunit (ALS – the subunits that constitute the main somatomedin complex in the circulation), and IGFBP‐1 and IGFBP‐2 (known to influence the bioavailability of the IGFs). Results A significantly lower height was observed in ALMS patients compared to age‐matched controls. ALMS patients were clinically obese (by weight and body mass index (BMI) standards) and leptin levels correlated with BMI. Renal and hepatic dysfunction was implicated in some patients by increased values of blood urea nitrogen (BUN) and creatinine, and transaminases, respectively. One‐third of the patients presented with fasting hyperglycaemia and 80% were hyperinsulinaemic. TSH was slightly increased in 20% of patients. Baseline FSH and LH in females were within the normal range, while half of the males had abnormally low testosterone values. Male patients with hypogonadism showed significantly lower testosterone, oestrogen and ALS levels. Baseline GH values were not found to be increased. ALS and IGFBP‐1 were significantly reduced and IGFBP‐2 was markedly increased in ALMS patients compared to age‐matched controls. The IGFs and IGFBPs were not significantly different between males and females affected with ALMS. No significant association was observed between IGFs or IGFBPs levels and weight, height, BMI, glycaemia, hyperinsulinaemia and testosterone levels. However, we found a significant association of gamma‐glutamyltransferase (GGT) with IGFBP‐2. IGF‐I levels were significantly associated with LH in female patients. Conclusions In summary, the reduction of ALS and the increase of IGFBP‐2 points to a growth hormone deficiency (GHD) condition in ALMS. However, further tests, including GH dynamics, are needed to determine whether, or to what degree disturbances in the GH/IGF axis contribute to the relatively short stature.     

The insulin‐like growth factor binding protein 3 ternary complex is reduced in cirrhosis

Abstract: Background/Aims: In healthy adults, serum insulin‐like growth factor I (IGF‐I), IGF binding protein 3 (IGFBP‐3) and acid labile subunit (ALS) form a 150‐kDa ternary complex under the control of growth hormone (GH). Approximately 80–90% of circulating IGF‐I is bound to the ternary complex. In cirrhosis the GH/IGF axis is severely disturbed and the individual components of the ternary complex are reduced. However, the degree of ternary complex formation in cirrhosis has not previously been described. Methods: Serum IGF‐I, IGFBP‐3, ALS, the 150‐kDa ternary complex and IGFBP‐3 proteolysis were all measured in six compensated and six decompensated cirrhotic patients and compared to six healthy controls. Results: Patients with compensated cirrhosis had decreased levels of IGF‐I (55%), IGFBP‐3 (64%) and ALS (53%), and in the decompensated patients these levels were decreased even further: IGF‐I (32%), IGFBP‐3 (37%) and ALS (27%) compared to healthy controls. The levels of the ternary complex followed this pattern, with low levels seen in the compensated patients (66%) and a further reduction in the decompensated patients (27%). Ternary complex levels correlated negatively with the Child–Pugh score. No increase in IGFBP‐3 proteolysis was found in cirrhotic patients compared to healthy controls. Conclusion: Cirrhosis is associated with reduced levels of the 150‐kDa ternary IGFBP‐3 complex correlating with the degree of liver disease.     

Growth hormone binding protein levels in children are associated with birth weight, postnatal weight gain, and insulin secretion

Rapid infancy weight gain is associated with subsequent higher circulating insulin-like growth factor (IGF) I levels in normal children. We hypothesized that circulating levels of growth hormone binding protein (GHBP), a putative marker of GH sensitivity, may also be associated with postnatal weight gain and insulin secretion. In 751 normal children aged 7 to 8 years, we measured insulin, glucose, GHBP, IGF-I, IGF binding protein (IGFBP) 1, and IGFBP-3 levels in a fasting venous blood sample. Insulin secretion was assessed by measuring insulin and glucose levels 30 minutes after an oral glucose load. After adjustment for current weight, birth weight was inversely related to IGF-I and GHBP levels. Children with lower birth weight and rapid weight gain between birth and 3 years had higher IGF-I and GHBP levels and also lower IGFBP-1 levels than other children. Allowing for current body mass index, GHBP levels were positively related to insulin secretion. In conclusion, children who showed rapid early postnatal weight gain after low birth weight have higher levels of GHBP than other children. Increased GH sensitivity in such children could contribute to links between rapid infancy weight gain and subsequent faster rates of childhood growth and maturation.     

