Early Insulin Resistance Research Articles

Early diagnosis of type 2 diabetes based on multiple biomarkers and non-invasive indices.

We previously reported that type 2 diabetes risk, early impaired glucose tolerance and insulin resistance can be predicted by measuring the fasting levels of certain biomarkers. Here we validated these findings in randomly recruited healthy volunteers (n = 101) based on biomarker expression as well as various non-invasive indices. Weight, body mass index, waist circumference and visceral fat differed between individuals with impaired fasting glucose and/or impaired glucose tolerance, and normal subjects. Fasting plasma levels of glycated hemoglobin, leptin, pro-insulin and retinol binding protein 4 differed between impaired fasting glucose/impaired glucose tolerance and normal subjects group and between newly detected diabetes and normal subjects group. Insulin resistance was correlated with fasting levels of insulin and leptin/adiponectin (r = 0.913); of insulin, retinol binding protein 4 and leptin/adiponectin (r = 0.903); and of insulin, glycated albumin, and leptin/adiponectin (r = 0.913). Type 2 diabetes risk, early impaired glucose tolerance and insulin resistance were predicted with >98% specificity and sensitivity by comparing fasting glucose levels to the estimated Matsuda Index based on fasting levels of insulin, adiponectin and leptin with or without oxidative lineolate metabolites. Non-invasive indices are slightly correlated with glucose tolerance and insulin resistance but do not increase the accuracy of predicting type 2 diabetes risk.

Water T2 as an early, global and practical biomarker for metabolic syndrome: an observational cross-sectional study

BackgroundMetabolic syndrome (MetS) is a highly prevalent condition that identifies individuals at risk for type 2 diabetes mellitus and atherosclerotic cardiovascular disease. Prevention of these diseases relies on early detection and intervention in order to preserve pancreatic β-cells and arterial wall integrity. Yet, the clinical criteria for MetS are insensitive to the early-stage insulin resistance, inflammation, cholesterol and clotting factor abnormalities that characterize the progression toward type 2 diabetes and atherosclerosis. Here we report the discovery and initial characterization of an atypical new biomarker that detects these early conditions with just one measurement.MethodsWater T2, measured in a few minutes using benchtop nuclear magnetic resonance relaxometry, is exquisitely sensitive to metabolic shifts in the blood proteome. In an observational cross-sectional study of 72 non-diabetic human subjects, the association of plasma and serum water T2 values with over 130 blood biomarkers was analyzed using bivariate, multivariate and logistic regression.ResultsPlasma and serum water T2 exhibited strong bivariate correlations with markers of insulin, lipids, inflammation, coagulation and electrolyte balance. After correcting for confounders, low water T2 values were independently and additively associated with fasting hyperinsulinemia, dyslipidemia and subclinical inflammation. Plasma water T2 exhibited 100% sensitivity and 87% specificity for detecting early insulin resistance in normoglycemic subjects, as defined by the McAuley Index. Sixteen normoglycemic subjects with early metabolic abnormalities (22% of the study population) were identified by low water T2 values. Thirteen of the 16 did not meet the harmonized clinical criteria for metabolic syndrome and would have been missed by conventional screening for diabetes risk. Low water T2 values were associated with increases in the mean concentrations of 6 of the 16 most abundant acute phase proteins and lipoproteins in plasma.ConclusionsWater T2 detects a constellation of early abnormalities associated with metabolic syndrome, providing a global view of an individual’s metabolic health. It circumvents the pitfalls associated with fasting glucose and hemoglobin A1c and the limitations of the current clinical criteria for metabolic syndrome. Water T2 shows promise as an early, global and practical screening tool for the identification of individuals at risk for diabetes and atherosclerosis.

