Background: Obesity represents a risk factor for insulin resistance, type 2 diabetes mellitus, and atherosclerosis. In addition, for any given amount of total body fat, an excess of visceral fat or fat accumulation in the liver and skeletal muscle augments the risk. Conversely, even in obesity, a metabolically benign fat distribution phenotype may exist.Methods: In 314 subjects, we measured total body, visceral, and subcutaneous fat with magnetic resonance (MR) tomography and fat in the liver and skeletal muscle with proton MR spectroscopy. Insulin sensitivity was estimated from oral glucose tolerance test results. Subjects were divided into 4 groups: normal weight (body mass index [BMI] [calculated as weight in kilograms divided by height in meters squared], Ͻ25.0), overweight (BMI, 25.0-29.9), obese-insulin sensitive (IS) (BMI, Ն30.0 and placement in the upper quartile of insulin sensitivity), and obese-insulin resistant (IR) (BMI, Ն30.0 and placement in the lower 3 quartiles of insulin sensitivity).Results: Total body and visceral fat were higher in the overweight and obese groups compared with the normal-weight group (PϽ.05); however, no differences were observed between the obese groups. In contrast, ectopic fat in skeletal muscle (PϽ.001) and particularly the liver (4.3%±0.6% vs 9.5%±0.8%) and the intima-media thickness of the common carotid artery (0.54±0.02 vs 0.59±0.01 mm) were lower and insulin sensitivity was higher (17.4±0.9 vs 7.3±0.3 arbitrary units) in the obese-IS vs the obese-IR group (PϽ.05). Unexpectedly, the obese-IS group had almost identical insulin sensitivity and the intima-media thickness was not statistically different compared with the normal-weight group (18.2±0.9 AU and 0.51±0.02 mm, respectively). Conclusions:A metabolically benign obesity that is not accompanied by insulin resistance and early atherosclerosis exists in humans. Furthermore, ectopic fat in the liver may be more important than visceral fat in the determination of such a beneficial phenotype in obesity.
OBJECTIVE -The ␣ 2 -Heremans-Schmid glycoprotein (AHSG; fetuin-A in animals) impairs insulin signaling in vitro and in rodents. Whether AHSG is associated with insulin resistance in humans is under investigation. In an animal model of diet-induced obesity that is commonly associated with hepatic steatosis, an increase in Ahsg mRNA expression was observed in the liver. Therefore, we hypothesized that the AHSG plasma protein, which is exclusively secreted by the liver in humans, may not only be associated with insulin resistance but also with fat accumulation in the liver.RESEARCH DESIGN AND METHODS -Data from 106 healthy Caucasians without type 2 diabetes were included in cross-sectional analyses. A subgroup of 47 individuals had data from a longitudinal study. Insulin sensitivity was measured by a euglycemic-hyperinsulinemic clamp, and liver fat was determined by 1 H magnetic resonance spectroscopy.RESULTS -AHSG plasma levels, adjusted for age, sex, and percentage of body fat, were higher in subjects with impaired glucose tolerance compared with subjects with normal glucose tolerance (P ϭ 0.006). AHSG plasma levels were negatively associated with insulin sensitivity (r ϭ Ϫ0.22, P ϭ 0.03) in cross-sectional analyses. Moreover, they were positively associated with liver fat (r ϭ 0.27, P ϭ 0.01). In longitudinal analyses, under weight loss, a decrease in liver fat was accompanied by a decrease in AHSG plasma concentrations. Furthermore, high AHSG levels at baseline predicted less increase in insulin sensitivity (P ϭ 0.02).CONCLUSIONS -We found that high AHSG plasma levels are associated with insulin resistance in humans. Moreover, AHSG plasma levels are elevated in subjects with fat accumulation in the liver. This is consistent with a potential role of AHSG as a link between fatty liver and insulin resistance. Diabetes Care 29:853-857, 2006I nsulin resistance plays a crucial role in the development of type 2 diabetes (1). Multiple mechanisms are thought to be involved in its pathogenesis. Among them, the human ␣ 2 -Heremans-Schmid glycoprotein (AHSG) was found to be important in animals and in in vitro studies. It is an abundant serum protein in mammals. Bovine and murine fetuin-A and pp63 in rats are homologues of AHSG (2,3). In humans, except for the tongue and the placenta, it is exclusively expressed in the liver (4). It is a natural inhibitor of the insulin-stimulated insulin receptor tyrosine kinase (3). Acute injection of human recombinant AHSG inhibi t e d i n s u l i n -s t i m u l a t e d t y r o s i n e phosphorylation of the insulin receptor and insulin receptor substrate-1 in rat liver and skeletal muscle (3). In addition, AHSG knockout mice display improved insulin sensitivity and are resistant to weight gain on a high-fat diet (5).While these data reflect that AHSG is an important candidate among the factors that induce insulin resistance, the role of this protein in the natural history of type 2 diabetes is still unclear (6). Recent reports from genetic studies suggest that single nucleotide polymor...
