Oncogenic osteomalacia: increased production of fibroblast growth factor 23 is not the unique actor

The importance of fibroblast growth factor 23 (FGF?23) has been highlighted in the mechanism of urinary leakage of phosphate in the oncogenic osteomalacia (OO). It is now a component of diagnosis of this disease. We report a 58-year-old man who presented with osteomalacia and hypophosphatemia secondary to urinary leakage of phosphorus. Although serum FGF?23 was normal, the diagnosis of OO was obtained after another cause of acquired prolonged hypophosphatemia has been excluded (hyperparathyroidism and Fanconi syndrome in particular). The search for a deep tumor was performed, allowing the detection of a 12?mm hemangiopericytoma in the upper thigh. Its removal allowed the rapid resolution of clinical symptoms and laboratory abnormalities. The importance of functional sequelae in OO depends on prompt diagnosis. Tumorectomy remains the optimal treatment. Thus, the search for a secreting tumor is essential even in the absence of elevated serum FGF?23.     

Mitochondrial diabetes is associated with insulin resistance in subcutaneous adipose tissue but not with increased liver fat content

We recently showed that patients with mitochondrial diabetes are insulin resistant in skeletal muscle before the decline in insulin secretion is observed. In this study, we further evaluate whether insulin resistance is associated with increased ectopic fat accumulation and altered adipose and hepatic tissue insulin sensitivity. We studied 15 nonobese patients with the m.3243A > G mutation. Five were without diabetes (group 1), three had newly diagnosed diabetes (group 2), and seven had previously diagnosed diabetes (group 3). Thirteen healthy volunteers of similar age and body mass index (BMI) served as controls. Insulin-stimulated glucose uptake was measured with positron emission tomography using 2- [¹⁸F]-fluoro-2-deoxyglucose during euglycemic hyperinsulinemia. Fat masses and liver fat content were measured with magnetic resonance imaging and spectroscopy. Compared with controls, insulin-stimulated glucose uptake in adipose tissue was decreased by ∼50% in all groups with the m.3243A > G mutation. In addition, fat masses were not different, but insulin-mediated suppression of lipolysis and adiponectin metabolism were blunted in patients with the m.3243A > G mutation. Hepatic fat content was normal (<5.6%) in 80% of patients and significantly elevated in one case only. Hepatic glucose metabolism in patients with m.3243A > G did not differ from that of controls. In conclusion, m.3243A > G mutation affects subcutaneous adipose tissue metabolism. This seems to occur before aberrant liver metabolism, if any, can be observed or before beta-cell failure results in mitochondrial diabetes.     

ALOX5AP expression, but not gene haplotypes, is associated with obesity and insulin resistance

OBJECTIVE: Inflammation in adipose tissue may link obesity to insulin resistance and atherosclerosis. Arachidonate 5-lipoxygenase activating protein (ALOX5AP) gene is involved in the pathogenesis of atherosclerotic cardiovascular disease (CVD). We investigated ALOX5AP expression in adipose tissue, and association of gene polymorphisms with obesity and insulin resistance. DESIGN: For gene expression analysis in adipose tissue, we studied 12 lean and 36 obese women, eight lean and 13 obese men, and nine women before and 2-4 years after gastric banding surgery. For genetic analysis, we studied 231 nonobese and 350 obese men. RESULTS: The ALOX5AP protein, 5-lipoxygenase activating protein (FLAP), as well as 5-lipoxygenase (5LO) itself, were detected in adipocytes. The mRNA expression of ALOX5AP in subcutaneous adipose tissue was increased in obesity and normalized following weight reduction. High adipose tissue mRNA expression of ALOX5AP is associated with insulin resistance as measured by homeostasis model assessment (HOMA(IR)). ALOX5AP haplotypes that associate with CVD are not associated with obesity or insulin resistance. CONCLUSION: ALOX5AP is present in adipose tissue, where its expression is associated with body weight and HOMA(IR), and may provide a link between adipose tissue, inflammation and insulin resistance. Investigated ALOX5AP haplotypes are not major primary risk factors for obesity and insulin resistance.     