Serum leptin and soluble leptin receptor in non-alcoholic fatty liver disease

AIM： To determine the role of leptin system in non-alcoholic fatty liver disease （NAFLD） development by delineating the changes in serum levels of leptin and soluble leptin receptor （sOB-R）.
METHODS： Blood samples were collected from 30 consecutive patients with liver-biopsy-proven NAFLD and 30 patients with cholecystolithiasis （stationary phase） as controls. Serum leptin levels were determined by radioimmunoassay and concentration of sOB-R was measured by ELISA. Body mass index （BMI） was calculated for all subjects, and serum insulin, C-peptide, and lipoprotein levels were also detected.
RESULTS： Mean serum leptin level and BMI in the NAFLD group were significantly higher than in the controls （both P 〈 0.001）, but mean sOB-R level was lower in the NAFLD group when compared to the controls. Both men and women in the NAFLD group had higher mean serum leptin levels and lower sOB-R levels than did the men and women in the control group （all P 〈 0.001）. There was a significant negative correlation between serum leptin and sOB-R levels （r = -0.725, P 〈 0.001）. Multivariate analysis showed that the percentage of hepatocyte steatosis, sex, BMI, and homeostasis model assessment of insulin resistance （HOMA IR） were independently related to serum leptin levels.
CONCLUSION： Elevated serum leptin seems to be afeature of steatosis, and serum leptin seems to increase as hepatocyte steatosis develops. An enhanced release of leptin is accompanied by an decrease in sOB-R concentration, which suggests higher resistance of peripheral tissues towards the action of leptin.     

Insulin sensitivity and hepatic steatosis in obese subjects with normal glucose tolerance

BACKGROUND AND AIM: Hepatic steatosis has recently been associated with insulin resistance and other metabolic abnormalities as a possible feature of the metabolic syndrome, but it is still uncertain how hepatic steatosis and insulin sensitivity are connected. Furthermore, obesity is a well characterized insulin resistant condition that is often associated with hepatic steatosis. The aim of this study was to verify whether hepatic steatosis further worsens insulin sensitivity in obese subjects by comparing the degree of insulin sensitivity in obese subjects with normal glucose tolerance on the basis of the presence or absence of hepatic steatosis. METHODS AND RESULTS: We analyzed 86 obese patients whose alcohol intake was less than 20 g/day and who showed no signs of viral hepatopathy. All of the subjects had normal glucose tolerance as shown by an oral glucose tolerance test. Insulin resistance was estimated using the homeostasis model assessment (HOMA) method and the diagnosis of steatosis was determined by an ultrasound scan of the liver. The subjects were comparable in terms of body mass index (BMI), lipid profile and serum uric acid levels; those with hepatic steatosis were slightly older and tended to have higher systolic blood pressure and fasting glycemia levels. The HOMA values were significantly higher in the group with hepatic steatosis (4.48 +/- 2.22 vs 3.11 +/- 1.47, p=0.002). There was no linear correlation between HOMA and alanine aminotransferase (ALT) levels, but a close linear correlation between HOMA and BMI (r=0.40; p<0.001). The effect of hepatic steatosis on HOMA remained significant after adjusting for age and gender (covariance analysis, p=0.006). When BMI was added to the covariance analysis, hepatic steatosis retained its statistical significance. CONCLUSION: Our data suggest that hepatic steatosis can increase insulin resistance independently of obesity.     