Prolonged exposure of mouse and human podocytes to insulin induces insulin resistance through lysosomal and proteasomal degradation of the insulin receptor

Aims/hypothesisPodocytes are insulin-responsive cells of the glomerular filtration barrier and are key in preventing albuminuria, a hallmark feature of diabetic nephropathy. While there is evidence that a loss of insulin signalling to podocytes is detrimental, the molecular mechanisms underpinning the development of podocyte insulin resistance in diabetes remain unclear. Thus, we aimed to further investigate podocyte insulin responses early in the context of diabetic nephropathy.MethodsConditionally immortalised human and mouse podocyte cell lines and glomeruli isolated from db/db DBA/2J mice were studied. Podocyte insulin responses were investigated with western blotting, cellular glucose uptake assays and automated fluorescent imaging of the actin cytoskeleton. Quantitative (q)RT-PCR was employed to investigate changes in mRNA. Human cell lines stably overproducing the insulin receptor (IR) and nephrin were also generated, using lentiviral constructs.ResultsPodocytes exposed to a diabetic environment (high glucose, high insulin and the proinflammatory cytokines TNF-α and IL-6) become insulin resistant with respect to glucose uptake and activation of phosphoinositide 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) signalling. These podocytes lose expression of the IR as a direct consequence of prolonged exposure to high insulin concentrations, which causes an increase in IR protein degradation via a proteasome-dependent and bafilomycin-sensitive pathway. Reintroducing the IR into insulin-resistant human podocytes rescues upstream phosphorylation events, but not glucose uptake. Stable expression of nephrin is also required for the insulin-stimulated glucose uptake response in podocytes and for efficient insulin-stimulated remodelling of the actin cytoskeleton.Conclusions/interpretationTogether, these results suggest that IR degradation, caused by high levels of insulin, drives early podocyte insulin resistance, and that both the IR and nephrin are required for full insulin sensitivity of this cell. This could be highly relevant for the development of nephropathy in individuals with type 2 diabetes, who are commonly hyperinsulinaemic in the early phases of their disease.

Combined effects of physical inactivity and acute hyperglycemia on arterial distensibility.

Arterial distensibility, an independent predictor of cardiovascular events, is transiently increased with acute hyperglycemia (AHG) in healthy individuals. Whether this response interacts with physical inactivity remains unknown. We examined the effects of short-term bed rest (BR) on the response of carotid artery distensibility (CD) to AHG, and the influence of underlying changes in insulin resistance and blood volume. CD was assessed with ultrasonography before as well as 30 and 120 minutes following ingestion of 75 g of glucose prior to and after 3 days of BR in 15 healthy male volunteers. Plasma insulin/glucose concentrations and blood volumes were concomitantly determined. On day 4 of BR, blood volume was re-established to pre-BR levels by albumin infusion and CD and insulin/glucose concentrations were determined as in the previous experimental days. Basal CD was not affected by BR. AHG increased CD before and after BR but reached a higher peak increment after BR (12% vs 60% at 30 min OGTT, p=0.028). BR also increased the plasma insulin concentration during AHG ( p=0.007). In regression analyses, plasma insulin and glucose concentrations were positively correlated to CD, particularly after BR ( r=0.31, p<0.05). Restoration of the BR-induced loss (5%) in blood volume did not affect the response of CD to AHG. In conclusion, short-term physical inactivity strongly accentuates the initial increase in CD in response to AHG in healthy individuals. This effect is associated with concomitant increases in circulating insulin concentration attributable to early insulin resistance.