Reduced plasma visfatin/pre-B cell colony-enhancing factor in obesity is not related to insulin resistance in humans

CONTEXT: Visfatin was recently identified as a protein highly expressed and secreted in adipose tissue with insulin-mimetic effect and is a candidate hormone to help explain the association among adipose tissue expansion, insulin resistance, and type 2 diabetes. OBJECTIVE: The objective of the study was to assess expression of visfatin in lean and obese subjects and in sc and visceral adipose tissue and moreover to explore the role of visfatin on insulin resistance in humans. DESIGN: We measured circulating visfatin and its mRNA expression in sc adipose tissue (SAT) in lean and obese subjects. Furthermore, we measured visfatin mRNA in visceral adipose (VAT) and SAT by quantitative RT-PCR. Finally, plasma visfatin and its mRNA in SAT were measured under free fatty acid-induced insulin resistance in healthy subjects. RESULTS: Plasma visfatin and its mRNA in SAT were significantly lower in obese subjects, compared with normal-weight controls. Both circulating visfatin and SAT visfatin mRNA were negatively correlated with body mass index, whereas no correlation was found with homeostasis model assessment. Significantly higher visfatin mRNA was found in VAT of obese subjects, compared with lean controls. Interestingly, visfatin mRNA in VAT was positively correlated with BMI. Elevation of free fatty acid induced a condition of insulin resistance but did not affect either circulating visfatin or its mRNA. CONCLUSIONS: Our findings show that, in human obesity, plasma visfatin is reduced, whereas visfatin mRNA is differentially regulated in SAT and VAT. Visfatin is not related to insulin resistance either as assessed by homeostasis model assessment or during lipid infusion.     

IL-7 concentration is increased in nonagenarians but is not associated with markers of T cell immunosenescence

Interleukin-7 is a homeostatic cytokine that contributes to the maintenance of the T cell pool. It also has proinflammatory effects and is involved in the pathogenesis of autoimmune diseases. Due to its homeostatic effects, IL-7 has been proposed as a potential rejuvenation factor for the elderly immune system. We analyzed the correlation of plasma IL-7 concentrations and the proportions of different T cell populations in nonagenarians (n=163) participating in the Vitality 90+ study. Young individuals (n=35, aged 19-30years) were used as controls. The numbers of CD3+, CD14+, CD4+ and CD8+ cells and the expression of the CD28 costimulatory molecule on CD4+ and CD8+ lymphocyte subsets were analyzed using flow cytometry. The plasma IL-7 levels were significantly higher in the nonagenarians compared to the controls (7.86 vs. 5.74pg/ml, p=0.004). In the nonagenarians, plasma IL-7 levels correlated inversely with the proportion of CD3+ T cells and directly with the proportion of CD14+ monocytes and plasma C-reactive protein. No correlation was observed between plasma IL-7 levels and the proportions of CD4+CD28- or CD8+CD28- subsets. These results suggest that the IL-7 levels in nonagenarians do not have an inhibitory effect on the development of immunosenescence; rather they are associated with increased inflammation.     

Increased serum interleukin-18 concentration is associated with hypoadiponectinemia in obesity, independently of insulin resistance

OBJECTIVE: Interleukin-18 (IL-18) is a cytokine with proinflammatory and proatherogenic properties, which might be associated with the development of insulin resistance. In contrast, adiponectin, a protein secreted by adipose tissue, might exert insulin-sensitizing and antiatherogenic effects. The aim of the present study was to analyze the association between serum IL-18 and adiponectin in lean and obese subjects, in relation to insulin resistance. DESIGN: Cross-sectional study. SUBJECTS: One hundred and thirty individuals, 62 lean (body mass index (BMI)<25 kg/m(2), 30 men and 32 women) and 68 with overweight or obesity (BMI>25 kg/m(2), 24 men and 44 women), with normal glucose tolerance and without concomitant diseases. MEASUREMENTS: Oral glucose tolerance test, euglycemic hyperinsulinemic clamp, serum concentrations of IL-18, IL-6, soluble tumor necrosis factor-alpha receptors and adiponectin. RESULTS: Obese subjects had lower insulin sensitivity (M value, P=0.00029) and serum adiponectin (P=0.01) and higher levels of serum IL-18 (P=0.00055). Circulating IL-18 was negatively related to adiponectin (r=-0.31, P=0.00027) and insulin sensitivity (r=-0.33, P=0.00012). Subgroup analysis revealed that these associations were present in the obese (adiponectin, r=-0.38, P=0.0014; M, r=-0.29, P=0.016), but not in lean individuals (r=-0.17, P=0.18 and r=-0.20, P=0.12, respectively). Association of IL-18 with adiponectin remained significant after adjustment for other estimated parameters, including insulin sensitivity. Also, relationship between IL-18 and insulin sensitivity was independent of other estimated parameters. CONCLUSION: Serum IL-18 is inversely related to serum adiponectin, independently of insulin resistance. The relationships of IL-18 with adiponectin and insulin sensitivity are influenced by the presence of overweight/obesity.     