Circulating levels of insulin‐like growth factors and their binding proteins in patients with chronic liver disease: lack of correlation with bone mineral density

Abstract: Background/Aims: Insulin‐like growth factor‐I (IGF‐I) levels are low in patients with chronic liver disease (CLD) and have been found to correlate with measurements of bone mineral density (BMD) in men with viral cirrhosis. The aim of this study was to investigate the relationship between circulating IGF‐I levels and BMD in patients with CLD of other causes. Methods: Fifty‐eight patients with CLD were included. Age‐ and sex‐matched normal individuals served as controls. Serum levels of IGF‐I and IGF‐II and their binding proteins (IGFBP‐1–3) were measured by radioimmunoassay. BMD was measured by dual energy X‐ray absorptiometry. Results: IGF‐I levels were 57±33 and 136±48 ng/ml; p<0.0001 in patients and controls, respectively. IGF‐II and IGFBP‐3 levels were lower (p<0.0001) and IGFBP‐1 and IGFBP‐2 levels were higher in patients compared with controls (p<0.0005 and p<0.0001, respectively). All growth factors, except for IGFBP‐2, correlated with parameters of liver function. In a multiple regression analysis, adjusting for age, no correlation was found between IGF‐I, IGF‐II, IGFBP‐1–3 and BMD in either patients or controls. Conclusion: Patients with CLD have low levels of IGF‐I, IGF‐II and IGFBP‐3 that correlate with liver function. No relationship was found between low levels of growth factors and BMD.     

Influence of Insulin Resistance and Adipokines in the Grade of Steatosis of Nonalcoholic Fatty Liver Disease

The objective of this work was to study the influence of insulin resistance and adipokines on the grade of steatosis in patients with NAFLD (nonalcoholic fatty liver disease) diagnosed by liver biopsy. A sample of 24 NAFLD patients was analyzed in a cross-sectional study. All patients with a two-week weight-stabilization period before recruitment were enrolled. A liver biopsy was realized. Weight, basal glucose, insulin, insulin resistance (HOMA), total cholesterol, LDL-cholesterol, HDL-cholesterol, triglycerides, and adipokines blood levels were measured. A nutritional evaluation (dietary intake, indirect calorimetry, and bioimpedance) was performed. The mean age was 41.6 ± 8.7 years and the mean body mass index (BMI) 29.4 ± 4.7. Twelve patients had a low grade of steatosis (grade 1 of the Brunt classification) and 12 patients had a high grade of steatosis (grade 2 or 3). Only HOMA was higher in patients with a high grade of steatosis (1.4 ± 0.5 vs. 2.8 ± 1.7 units; P < 0.05). Anthropometric data and dietary intake were similar for both groups. Blood levels of adiponectin were higher in patients with a low grade of steatosis (37.7 ± 22.5 vs. 24.2 ± 33 ng mL⁻¹; P < 0.05). Blood levels of resistin were higher in patients with a high grade of steatosis (2.36 ± 0.6 vs. 2.8 ± 0.6 mg mL⁻¹; P < 0.05), without differences in TNF-α or leptin levels. In logistic regression analysis, the HOMA-IR remained in the model, with an odds ratio to develop high grade of steatosis of 7.8 (95% CI: 1.8–75) with each 1 unit of HOMA-IR adjusted by age, sex, BMI, and dietary intake. This study demonstrates that insulin resistance determined with the HOMA model is associated with a high grade of steatosis in patients with NAFLD.     

Hepatic steatosis and insulin resistance: does etiology make a difference?