Abstract P041: New Biomarkers for Detecting and Subtyping Insulin Resistance

Introduction: The metabolic abnormalities that precede type 2 diabetes progress slowly and in stages. Current evidence-based diabetes prevention programs target individuals in Stage 2 (impaired glucose tolerance or prediabetes). However, by that stage, 70% of pancreatic beta-cell insulin secretory capacity has been lost irreversibly. Thus, it is imperative to identify individuals in Stage I (early insulin resistance syndrome) in order to preserve pancreatic insulin secretion and prevent both diabetes and prediabetes. Early insulin resistance syndrome is characterized by compensatory hyperinsulinemia, dyslipidemia, sub-clinical inflammation and acid-base abnormalities. The nature of the association between these elements is unclear, and different subtypes of insulin resistance syndrome may exist. Hypothesis: We have developed two novel and unconventional biomarkers for characterizing insulin resistance in non-diabetic subjects. One approach is based on dynamic light scattering (DLS) of human serum. The second approach measures the T 2 relaxation time of water in human plasma using compact time-domain NMR relaxometry (TD-NMR). We hypothesize that these methods can detect subtypes, i.e. , insulin resistance with or without inflammation, hypercholesterolemia, or acid-base abnormalities. Methods: Seventy-two asymptomatic non-diabetic human subjects were recruited through an IRB-approved biomarker discovery protocol. Medical histories, anthropomorphic measurements and fasting blood samples were obtained, and over 1300 blood biomarkers were measured on each subject along with DLS and TD-NMR parameters. Bi-variate correlation analyses and multiple regression models were used to analyze continuous variables, and categorical variables were established for insulin resistance, inflammation, acid-base abnormalities and lipid abnormalities. Multiple means comparisons were performed using one-way ANOVA and Tukey-Kramer testing. Results: Plasma water T 2 from TD-NMR was strongly correlated with markers of early insulin resistance syndrome. Multiple regression analysis showed independent contributions from markers of hyperinsulinemia, hypercholesterolemia and inflammation. Multiple means comparisons showed significant differences for insulin resistance with and without inflammation. By contrast, DLS parameters were strongly correlated with insulin markers, but could not distinguish the inflammatory subtypes. Conclusions: Both TD-NMR and DLS are able to detect early insulin resistance in individuals who do not meet the criteria for prediabetes or metabolic syndrome. However, TD-NMR has the unique ability to distinguish inflammatory vs. non-inflammatory subtypes of insulin resistance. Subtyping and risk stratification are important for the design of personalized interventions to prevent diabetes, prediabetes and cardiovascular disease.

Clinical impact of angiotensin I converting enzyme polymorphisms in subjects with resistant hypertension.

Angiotensin I converting enzyme (ACE) insertion/deletion (I/D) polymorphism is thought to affect renin-angiotensin system (RAS) activity and development of cardiovascular disease; significant associations between I/D polymorphism and atherosclerosis, stroke, nephropathy, and early mortality were already found. We investigated whether Southern Italy resistant hypertensives presented an association between the presence of I and/or D alleles and early vascular damage, inflammation, and insulin resistance. One-hundred-fifty resistant hypertensives were enrolled, studied, and genotyped; carotid intima-media thickness (cIMT), arterial stiffness (AS), and HOMA indices were also evaluated. D allele was more prevalent, and 74 patients presented DD homozygosis. Sixty-eight patients had metabolic syndrome (MetS), without significant differences between DD and I allele carriers. DD genotype appeared strongly associated with higher HOMA values (p < 0.001), and also with both Augmentation Index (AIx, p = 0.003) and Pulse Wave Velocity (PWV, p = 0.023). A significant association was found between DD genotype and cIMT (p < 0.005), while no association between ACE genotype and the presence of carotid plaques. HOMA was correlated with AS (PWV: p < 0.001; AIx: p < 0.01). DD genotype appeared to be associated with AS and HOMA index, but not with inflammation, independently from blood pressure values and the presence of other MetS factors, confirming D allele as an independent risk marker. Vascular damage may develop and progress independently from other risk factors in resistant hypertensives, likely through the interplay between ACE gene, RAS activity, and insulin resistance.

Lipid and inflammatory biomarker profiles in early insulin resistance.

To analyze the serum lipid and inflammatory biomarker profile in the early insulin resistance (e-IR). Cross-sectional study of 5943 adults without diabetes, stratified into no IR group (C-peptide <third tertile and glucose <100mg/dL), e-IR group (C-peptide ≥third tertile and glucose <100mg/dL) and advanced IR group (glucose ≥100mg/dL). E-IR showed significant differences with no IR in the serum concentration of triglycerides (P<0.001), HDL cholesterol (P<0.001), LDL cholesterol (P<0.001), sCD40L (P<0.001), C-reactive protein (P<0.004), leptin (P<0.001) and adiponectin (P<0.001). Adjusting for age, gender and abdominal obesity, corroborated the association of e-IR with highest quintile of triglycerides (OR 3.88 [3.07-4.89]), HDL cholesterol (OR 0.35 [0.28-0.44]), sCD40L (OR 0.47 [0.24-0.94]), C-reactive protein (OR 2.31 [1.29-4.12]), adiponectin (OR 0.11 [0.04-0.32]), PAI-1 (OR 3.29 [1.29-8.40]) and resistin (OR 1.25 [1.01-1.54]); the same biomarkers were associated with advanced IR although resistin was a protective factor (OR 0.73 [0.58-0.93]). Euglycemic patients with e-IR present an unfavorable serum lipid and inflammatory biomarker profile. Measuring C-peptide in euglycemic patients with elevated triglycerides identifies e-IR.