Offspring birthweight is not associated with paternal insulin resistance

Aims/hypothesis Low birthweight is associated with insulin resistance and other insulin resistance-related phenotypes: diabetes, hypertension, and vascular disease in later life. The underlying mechanism is unclear. The foetal insulin hypothesis proposes that a single genetic predisposition to beta cell dysfunction/insulin resistance results in both reduced insulin-dependent foetal growth in utero, hence low birthweight, and predisposition to type 2 diabetes. The aim of this study was to test whether, as predicted by the foetal insulin hypothesis, there is an association between measures of paternal insulin resistance and offspring birthweight.Subjects and Methods The Exeter Family Study of Childhood Health (EFSOCH) is a community-based study within central Exeter (UK), established to test the foetal insulin hypothesis prospectively. Associations were tested between offspring birthweight and paternal insulin resistance, calculated by homeostasis model assessment analysis in 986 families using data relating to singleton, non-diabetic, UK white pregnancies. Ethics approval was given by the North and East Devon local ethics committee.Results Offspring birthweight was not significantly correlated with log paternal insulin resistance (r=0, p=0.91), log HDL cholesterol concentration (r=−0.02, p=0.47) or log triglyceride concentration (r=0, p=0.99) when corrected for paternal BMI and common confounders. Multiple linear regression analysis confirmed that paternal insulin resistance was not an independent predictor of offspring birthweight.Conclusions/interpretation Results from a young, adult, non-diabetic population do not support the foetal insulin hypothesis as an explanation for the association of low birthweight with insulin resistance.     

Increased plasma concentration of nitric oxide in type 2 diabetes but not in nondiabetic individuals with insulin resistance

OBJECTIVE: Insulin resistance (IR) is a key element in the pathogenesis of type 2 diabetes. The results of recent experiments on insulin-mediated vasodilatation have suggested that vascular insensitivity is a component of IR. However, it is still controversial that patients with type 2 diabetes have a decreased ability of insulin to increase endothelial nitric oxide (NO) release. METHOD: Plasma concentration of NO was examined in 26 patients with type 2 diabetes and 78 nondiabetic volunteers during an insulin suppression test. The test measured the efficacy of insulin in promoting disposal of the infused glucose load, in which the steady state plasma glucose (SSPG) during the 150-180 min of the test was used as an index of IR. Plasma NO levels were assayed by measurement of the stable end products of their metabolism. Comparison of plasma NO levels between groups were performed by Mann-Whitney test and relationships between SSPG and different variables were analyzed by partial correlations. RESULTS: Our results showed that the plasma NO levels were significantly higher in the diabetic group. When the nondiabetic subjects were analyzed according to their SSPG levels, there was no difference of plasma NO levels between those with SSPG>160 mg/dl and those with SSPG<160 mg/dl. There were also no difference of NO levels between those with a family history of type 2 diabetes and those without. In the nondiabetic group, SSPG correlated with BMI, fasting insulin, triglyceride and HDL-cholesterol, but neither with plasma NO levels nor fasting plasma glucose. CONCLUSION: Our data suggests that the impairment of NO activity in patients with type 2 diabetes is due to an impaired effect rather than its production. This altered NO signaling pathway is not an early event in insulin resistant individuals. Any such changes will not be apparent until type 2 diabetes with overt hyperglycemia develops.     