BACKGROUND/AIMS: To ascertain whether the etiology of hepatic steatosis modulates insulin resistance (IR) and to determine the predictors of IR. METHODS: We studied IR through HOMA IR in 146 subjects, 99 of whom had ultrasonographic and/or histologic steatosis. Twenty-two had familial heterozygous hypobetalipoproteinemia (FHBL), 48 had non-alcoholic fatty liver disease (NAFLD), 34 HCV infection (17 with HCV1b, 17 with HCV3a) and 42 were healthy controls without steatosis. RESULTS: Steatosis was present in 77.3% of FHBL and, by enrolment criteria, in all NAFLD and HCV cases. Overall HOMA-IR correlated with BMI and GGT (P<0.01). FHBL and healthy groups had similar HOMA-IR and GGT values, whereas higher levels were observed in HCV and NAFLD. HCV3a and FHBL patients were hypolipidemic. HOMA-IR was similar in FHBL patients and controls and lower than in HCV and NAFLD. FHBL patients had a high extent of steatosis, similar to that observed in HCV3a, but lower grading and staging than NAFLD and HCV. At multivariate analysis, steatosis and GGT predicted HOMA-IR. CONCLUSIONS: Data suggest that not all hepatic fat associates with IR. FHBL patients, for some aspects, resemble HCV3a infection, possibly suggesting a shared steatogenic mechanism. Among steatotic patients serum GGT levels is the independent predictor of IR.     

Correlation of insulin sensitivity with bone mineral status in obese adolescents with nonalcoholic fatty liver disease

Aim The aim of this study was to investigate the relationships between bone mineral density (BMD) vs insulin resistance and metabolic risk factors in obese adolescents with nonalcoholic fatty liver disease (NAFLD). Patients and methods Eighty‐two obese adolescents [45 girls and 37 boys, mean age: 12·3 ± 1·7 years, mean body mass index‐standard deviation score (BMI‐SDS): 1·9 ± 0·2] and 30 control subjects (15 girls and 15 boys, mean age: 12·3 ± 1·45 years, mean BMI‐SDS: 0·5 ± 0·7) were enrolled the study. The obese subjects were divided into two groups based on the presence or absence of liver steatosis with high transaminases (NAFLD group and non‐NAFLD group). Insulin resistance was evaluated by homeostasis model assessment (HOMA‐IR) from fasting samples. BMD was determined by dual‐energy X‐ray absorptiometry. Results Fasting insulin levels in the NAFLD group were significantly higher than in the non‐NAFLD obese (32·3 ± 24·0 vs 11·02 ± 2·95 mU/l, P < 0·001) and control groups (8·4 ± 2·4 mU/l, P< 0·001). The NAFLD group had higher values of HOMA‐IR than the non‐NAFLD obese (7·3 ± 0·1 vs 2·3 ± 0·7, P < 0·001) and control groups (1·8 ± 0·5, P < 0·001). BMD‐SDS measurements were lower in the NAFLD group than in the non‐NAFLD (0·56 ± 0·3 vs 1·02 ± 0·9, P < 0·001) and control groups (0·56 ± 0·3 vs 1·37 ± 1·04, P < 0·001). BMD‐SDS was positively correlated with BMI‐SDS (r = 0·530, P = 0·004) and negatively correlated with HOMA‐IR (r = ?0·628, P = 0·017) in the NAFLD obese group. Conclusion This study reports the association between BMD‐SDS and insulin resistance in obese adolescents both with and without NAFLD, although the NAFLD group had a lower BMD‐SDS than the non‐NAFLD group. We suggest that NAFLD has a detrimental effect on bone health in adolescents, and it is correlated with increased insulin resistance.     

Non-alcoholic fatty liver disease in young adult severely obese non-diabetic patients in South Italy