Development of a Representative Mouse Model with Nonalcoholic Steatohepatitis.

Non-alcoholic fatty liver disease (NAFLD) is the most prevalent liver disease in the Western world. It represents a disease spectrum ranging from isolated steatosis to non-alcoholic steatohepatitis (NASH). In particular, NASH can evolve to fibrosis, cirrhosis, hepatocellular carcinoma, and liver failure. The development of novel treatment strategies is hampered by the lack of representative NASH mouse models. Here, we describe a NASH mouse model, which is based on feeding non-genetically manipulated C57BL6/J mice a 'Western style' high-fat/high-sucrose diet (HF-HSD). HF-HSD leads to early obesity, insulin resistance, and hypercholesterolemia. After 12weeks of HF-HSD, all mice exhibit the complete spectrum of features of NASH, including steatosis, hepatocyte ballooning, and lobular inflammation, together with fibrosis in the majority of mice. Hence, this model closely mimics the human disease. Implementation of this mouse model will lead to a standardized setup for the evaluation of (i) underlying mechanisms that contribute to the progression of NAFLD to NASH, and (ii) therapeutic interventions for NASH. © 2016 by John Wiley & Sons, Inc.

Adrenomedullin 2 Improves Early Obesity-Induced Adipose Insulin Resistance by Inhibiting the Class II MHC in Adipocytes.

MHC class II (MHCII) antigen presentation in adipocytes was reported to trigger early adipose inflammation and insulin resistance. However, the benefits of MHCII inhibition in adipocytes remain largely unknown. Here, we showed that human plasma polypeptide adrenomedullin 2 (ADM2) levels were negatively correlated with HOMA of insulin resistance in obese human. Adipose-specific human ADM2 transgenic (aADM2-tg) mice were generated. The aADM2-tg mice displayed improvements in high-fat diet-induced early adipose insulin resistance. This was associated with increased insulin signaling and decreased systemic inflammation. ADM2 dose-dependently inhibited CIITA-induced MHCII expression by increasing Blimp1 expression in a CRLR/RAMP1-cAMP-dependent manner in cultured adipocytes. Furthermore, ADM2 treatment restored the high-fat diet-induced early insulin resistance in adipose tissue, mainly via inhibition of adipocyte MHCII antigen presentation and CD4(+) T-cell activation. This study demonstrates that ADM2 is a promising candidate for the treatment of early obesity-induced insulin resistance.

Retrospective Analysis of Neonatal Hypoglycemia and Its Relationship to Maternal Parameters [20L

INTRODUCTION: To identify incidence of unsuspected neonatal hypoglycemia, adverse neonatal outcome and their relationship to 50 Gm. oral glucose challenge test (GCT 135 mg/dL) and a diagnostic 100 Gm. oral glucose tolerance test (OGTT; Carpenter and Coustan criteria) in our population. METHODS: This was a retrospective cohort study of infants identified with hypoglycemia (glucose <45 mg/dL) from 2014 to 2015 requiring entry into the protocol for 24 hours. Maternal glycemic parameters were reviewed and matched accordingly. Chi-squared and independent samples t tests were used to determine if significant differences in neonatal outcome between women with abnormal GCT compare to those with one abnormal GTT value or two abnormal GTT values. RESULTS: Overall, 477 cases of neonatal hypoglycemia were identified and corresponding maternal data was available in 252 mothers. Abnormal GCT was observed in 33.1%, 8.2% had one abnormal value and 11% had GDM. Abnormal GCT and 1 abnormal value on GTT accounted for 31.9% and 5.5% of GDM mothers accounted for NICU admissions. The mean birth weight in abnormal GCT group was 3.5 kg. in comparison to normal GCT group (316 mothers) 3.32 kg. (P=.004). There was no difference observed in the mean APGAR scores or mode of delivery. CONCLUSION: In our population GCT identified women with early insulin resistance and associated neonatal hypoglycemia and increased birth weight. Hence life style changes need to be implemented to decrease the NICU admissions, neonatal adiposity and childhood obesity later in life.