Insulin-dependent diabetes is a complex multifactorial disorder characterized by loss or dysfunction of β-cells. Pancreatic β-cells differ in size, glucose responsiveness, insulin secretion and precursor cell potential; understanding the mechanisms that underlie this functional heterogeneity might make it possible to develop new regenerative approaches. Here we show that Fltp (also known as Flattop and Cfap126), a Wnt/planar cell polarity (PCP) effector and reporter gene acts as a marker gene that subdivides endocrine cells into two subpopulations and distinguishes proliferation-competent from mature β-cells with distinct molecular, physiological and ultrastructural features. Genetic lineage tracing revealed that endocrine subpopulations from Fltp-negative and -positive lineages react differently to physiological and pathological changes. The expression of Fltp increases when endocrine cells cluster together to form polarized and mature 3D islet mini-organs. We show that 3D architecture and Wnt/PCP ligands are sufficient to trigger β-cell maturation. By contrast, the Wnt/PCP effector Fltp is not necessary for β-cell development, proliferation or maturation. We conclude that 3D architecture and Wnt/PCP signalling underlie functional β-cell heterogeneity and induce β-cell maturation. The identification of Fltp as a marker for endocrine subpopulations sheds light on the molecular underpinnings of islet cell heterogeneity and plasticity and might enable targeting of endocrine subpopulations for the regeneration of functional β-cell mass in diabetic patients.
The adipocyte-derived hormone adiponectin seems to protect from insulin resistance, a key factor in the pathogenesis of type 2 diabetes. Genome-wide scans have mapped a susceptibility locus for type 2 diabetes and the metabolic syndrome to chromosome 3q27, where the adiponectin gene is located. A common silent T-G exchange in nucleotide 94 (exon 2) of the adiponectin gene has been associated with increased circulating adiponectin levels. Metabolic abnormalities associated with the G allele have not been reported. We therefore assessed whether this polymorphism alters insulin sensitivity and/or measures of obesity using the Tü bingen Family Study database (prevalence of the G allele, 28%). In 371 nondiabetic individuals, we found a significantly greater BMI in GG ؉ GT (25.5 ؎ 0.7 kg/m 2 ) compared with TT (24.1 ؎ 0.3 kg/m 2 ; P ؍ 0.02). Insulin sensitivity (determined by euglycemic clamp, n ؍ 209) was significantly lower in GG ؉ GT (0.089 ؎ 0.007 units) compared with TT (0.112 ؎ 0.005 units; P ؍ 0.02). This difference disappeared completely on adjustment for BMI. Because our population contains a relatively high proportion of first-degree relatives of patients with type 2 diabetes, we stratified by family history (FHD). Much to our surprise, the genotype differences in BMI and insulin sensitivity in the whole population were attributable entirely to differences in the subgroup without FHD, whereas in the subgroup with FHD, the G allele had absolutely no effect. Moreover, individuals without FHD had a significantly lower BMI than individuals with FHD (25.2 ؎ 0.4 vs. 26.2 ؎ 0.5 kg/m 2 ; P ؍ 0.01), which was not the case for the GG ؉ GT subgroup without FHD (27.0 ؎ 0.9 kg/m 2 ; NS). This suggests that in individuals without familial predisposition for type 2 diabetes, the adiponectin polymorphism may mildly increase the obesity risk (and secondarily insulin resistance). In contrast, in individuals who are already burdened by other genetic factors, this small effect may be very hard to detect. Diabetes 51:37-41, 2002