Low circulating insulin-like growth factor I bioactivity in elderly men is associated with increased mortality

CONTEXT: Low IGF-I signaling activity prolongs lifespan in certain animal models, but the precise role of IGF-I in human survival remains controversial. The IGF-I kinase receptor activation assay is a novel method for measuring IGF-I bioactivity in human serum. We speculated that determination of circulating IGF-I bioactivity is more informative than levels of immunoreactive IGF-I. OBJECTIVE: Our objective was to study IGF-I bioactivity in relation to human survival. DESIGN, SETTING, AND STUDY PARTICIPANTS: We conducted a prospective observational study at a clinical research center at a university hospital of 376 healthy elderly men (aged 73-94 yr). MAIN OUTCOME MEASURES: IGF-I bioactivity was determined by the IGF-I kinase receptor activation assay. Total and free IGF-I were determined by IGF-I immunoassays. Mortality was registered during follow-up (mean 82 months). RESULTS: During the follow-up period of 8.6 yr, 170 men (45%) died. Survival of subjects in the highest quartile of IGF-I bioactivity was significantly better than in the lowest quartile, both in the total study group [hazard ratio (HR) = 1.8; 95% confidence interval (95% CI) = 1.2-2.8; P = 0.01] as well as in subgroups having a medical history of cardiovascular disease (HR = 2.4; 95% CI = 1.3-4.3; P = 0.003) or a high inflammatory risk profile (HR = 2.3; 95% CI = 1.2-4.5; P = 0.01). Significant relationships were not observed for total or free IGF-I. CONCLUSION: Our study suggests that a relatively high circulating IGF-I bioactivity in elderly men is associated with extended survival and with reduced cardiovascular risk.     

Circulating hepatocyte growth factor level but not basic fibroblast growth factor level is elevated in angiography-proven symptomatic peripheral artery disease

Circulating vasogenic factors may be up-regulated in response to ischemia to promote angiogenesis in patients with peripheral artery disease (PAD). Studies on this are limited in number and size, and results are inconsistent, especially regarding basic fibroblast growth factor (bFGF) level. From March 1999 to April 2004, all consecutive patients with lower limb PAD having serum samples at the time of intervention were recruited. The diameter of the primary PAD lesion had to be at least 70% stenotic at the lower limb artery. Control subjects, who underwent angiography, were free of PAD, coronary disease, and other major medical diseases. Serum samples were analyzed for circulating hepatocyte growth factor (HGF) and bFGF levels. Patients with PAD (n = 60) had higher circulating HGF levels (mean +/- SEM, 1,544 +/- 238 vs 970 +/- 129 pg/mL; P = .04) but similar bFGF distribution tertiles (P = .55) compared with control subjects (n = 30). Thirty-six patients with summed PAD lesion lengths exceeding 5 cm demonstrated a significantly higher circulating HGF level compared with control subjects (mean +/- SEM, 1,701 +/- 335 vs 970 +/- 129 pg/mL; P = .048). Patients with concurrent coronary artery disease tend to have a higher circulating HGF level (mean +/- SEM, 1,606 +/- 365 vs 970 +/- 129 pg/mL; P = .06) but not a higher bFGF level compared with control subjects. Circulating HGF level, but not bFGF level, is significantly elevated in patients with symptomatic angiographically documented PAD, especially in those with more extensive involvement.     

Hypothalamic growth hormone-releasing hormone (GHRH) cell number is increased in human illness,but is not reduced in Prader-Willi syndrome or obesity