Oral glucose tolerance test unravels circulating miRNAs associated with insulin resistance in obese preschoolers.

Circulating microRNAs (miRNAs) may act as biomarkers of metabolic disturbances. The aim of this study was to identify serum miRNAs signature of early insulin resistance in obese preschoolers. Twelve obese children, aged 2-6 years, six insulin resistant (IR) and six controls were selected being age-matched, sex-matched and body mass index-matched. Profiling of 179 circulating miRNAs, known to be widely expressed in the bloodstream, was investigated by quantitative polymerase chain reaction at fasting and 120 min following a standard oral glucose tolerance test (OGTT). Twenty-one miRNAs were differentially regulated in IR obese preschoolers. miR-200c-3p, miR-190a and miR-95 were differently regulated both at fasting and 120 min after the OGTT. In controls, the fold changes of some miRNAs were correlated with Δglucose0-120 (miR-660, miR-26b-5p and miR-22-3p: p = 0.005 for all) and Δinsulin0-120 (miR-660 and miR-22-3p: p = 0.02 for both and miR-423-5p: p = 0.042). In IR patients, miR-1 fold changes were correlated with Δglucose0-120( r = -0.786; p = 0.036) and Δinsulin0-120( r = -0.821; p = 0.023). Our study identifies circulating miR-200c-3p, miR-190a and miR-95 as biomarkers of insulin resistance in obese preschoolers, being differentially regulated in IR patients both in fasting condition and after the OGTT. Expression of some circulating miRNAs seems reflecting glucose and insulin excursion following the OGTT differently in controls and IR obese preschoolers.

Baicalin attenuates high fat diet-induced insulin resistance and ectopic fat storage in skeletal muscle, through modulating the protein kinase B/Glycogen synthase kinase 3 beta pathway

Insulin resistance is the pathophysiological basis of many diseases. Overcoming early insulin resistance highly significant in prevention diabetes, non-alcoholic fatty liver, and atherosclerosis. The present study aimed at evaluating the therapeutic effects of baicalin on insulin resistance and skeletal muscle ectopic fat storage in high fat diet-induced mice, and exploring the potential molecular mechanisms. Insulin resistance in mice was induced with a high fat diet for 16 weeks. Animals were then treated with three different doses of baicalin (100, 200, and 400 mg·kg−1·d−1) for 14 weeks. Fasting blood glucose, fasting serum insulin, glucose tolerance test (GTT), insulin tolerance test (ITT), and skeletal muscle lipid deposition were measured. Additionally, the AMP-activated protein kinase/acetyl-CoA carboxylase and protein kinase B/Glycogen synthase kinase 3 beta pathways in skeletal muscle were further evaluated. Baicalin significantly reduced the levels of fasting blood glucose and fasting serum insulin and attenuated high fat diet induced glucose tolerance and insulin tolerance. Moreover, insulin resistance was significantly reversed. Pathological analysis revealed baicalin dose-dependently decreased the degree of the ectopic fat storage in skeletal muscle. The properties of baicalin were mediated, at least in part, by inhibition of the AMPK/ACC pathway, a key regulator of de novo lipogenesis and activation of the Akt/GSK-3β pathway, a key regulator of Glycogen synthesis. These data suggest that baicalin, at dose up to 400 mg·kg−1·d−1, is safe and able to attenuate insulin resistance and skeletal muscle ectopic fat storage, through modulating the skeletal muscle AMPK/ACC pathway and Akt/GSK-3β pathway.