BACKGROUND/AIMS: In the absence of other causes, obesity increases the risk of liver disease. We evaluated the prevalence and degree of metabolic and hepatic abnormalities associated with non-alcoholic fatty liver disease (NAFLD) in type II-III obesity in a metropolitan area of South Italy. METHODS: 187 (81 M, 106 F) young adult non-diabetic obese patients, age range 18-50 years (mean 31.9 +/- 8.8), body mass index (BMI) > or =30 (mean 47.5 +/- 9.6), consecutively admitted from January 2000 to April 2003 to the Obesity Outpatients Clinic entered into the study. Patients were divided into two groups: (1) BMI 30.0-39.9, and (2) BMI> or =40. Ultrasound detected liver steatosis was classified as: (I) mild; (II) moderate, and (III) severe. RESULTS: All patients, except 4, showed a variable degree of steatosis: mild was more frequent among females, severe steatosis present only in grade III obesity, with higher prevalence in males than in females (p < 0.001). Mean serum transaminases, in particular alanine aminotransferase (ALT), increased according to BMI and degree of steatosis. Homeostasis Model Assessment (HOMA) index, ferritin and fibrinogen levels increased with BMI, particularly in severe steatosis. In group 2, patients with BMI> or =40 showed a positive correlation between ferritin, aspartate aminotransferase (AST) (r = 0.46, p < 0.018), ALT (r = 0.41, p < 0.036) and gamma-glutamyltransferase (gammaGT) (r = 0.51, p < 0.007), between serum triglycerides (TG) and AST (r = 0.28, p < 0.036), ALT (r = 0.30, p < 0.02) and between HOMA and ALT (r = 0.30, p < 0.03) and gammaGT (r = 0.35, p < 0.012). In group 2 patients with severe steatosis the prevalence of metabolic syndrome according to Adult Treatment Panel III (ATP III) was 40%. CONCLUSION: These data suggest that, in young adult non-diabetic grade III obese patients, fatty liver is always present and strictly related to insulin resistance which, in the presence of severe liver steatosis, is also related to serum ferritin.     

Thyroid Hormone Levels in Obese Children and Adolescents with Non-Alcoholic Fatty Liver Disease

Ob­jec­ti­ve: We aimed to determine the association of thyroid functions with the components of metabolic syndrome (MS) and non-alcoholic fatty liver disease (NAFLD) in pediatric obese patients.Methods: The study included 109 obese children (aged 9-15 years) and a control group of 44 healthy age and gender-matched children of normal weight. NAFLD was diagnosed by conventional ultrasound examination. We assessed the anthropometric data and serum biochemical parameters including lipid profile, alanine aminotransferase (ALT), fasting glucose and insulin levels and thyroid stimulating hormone (TSH), free thyroxine (fT4) and free triiodothyronine (fT3) levels. The homeostasis model assessment of insulin resistance (HOMA-IR) was calculated as a measure of IR.Results: The mean age and gender distributions in the groups were similar (p=0.23). The mean body mass index (BMI) z-scores of obese children with grade 2-3 NAFLD were significantly higher than those of the obese children without hepatic steatosis (p<0.001). Mean ALT, triglyceride (TG) and LDL cholesterol increased and HDL-cholesterol significantly decreased as the hepatic steatosis increased (p<0.05). HOMA-IR levels in obese subjects with grade 2-3 NAFLD were significantly higher than those in both obese children without NAFLD and grade 1 NADFL (p=0.05 and 0.001, respectively). In the obese subjects, TSH levels were increased significantly as the degree of steatosis increased (p=0.04) but fT3 and fT4 levels were not different. In correlation analysis, TSH was significantly correlated with ALT, BMI SDS and the degree of steatosis.Conclusions: Obese children demonstrate an increase in TSH levels as the degree of steatosis increased.     

Plasma apelin levels in subjects with nonalcoholic fatty liver disease

Nonalcoholic fatty liver disease (NAFLD), one of the most common forms of chronic liver disease, is closely associated with obesity and insulin resistance. Recent studies suggest that apelin, a newly described adipokine, is associated with hyperinsulinemia and inflammation. The aim of the study was to investigate plasma apelin concentrations in biopsy-proven NAFLD patients who had no metabolic confounders and also to search for the association of apelin with adiponectin, body mass index (BMI), and insulin sensitivity. Fifty male patients with NAFLD and 30 healthy male controls were enrolled. Apelin was measured along with BMI, lipids, glucose, insulin, adiponectin, and homeostasis model assessment (HOMA) of insulin resistance indexes. Plasma apelin levels were significantly higher and adiponectin levels were lower in NAFLD patients when compared with the controls (P < .001 and P = .013, respectively). In multivariate analysis adjusted for BMI and HOMA indexes, the differences in apelin and adiponectin disappeared in the 2 groups (P = .3 and P = .1, respectively). In addition, apelin levels were positively correlated with BMI (r = 0.29, P = .05) and HOMA indexes (r = 0.4, P = .008) in subjects with NAFLD. The results of this preliminary study suggest that plasma apelin levels are not altered in nondiabetic and normotensive male subjects with NAFLD.     