BACKGROUND: Acute illness leads to increased GH, but reduced IGF-I secretion, while both are reduced in chronic illness. Prader-Willi syndrome (PWS) is a genetic obesity syndrome, with GH deficiency a feature independent of obesity. Reduced GH secretion may result from decreased hypothalamic release of GH-releasing hormone (GHRH). OBJECTIVE: To quantify hypothalamic GHRH neurone cell number in control subjects with various lengths of premorbid illness duration, PWS and non-PWS obese subjects. DESIGN: We examined GHRH neurones in the infundibular nucleus/median eminence complex of control subjects (n = 26, including four children), PWS (n = 6) and non-PWS (n = 4) obese adults and PWS children (n = 2), by quantitative immunocytochemistry, using postmortem material. RESULTS: We found: (i) higher GHRH cell number during prolonged illness prior to death in both control adults (r = +0.62, P = 0.002, cell number vs. premorbid illness duration) and PWS adults (r = +0.90, P = 0.02); (ii) higher GHRH cell number in female than male adults [by 53% (95% confidence interval 28-83%) in controls, P = 0.005, correcting for premorbid illness duration]; (iii) no difference in GHRH cell number between PWS adults and control or non-PWS obese adults (P = 0.7 and P = 0.4, adjusting for sex and illness duration); and (iv) low GHRH cell number in only one PWS child (who had been receiving exogenous GH therapy). CONCLUSIONS: These findings suggest continued activation of GHRH neurones during prolonged illness. There is no evidence that the GH deficiency in PWS results from reduced GHRH cell number, and GHRH neuronal responses to illness and exogenous GH treatment appear normal in PWS.     

Liver steatosis,but not fibrosis,is associated with insulin resistance in nonalcoholic fatty liver disease

Background To address the hypothesis that liver steatosis causes systemic insulin resistance, we sought to determine the liver histological feature that most strongly contributes to insulin resistance in patients with nonalcoholic fatty liver disease (NAFLD). Methods Liver biopsy specimens were obtained from 131 patients with clinically suspected NAFLD. The stage, grade of nonalcoholic steatohepatitis (NASH), and level of steatosis were scored and analyzed in relation to the homeostasis model assessment of insulin resistance (HOMA-IR) and the metabolic clearance rate (MCR), measured using the glucose clamp method. Results In the univariate analysis, the degree of hepatic steatosis (r = 0.458, P < 0.001), stage (r = 0.360, P < 0.001), and grade (r = 0.349, P < 0.01) of NASH were significantly correlated with the HOMA-IR. Multiple regression analysis adjusting for age, sex, body mass index, and each histological score showed that steatosis was significantly and independently associated with HOMA-IR (coefficient = 1.42, P < 0.001), but not with the stage (coefficient = 0.33, P = 0.307) or grade (coefficient = 0.67, P = 0.134) of NASH. Similar independent relationships were observed between steatosis and MCR, but the relationship was weaker (coefficient = −0.98, P = 0.076). Conclusions Steatosis of the liver, but not the stage or the grade of NASH, is associated with insulin resistance in patients with NAFLD.     

Retinol-binding protein 4 is not associated with insulin resistance in pregnancy

Retinol-binding protein 4 (RBP4) is an adipokine proposed to be specifically associated with insulin resistance (IR). We examined whether serum levels of RBP4 were associated with IR in pregnancy. One hundred seventy-two women with gestational diabetes mellitus (GDM) and 361 pregnant Thai women who did not have GDM but had a positive 50-g glucose challenge test result (plasma glucose level was ≥7.2 mmol/L after 1 hour) were enrolled. We measured fasting serum levels of RBP4 and assessed IR at a 100-g oral glucose tolerance test. We found a higher degree of IR in the GDM group compared with the non-GDM group, but serum RBP4 levels between the 2 groups were not different. Retinol-binding protein 4 levels were associated with serum triglyceride levels but were not associated with the degree of IR assessed by homeostasis model assessment or quantitative insulin sensitivity check index. Our results suggest that serum RBP4 levels in pregnancy are not associated with IR.     

Insulin resistance but not inflammation is associated with gestational hypertension

Hypertensive disorders of pregnancy, including gestational hypertension and preeclampsia, are leading causes of pregnancy-associated morbidity. Although insulin resistance and inflammation contribute to preeclampsia, prospective data regarding mechanisms of gestational hypertension are sparse. We conducted a prospective, nested case-control study to test the hypotheses that insulin resistance, marked by reduced sex hormone-binding globulin (SHBG) levels, and inflammation, marked by increased C-reactive protein levels, are similarly associated with gestational hypertension. We measured first-trimester C-reactive protein and SHBG levels in 51 women who subsequently developed gestational hypertension and 102 randomly selected normotensive pregnant controls. Compared with controls, first-trimester SHBG levels were significantly reduced among women who later developed gestational hypertension (176+/-73 versus 203+/-79 nmol/L; P=0.03), but there was no difference in C-reactive protein levels. There was statistically significant interaction among nulliparity, first-trimester SHBG levels, and risk of gestational hypertension, such that increasing SHBG levels were associated with significantly reduced risk of gestational hypertension among nulliparous women (odds ratio, 0.64 per 50-nmol/L increase; 95% confidence interval, 0.46, 0.90; P<0.01) but not among multiparous women. This association remained significant after adjusting for potential confounders (odds ratio, 0.55; 95% confidence interval, 0.31, 0.98; P=0.04). We conclude that insulin resistance, but not inflammation, is an independent risk factor for gestational hypertension among nulliparous women. Furthermore, important mechanistic differences exist in the pathogenesis of gestational hypertension comparing nulliparous and multiparous women.     