Early insulin resistance predicts weight gain and waist circumference increase in first-episode psychosis – A one year follow-up study

First-episode psychosis (FEP) is associated with weight gain during the first year of treatment, and risk of abdominal obesity is particularly increased. To identify early risk markers of weight gain and abdominal obesity, we investigated baseline metabolic differences in 60 FEP patients and 27 controls, and longitudinal changes during the first year of treatment in patients. Compared to controls at baseline, patients had higher low-density lipoprotein, triglyceride and apolipoprotein B levels, and lower levels of high-density lipoprotein and apolipoprotein A-I but no difference in body mass index or waist circumference. At 12-month follow-up, 60.6% of patients were overweight or obese and 58.8% had abdominal obesity. No significant increase during follow-up was seen in markers of glucose and lipid metabolism or blood pressure, but increase in C-reactive protein between baseline and 12-month follow-up was statistically significant. Weight increase was predicted by baseline insulin resistance and olanzapine use, while increase in waist circumference was predicted by baseline insulin resistance only. In conclusion, insulin resistance may be an early marker of increased vulnerability to weight gain and abdominal obesity in young adults with FEP. Olanzapine should be avoided as a first-line treatment in FEP due to the substantial weight increase it causes. In addition, the increase in the prevalence of overweight and abdominal obesity was accompanied by the emergence of low-grade systemic inflammation.

Genome-wide association study identifies African-ancestry specific variants for metabolic syndrome.

The metabolic syndrome (MetS) is a constellation of metabolic disorders that increase the risk of developing several diseases including type 2 diabetes and cardiovascular diseases. Although genome-wide association studies (GWAS) have successfully identified variants associated with individual traits comprising MetS, the genetic basis and pathophysiological mechanisms underlying the clustering of these traits remain unclear. We conducted GWAS of MetS in 1427 Africans from Ghana and Nigeria followed by replication testing and meta-analysis in another continental African sample from Kenya. Further replication testing was performed in an African American sample from the Atherosclerosis Risk in Communities (ARIC) study. We found two African-ancestry specific variants that were significantly associated with MetS: SNP rs73989312[A] near CA10 that conferred increased risk (P=3.86 × 10(-8), OR=6.80) and SNP rs77244975[C] in CTNNA3 that conferred protection against MetS (P=1.63 × 10(-8), OR=0.15). Given the exclusive expression of CA10 in the brain, our CA10 finding strengthens previously reported link between brain function and MetS. We also identified two variants that are not African specific: rs76822696[A] near RALYL associated with increased MetS risk (P=7.37 × 10(-9), OR=1.59) and rs7964157[T] near KSR2 associated with reduced MetS risk (P=4.52 × 10(-8), Pmeta=7.82 × 10(-9), OR=0.53). The KSR2 locus displayed pleiotropic associations with triglyceride and measures of blood pressure. Rare KSR2 mutations have been reported to be associated with early onset obesity and insulin resistance. Finally, we replicated the LPL and CETP loci previously found to be associated with MetS in Europeans. These findings provide novel insights into the genetics of MetS in Africans and demonstrate the utility of conducting trans-ethnic disease gene mapping studies for testing the cosmopolitan significance of GWAS signals of cardio-metabolic traits.

Multi-Biomarkers for Early Detection of Type 2 Diabetes, Including 10- and 12-(Z,E)-Hydroxyoctadecadienoic Acids, Insulin, Leptin, and Adiponectin.