Effects of combined low‐dose spironolactone plus vitamin E vs vitamin E monotherapy on insulin resistance,non‐invasive indices of steatosis and fibrosis,and adipokine levels in non‐alcoholic fatty liver disease: a randomized controlled trial

The beneficial effects of mineralocorticoid receptor blockade by spironolactone have been shown in animal models of non‐alcoholic fatty liver disease (NAFLD). The aim of the present 52‐week randomized controlled trial was to compare the effects of low‐dose spironolactone and vitamin E combination with those of vitamin E monotherapy on insulin resistance, non‐invasive indices of hepatic steatosis and fibrosis, liver function tests, circulating adipokines and hormones in patients with histologically confirmed NAFLD. Homeostasis model of assessment of insulin resistance (HOMA‐IR) and non‐invasive indices of steatosis and fibrosis were calculated. Analysis was intention‐to‐treat. NAFLD liver fat score, an index of steatosis, decreased significantly in the combination treatment group (P = .028), but not in the vitamin E group, and the difference for group*time interaction was significant (P = .047). Alanine aminotransferase‐to‐platelet ratio index, an index of fibrosis, did not change. Insulin levels and HOMA‐IR decreased significantly only within the combination group (P = .011 and P = .011, respectively). In conclusion, the combined low‐dose spironolactone plus vitamin E regimen significantly decreased NAFLD liver fat score. Larger‐scale trials are needed to clarify the effect of low‐dose spironolactone on hepatic histology.     

非酒精性脂肪肝血尿酸水平与胰岛素抵抗的相关性

目的:研究非酒精性脂肪肝(non-alcoholic fatty liver,NAFL)患者血尿酸水平及其与胰岛素抵抗程度的相关性.方法:选取单纯NAFL患者40例,NAFL合并2型糖尿病患者(type2diabetes mellitus,T2DM)72例,健康体检者62名为研究对象.测定体重指数(body mass index,BMI),检测空腹血糖(fasting blood glucose,FBG)、尿酸(serum uric acid,SUA)、丙氨酸氨基转移酶(alanine aminotransferase,ALT)、门冬氨酸氨基转移酶(aspartate aminotransferase,AST)、胆固醇(cholesterol,TC)、甘油三酯(triglyceride,TG)、糖化血红蛋白(glycated hemoglobin,HbA1C)、尿微量白蛋白/尿肌酐(Ualb/UCr)等生化指标并行肝脏B超检查.放射免疫法测定空腹胰岛素(fasting insulin,FINS),计算胰岛素抵抗指数(HOMA IR).结果:NAFL合并T2DM组BMI、SUA、ALT、AST、TG、FBG、FINS、HOMA IR、HbA1C、Ualb/UCr、SF均高于对照组;与单纯NAFL比较,NAFL合并T2DM组胰岛素抵抗及SUA水平更重;相关性研究表明FBG、HOMA IR、HbA1C与SUA呈正相关.结论:NAFL患者存在明显的胰岛素抵抗及高血尿酸血症,且两者具有一定的相关性.降低胰岛素抵抗联合纠正尿酸代谢紊乱对防止NAFL的发生发展具有重要的临床意义.     

Leptin does not mediate short-term fasting-induced changes in growth hormone pulsatility but increases IGF-I in leptin deficiency states