BackgroundThe secreted liver protein fetuin-A (AHSG) is up-regulated in hepatic steatosis and the metabolic syndrome. These states are strongly associated with low-grade inflammation and hypoadiponectinemia. We, therefore, hypothesized that fetuin-A may play a role in the regulation of cytokine expression, the modulation of adipose tissue expression and plasma concentration of the insulin-sensitizing and atheroprotective adipokine adiponectin.Methodology and Principal FindingsHuman monocytic THP1 cells and human in vitro differenttiated adipocytes as well as C57BL/6 mice were treated with fetuin-A. mRNA expression of the genes encoding inflammatory cytokines and the adipokine adiponectin (ADIPOQ) was assessed by real-time RT-PCR. In 122 subjects, plasma levels of fetuin-A, adiponectin and, in a subgroup, the multimeric forms of adiponectin were determined. Fetuin-A treatment induced TNF and IL1B mRNA expression in THP1 cells (p<0.05). Treatment of mice with fetuin-A, analogously, resulted in a marked increase in adipose tissue Tnf mRNA as well as Il6 expression (27- and 174-fold, respectively). These effects were accompanied by a decrease in adipose tissue Adipoq mRNA expression and lower circulating adiponectin levels (p<0.05, both). Furthermore, fetuin-A repressed ADIPOQ mRNA expression of human in vitro differentiated adipocytes (p<0.02) and induced inflammatory cytokine expression. In humans in plasma, fetuin-A correlated positively with high-sensitivity C-reactive protein, a marker of subclinical inflammation (r = 0.26, p = 0.01), and negatively with total- (r = −0.28, p = 0.02) and, particularly, high molecular weight adiponectin (r = −0.36, p = 0.01).Conclusions and SignificanceWe provide novel evidence that the secreted liver protein fetuin-A induces low-grade inflammation and represses adiponectin production in animals and in humans. These data suggest an important role of fatty liver in the pathophysiology of insulin resistance and atherosclerosis.
OBJECTIVEIn a genome-wide association scan, the rs738409 C>G single nucleotide polymorphism (SNP) in the patatin-like phospholipase 3 gene (PNPLA3) was strongly associated with increased liver fat but not with insulin resistance estimated from fasting values. We investigated whether the SNP determines liver fat independently of visceral adiposity and whether it may even play a role in protecting from insulin resistance.RESEARCH DESIGN AND METHODSLiver fat was measured by 1H magnetic resonance spectroscopy and total and visceral fat by magnetic resonance tomography in 330 subjects. Insulin sensitivity was estimated during an oral glucose tolerance test and the euglycemic-hyperinsulinemic clamp (n = 222). PNPLA3 and tumor necrosis factor-α mRNA and triglyceride content were measured in liver biopsies from 16 subjects.RESULTSLiver fat correlated strongly with insulin sensitivity (P < 0.0001) independently of age, sex, total fat, and visceral fat. G allele carriers of the SNP rs738409 had higher liver fat (P < 0.0001) and an odds ratio of 2.38 (95% CI 1.37–4.20) for having fatty liver compared to C allele homozygotes. Interestingly, insulin sensitivity (oral glucose tolerance test: P = 0.99; clamp: P = 0.32), serum C-reactive protein levels, lipids, or liver enzymes (all P > 0.14) were not different among the genotypes. Additional adjustment for liver fat actually revealed increased insulin sensitivity in more obese carriers of the G allele (P = 0.01). In liver biopsies triglyceride content correlated positively with expression of the proinflammatory gene tumor necrosis factor-α in C allele homozygotes (n = 6, P = 0.027) but not in G allele carriers (n = 10, P = 0.149).CONCLUSIONSPNPLA3 may be an important key to understand the mechanisms discriminating fatty liver with and without metabolic consequences.