We have previously found that fasting plasma levels of totally assessed 10- and 12-(Z,E)-hydroxyoctadecadienoic acid (HODE) correlated well with levels of glycated hemoglobin (HbA1c) and glucose during oral glucose tolerance tests (OGTT); these levels were determined via liquid chromatography—mass spectrometry after reduction and saponification. However, 10- and 12-(Z,E)-HODE alone cannot perfectly detect early impaired glucose tolerance (IGT) and/or insulin resistance, which ultimately lead to diabetes. In this study, we randomly recruited healthy volunteers (n = 57) who had no known history of any diseases, and who were evaluated using the OGTT, the HODE biomarkers, and several additional proposed biomarkers, including retinol binding protein 4 (RBP4), adiponectin, leptin, insulin, glycoalbumin, and high sensitivity-C-reactive protein. The OGTT revealed that our volunteers included normal individuals (n = 44; Group N), “high-normal” individuals (fasting plasma glucose 100–109 mg/dL) with IGT (n = 11; Group HN+IGT), and diabetic individuals (n = 2; Group D). We then used these groups to evaluate the potential biomarkers for the early detection of type 2 diabetes. Plasma levels of RBP4 and glycoalbumin were higher in Group HN+IGT, compared to those in Group N, and fasting levels of 10- and 12-(Z,E)-HODE/linoleic acids were significantly correlated with levels of RBP4 (p = 0.003, r = 0.380) and glycoalbumin (p = 0.006, r = 0.316). Furthermore, we developed a stepwise multiple linear regression models to predict the individuals’ insulin resistance index (the Matsuda Index 3). Fasting plasma levels of 10- and 12-(Z,E)-HODE/linoleic acids, glucose, insulin, and leptin/adiponectin were selected as the explanatory variables for the models. The risks of type 2 diabetes, early IGT, and insulin resistance were perfectly predicted by comparing fasting glucose levels to the estimated Matsuda Index 3 (fasting levels of 10- and 12-(Z,E)-HODE/linoleic acids, insulin, and leptin/adiponectin).

Early and progressive insulin resistance in young, non-obese cancer survivors treated with hematopoietic stem cell transplantation.

It is unclear whether there is a causative relationship between the development of metabolic syndrome (MS) and increased risk of early cardiovascular morbidity in patients receiving hematopoietic stem cell transplantation (HSCT) during childhood. Early identification of risk factors associated with insulin resistance, MS, and abnormal glucose tolerance during childhood or adolescence in these patients could represent a useful tool for preventing cardiovascular disorders. In a single-center, prospective, descriptive, cross-sectional study, we studied 45 survivors of hematological malignancies (age: 13.9 ± 4.8 years) treated with HSCT before the age of 18 years and 90 matched healthy controls. We collected clinical, imaging, and laboratory data including oral glucose tolerance test (OGTT). 7/45 patients (15.6%) showed abnormal glucose tolerance at OGTT, 1/45 (2.2%) was obese, and none fulfilled the criteria for MS. A waist/height ratio >0.5 was associated with patients with abnormal glucose tolerance (85.7% of cases), compared to patients with normal glucose tolerance (42.1%) and controls (23.3%). In patients with abnormal glucose tolerance, use of total body irradiation (TBI) as conditioning regimen was more common, and time elapsed from HSCT was longer. Patients treated with HSCT may develop insulin resistance early after transplantation. They do not show overt obesity, but have redistribution of fat tissue with central fat accumulation. The main factors associated with increased metabolic risk are TBI and time from HSCT. Evaluation of MS and glucose tolerance should be part of hormonal follow-up, which should be routinely proposed to these patients.

Insulin is a key determinant of elevated retinal arteriolar flicker response in insulin-resistant individuals.

Insulin may link metabolic disorders to retinal microvascular pathology. The aim of the present study was to investigate the impact of early insulin resistance on retinal microcirculation. Retinal diameter responses to flicker-light stimulation were investigated in 81 clinically healthy participants (32 ± 6 years [mean ± SD], 59% women) who were recruited according to their BMI. All participants underwent an OGTT and euglycaemic-hyperinsulinaemic clamp (40 mU/m(2) · min(-1) insulin dose). After stratification by low and high insulin sensitivity based on a clamp-derived glucose disposal rate of ≤ or >4.9 mg/kg body mass, respectively, baseline retinal diameters and their relative changes to flicker stimulation were compared while controlling for mean arterial pressure, BMI and sex. The arterial vasodilator response at the end of flicker stimulation (p = 0.044) and the area under the arterial reaction curve during flicker stimulation (p = 0.015) were significantly higher in individuals with low vs high insulin sensitivity. Vasodilatory responses of retinal veins to flicker stimulation and baseline retinal diameters did not differ between insulin-sensitive and insulin-resistant participants (p > 0.05). In a stepwise linear regression analysis, fasting insulin remained the only predictor of the arterial vasodilator response to flicker-light (p < 0.01). Waist circumference also contributed, although to a lesser extent, to the arterial vasodilator response (p = 0.023). Insulin sensitivity is an important determinant of retinal microvascular function. We propose that the elevated arterial flicker response in insulin-resistant states is a result of higher circulating insulin levels.