CONTEXT: States of acute and chronic energy deficit are characterized by increased GH secretion and decreased IGF-I levels. Objective: The objective of the study was to determine whether changes in levels of leptin, a key mediator of the adaptation to starvation, regulate the GH-IGF system during energy deficit. DESIGN, SETTING, PATIENTS, AND INTERVENTION: We studied 14 healthy normal-weight men and women during three conditions: baseline fed and 72-h fasting (to induce hypoleptinemia) with administration of placebo or recombinant methionyl human leptin (r-metHuLeptin) (to reverse the fasting associated hypoleptinemia). We also studied eight normal-weight women with exercise-induced chronic energy deficit and hypothalamic amenorrhea at baseline and during 2-3 months of r-metHuLeptin treatment. MAIN OUTCOME MEASURES: GH pulsatility, IGF levels, IGF and GH binding protein (GHBP) levels were measured. RESULTS: During short-term energy deficit, measures of GH pulsatility and disorderliness and levels of IGF binding protein (IGFBP)-1 increased, whereas leptin, insulin, IGF-I (total and free), IGFBP-4, IGFBP-6, and GHBP decreased; r-metHuLeptin administration blunted the starvation-associated decrease of IGF-I. In chronic energy deficit, total and free IGF-I, IGFBP-6, and GHBP levels were lower, compared with euleptinemic controls; r-metHuLeptin administration had no major effect on GH pulsatility after 2 wk but increased total IGF-I levels and tended to increase free IGF-I and IGFBP-3 after 1 month. CONCLUSIONS: The GH/IGF system changes associated with energy deficit are largely independent of leptin deficiency. During acute energy deficit, r-metHuLeptin administration in replacement doses blunts the starvation-induced decrease of IGF-I, but during chronic energy deficit, r-metHuLeptin administration increases IGF-I and tends to increase free IGF-I and IGFBP-3.     

Increased serum resistin in nonalcoholic fatty liver disease is related to liver disease severity and not to insulin resistance

CONTEXT: The recently discovered hormone resistin is linked to the development of insulin resistance, but direct evidence of resistin levels in humans with nonalcoholic fatty liver disease (NAFLD) is lacking. METHODS: We conducted this study to assess the relationship between serum resistin and NAFLD. We measured serum resistin and biochemical, hormonal, and histological correlates in 28 NAFLD patients, 33 controls, and 30 obese patients [body mass index (BMI), >30 kg/m2] without NAFLD. RESULTS: Resistin and adiponectin expression were measured in sc adipose tissue by quantitative RT-PCR. Resistin was higher in NAFLD patients compared with controls (5.87 +/- 0.49 vs. 4.30 +/- 0.20 ng/ml; P = 0.002) and obese patients (4.37 +/- 0.27 ng/ml; P = 0.002). Increased resistin mRNA was also found in the adipose tissue of NAFLD patients compared with controls and obese subjects. CONCLUSIONS: Both NAFLD and obese patients had lower adiponectin levels, whereas leptin was increased only in the obese group. No correlation was found between resistin and high-sensitivity C-reactive protein, BMI, homeostasis model assessment, insulin, glucose, transaminases, and lipid values. A positive correlation was found between resistin and histological inflammatory score. These data report increased resistin in NAFLD patients that is related to the histological severity of the disease, but do not support a link between resistin and insulin resistance or BMI in these patients.     

Growth hormone-binding protein related immunoreactivity is regulated by the degree of insulinopenia in diabetes mellitus