Acute hyperinsulinemia is associated with increased plasma adrenomedullin concentrations in uncomplicated obesity.

OBJECTIVE: Adrenomedullin (AM) is a potent hypotensive peptide which may be implicated in the insulin regulatory system. Acute hyperinsulinemia exerts no influence on plasma AM in normal subjects while no data on obese subjects has been reported. PURPOSE: The aim of the study was to investigate the effect of acute hyperinsulinemia on the plasma AM concentration in patients with uncomplicated obesity. RESEARCH METHODS: We measured the plasma AM levels in 23 obese subjects (BMI 41.9 +/- 9.8 kg/m2), 21 females and 2 males (mean age 31 +/- 7.2 years), before and during a euglycemic hyperinsulinemic clamp. The control group consisted of 43 healthy subjects (HS) (22 males and 21 females; mean age 38 +/- 12 years; BMI 23.3 +/- 3.2 kg/m2). RESULTS: Baseline plasma AM was found to be higher in obese subjects (20.4 +/- 8.4 pg/ml) than in normal subjects (11.3 +/- 0.8 pg/ml) (p < 0.001). A significant increase in the plasma AM levels was observed in obese subjects during acute hyperinsulinemia (from 20.4 +/- 8.4 pg/ml at 0 min to 26 +/- 8.9 pg/ml at 120 min, p < 0.02). Plasma AM concentrations were significantly correlated with insulin levels at 30 min (r = 0.44; p = 0.04) and 120 min (r = 0.40, p = 0.05) during the clamp. DISCUSSION: In conclusion, acute hyperinsulinemia induced a significant increase in the plasma levels of AM in uncomplicated obese subjects. Hyperinsulinemia may, at least in part, regulate levels of AM in obesity, explaining the high levels of the peptide in these subjects.     

Serum fibroblast growth factor-21 concentration is associated with residual renal function and insulin resistance in end-stage renal disease patients receiving long-term peritoneal dialysis

Fibroblast growth factor-21 (FGF-21) is a new metabolic regulator, which is related to antiobesity and insulin sensitivity in vivo. However, the clinical implication of FGF-21 is poorly understood. To investigate whether FGF-21 may play a role as a metabolic regulator in patients with end-stage renal disease, we measured serum concentrations of FGF-21, inflammatory markers, and metabolic parameters in healthy people (n = 63) and nondiabetic patients receiving peritoneal dialysis (PD, n = 72). The patients were treated with angiotensin receptor blocker for 6 months, and the changes in FGF-21 concentration and metabolic parameters were assessed. Compared with controls, serum FGF-21 concentration was 8 times higher in patients undergoing PD (754.2 ± 463.5 vs 86.9 ± 60.2 pg/mL, P < .001). In controls, only lipid parameters correlated positively with FGF-21 concentration. In contrast, inflammatory markers (interleukin-6, fibrinogen, high-sensitivity C-reactive protein) and homeostasis model assessment of insulin resistance (HOMA-IR) correlated positively and residual renal function correlated inversely with serum FGF-21 concentration in PD patients. In a multivariate analysis adjusting these factors, residual renal function, HOMA-IR, and fibrinogen concentration were independent determinants of serum FGF-21 concentration. After 6-month angiotensin receptor blocker treatment, serum FGF-21 concentration declined significantly by 13% and HOMA-IR and inflammatory markers improved in PD patients. These findings suggest that FGF-21 may play a role in insulin resistance in patients with end-stage renal disease.