Febrile morbidity is the most commonly reported adverse event after hysterectomy. Its incidence ranges from 9.1 to 37.4%. Risk factors reported in the literature include prolonged operative time, history of previous surgery, higher parity, greater blood loss, abdominal approach, and no antibiotic prophylaxis.Antibiotic prophylaxis in abdominal hysterectomy may provide protection against febrile morbidity and reduce its incidence, but does not eliminate it. Limited data are available evaluating risk factors for febrile morbidity after hysterectomy. This historical cohort study assessed the incidence of febrile morbidity and associated risk factors in 1980 Thai women, who had an abdominal hysterectomy between 1998 and 2005.Of the 1980 women, febrile morbidity occurred in 517. This represents an overall incidence of 26.1%. Univariate analysis of potential risk factors showed that the incidence of febrile morbidity was higher in patients with lower preoperative hematocrit, more extensive surgery, longer operative time, greater intraoperative blood loss and malignant disease. Median intraoperative blood loss was lower in the nonfebrile group than the febrile group (400 versus 500 ml, P Յ .0005) and median operative time was shorter (135 versus 150 minute, P Յ .0005).When both pre and postoperative variables were included in the logistic regression model, the only two risk factors independently associated with febrile morbidity were intraoperative blood loss of Ն750 ml (odds ratio [OR],1.52; 95% confidence interval [CI], 1.08-2.13; P ϭ .036) and a diagnosis of malignant disease (OR 1.86; 95% CI 1.45-2.13, P Ͻ .0005). GYNECOLOGY Volume 64, Number 1 OBSTETRICAL AND GYNECOLOGICAL SURVEY ABSTRACTAlternatives to hysterectomy such as medical treatment, uterine artery embolization (UAE), and ablative therapy have become available and widely used in the last 10 years. It is unclear if these alternatives are replacing hysterectomy or delaying it. To determine the effect of patient clinical factors on the utilization of hysterectomy and alternatives of hysterectomy, the investigators examined all claims relating to a hysterectomy procedure or a hysterectomy-associated diagnosis in the database of a large insurance provider for 48 consecutive months from 2001 to 2005. A total of 295,148 claim lines were abstracted and analyzed by CPT and diagnostic grouping codes.Of the 7049 procedures represented in the claim lines, 1972 were hysterectomies and 5077 were hysterectomy alternatives. The mean age of patients filing claims was 39.1 years. Patients submitting claims for a hysterectomy were older than those having an alternative procedure (mean age, 49.7 v 46.0 years, P Ͻ .0001). The diagnostic group associated with the majority of all claims was abnormal bleeding (33%); the inflammation/mass/pain/endometriosis group accounted for 32%. The most common diagnostic groups associated with a hysterectomy were fibroids (39.4%), the inflammation/mass/pain/endometriosis category (14.7%), and cancer (13.0%). Bleeding represented the majority o...
Circulating interleukin-6 (IL-6), insulin, and free fatty acid (FFA) concentrations are associated with impaired insulin action in obese and type 2 diabetic individuals. However, a causal relationship between elevated plasma FFAs and IL-6 has not been shown. Because skeletal muscle represents a major target of impaired insulin action, we studied whether FFAs may affect IL-6 expression in human myotubes. We demonstrate that specifically saturated FFAs, e.g. palmitate (0.25 mM), induce IL-6 mRNA expression and protein secretion by a proteasome-dependent mechanism that leads to a rapid and chronic activation of nuclear factor-B. Insulin, high glucose concentrations, or unsaturated FFAs did not activate IL-6 expression. In fact, the unsaturated FFA linoleate inhibited palmitate-induced IL-6 production. Because inhibition of palmitate metabolism by the acyl-CoA synthetase inhibitor triacsin C did not abolish IL-6 expression, it appears that the palmitate molecule per se exerts the observed effects. Furthermore, we show that in human myotubes, IL-6 activates the phosphorylation of signal transducer and activator of transcription 3 in concentrations similar to hepatocytes. However, no inhibitory effect of IL-6 on insulin action, determined as phosphatidylinositol 3-kinase association with insulin receptor substrate-1, Akt phosphorylation, and glycogen synthesis, was detected. We conclude that IL-6 expression may be modulated by the composition of circulating FFA, e.g. by diet, and that skeletal muscle cells could be target cells for IL-6.
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