OBJECTIVE Derangements in the GH/IGF axis are common in patients with diabetes mellitus. In insulin-dependent diabetes mellitus (IDDM), these disturbances seem to be due to a partial defect in GH action on its own receptor or via a post-receptor defect. In non-insulin-dependent diabetes mellitus (NIDDM), data are limited, and the regulation of the GH receptor (GHR) remains unclear. However, animal studies with diabetic rats demonstrated that the GHR density may be influenced by insulin disposal at the hepatocyte. With respect to this hypothesis we studied the relation between peripheral insulin status and the serum GH-binding protein (GHBP), which reflects indirectly the GHR density in the tissues. Patients with IDDM were compared to a NIDDM group as well as to a group of healthy subjects. DESIGN AND PATIENTS Basal blood samples for the determination of serum GHBP, GH, and IGF-I were obtained from patients with IDDM (n = 27), subjects with NIDDM (n = 112) and healthy controls (n = 42). Insulin, proinsulin, C-peptide and IGF-binding protein 1 (IGFBP-1) serum levels were used to estimate the insulin status in diabetic patients. RESULTS GHBP serum levels were significantly lower in patients with IDDM than in either NIDDM or controls (P < 0.001). Conversely, the IGF-I levels were reduced in both groups of diabetics. A subgroup of hypoinsulinaemic NIDDM patients showed significantly decreased GHBP concentrations (P < 0.05) compared to the NIDDM subgroup with hyperinsulinaemia. Furthermore, GHBP levels were significantly decreased in insulin-treated patients with NIDDM compared to either non-insulin-requiring subjects or normal controls (P < 0.05). A significant direct relation was found between levels of GHBP and total insulin dose (P < 0.01) in patients with IDDM. In the NIDDM group, GHBP was correlated with proinsulin (P < 0.001), C-peptide (P < 0.01), insulin (P < 0.05) and inversely with IGFBP-1 (P < 0.001). Multiple linear regression analysis indicated a significant contribution of proinsulin and IGFBP-1 to the variation of GHBP. CONCLUSIONS Decreased GHBP levels in IDDM as well as in NIDDM correlate with insulinopenia. Since the degree of insulinopenia depends on the capability of the β-cells to secrete proinsulin, C-peptide and insulin, we hypothesize that these hormones at least partially influence the serum level of GHBP. Low GHBP levels may reflect a reduced GH receptor density and a concomitant GH insensitivity, which leads to an impaired IGF generation in insulin-deficient patients.     

The i148m Pnpla3 polymorphism influences serum adiponectin in patients with fatty liver and healthy controls

ABSTRACT: BACKGROUND: Reduced adiponectin is implicated in the pathogenesis of nonalcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH), and the I148M Patatin-like phospholipase domain-containing 3 (PNPLA3) polymorphism predisposes to NAFLD and liver damage progression in NASH and chronic hepatitis C (CHC) by still undefined mechanisms, possibly involving regulation of adipose tissue function. Aim of this study was to evaluate whether the I148M PNPLA3 polymorphism influences serum adiponectin in liver diseases and healthy controls. METHODS: To this end, we considered 144 consecutive Italian patients with NAFLD, 261 with CHC, 35 severely obese subjects, and 257 healthy controls with very low probability of steatosis, all with complete clinical and genetic characterization, including adiponectin (ADIPOQ) genotype. PNPLA3 rs738409 (I148M) and ADIPOQ genotypes were evaluated by Taqman assays, serum adiponectin by ELISA. Adiponectin mRNA levels were evaluated by quantitative real-time PCR in the visceral adipose tissue (VAT) of 35 obese subjects undergoing bariatric surgery. RESULTS: Adiponectin levels were independently associated with the risk of NAFLD and with the histological severity of the disease. Adiponectin levels decreased with the number of 148 M PNPLA3 alleles at risk of NASH both in patients with NAFLD (p = 0.03), and in healthy subjects (p = 0.04). At multivariate analysis, PNPLA3 148 M alleles were associated with low adiponectin levels (<6 mg/ml, median value) independently of NAFLD diagnosis, age, gender, BMI, and ADIPOQ genotype (OR 1.67, 95% c.i. 1.07-2.1 for each 148 M allele). The p.148 M PNPLA3 variant was associated with decreased adiponectin mRNA levels in the VAT of obese patients (p < 0.05) even in the absence of NASH. In contrast, in CHC, characterized by adiponectin resistance, low adiponectin was associated with male gender and steatosis, but not with PNPLA3 and ADIPOQ genotypes and viral features. CONCLUSIONS: The I148M PNPLA3 variant is associated with adiponectin levels in patients with NAFLD and in healthy subjects, but in the presence of adiponectin resistance not in CHC patients. The I148M PNPLA3 genotype may represent a genetic determinant of serum adiponectin levels. Modulation of serum adiponectin might be involved in mediating the susceptibility to steatosis, NASH, and hepatocellular carcinoma in carriers of the 148 M PNPLA3 variant without CHC, with potential therapeutic implications.