Maternal Obesity Alters Offspring Muscle Mitochondrial Function in Nonhuman Primates

Offspring of obese mothers have increased risk for early obesity and insulin resistance. Impairment in mitochondrial (MT) function may be a primary mechanism leading to insulin resistance. This study seeks to determine if maternal western‐style diet (WSD) or obesity alone alter fetal muscle MT function and if this persists at 3yrs. Adult Japanese Macaques were chronically (&gt;2yr) fed a control (CON) or WSD. Some WSD‐induced obese dams were switched to CON at the start of pregnancy (REV). Fetal samples were collected at gestational day 130/165. Offspring carried to term were weaned to a CON or WSD after exposure to either gestational WSD (WSD/WSD;WSD/CON) or CON (CON/WSD;CON/CON). Fetal and juvenile gastrocnemius fibers were assayed for MT function in the presence of carbohydrate (CHO) or palmitate (PALM) using high‐resolution respirometry. Fetal respiratory control ratios (RCR) decreased in WSD and REV, demonstrating 24% increased uncoupling. CHO‐stimulated state 3 respiration was reduced by 20% (p&lt;0.01) in WSD and REV, but neither were significantly decreased in PALM. In juveniles, RCR was doubled in CON/WSD vs. CON/CON, but this increase did not occur in WSD/WSD. Likewise, CHO coupling control ratio was doubled in CON/CON vs. CON/WSD (p&lt;0.05), but not in WSD/WSD. Maternal obesity with or without WSD reduces MT function and metabolic flexibility in fetal muscle. Inflexibility persists in the postnatal period, but only when lean offspring are challenged with WSD. Our data suggest that exposure to maternal obesity alters cellular systems responsible for MT adaptation to WSD and may contribute to increased risk of metabolic disease.Funding: NIH DK090964

Use of in vivo magnetic resonance spectroscopy for studying metabolic diseases.

Owing to the worldwide obesity epidemic and the sedentary lifestyle in industrialized countries, the number of people with metabolic diseases is explosively increasing. Magnetic resonance spectroscopy (MRS), which is fundamentally similar to magnetic resonance imaging, can detect metabolic changes in vivo noninvasively. With its noninvasive nature, 1H, 13C and 31P MRS are being actively utilized in clinical and biomedical metabolic studies to detect lipids and important metabolites without ionizing radiation. 1H MRS can quantify lipid content in liver and muscle and can detect other metabolites, such as 2-hydroxyglutarate, in vivo. Of interest, many studies have indicated that hepatic and intramyocellular lipid content is inversely correlated with insulin sensitivity in humans. Thus, lipid content can be utilized as an in vivo biomarker for detecting early insulin resistance. Employing 13C MRS, hepatic glycogen synthesis and breakdown can be directly detected, whereas 31P MRS provides in vivo adenosine triphosphate (ATP) synthesis rates by saturation transfer methods in addition to ATP content. These in vivo data can be very difficult to assess by other methods and offer a critical piece of metabolic information. To aid the reader in understanding these new methods, fundamentals of MRS are described in this review in addition to promising future applications of MRS and its limitations.

An age-dependent alteration of the respiratory exchange ratio in the db/db mouse.

The leptin receptor-deficient db/db mouse is a rodent model of type 2 diabetes and obesity. Diabetes in db/db mice shows an age-dependent progression, with early insulin resistance followed by an insulin secretory defect resulting in profound hyperglycemia. However, there is insufficient data on agedependent changes of energy metabolism in db/db mice. We demonstrated an age-dependent decrease in the respiratory exchange ratio (RER), calculated by a ratio of VO2/VCO2, in db/db mice. The RER determined by indirect calorimetry, was 1.03 in db/db mice under 6 weeks of age, which were similar to those in heterozygote (db/+) and wild-type (+/+) mice. However, RER decreased from approximately 0.9 to 0.8 by 10 weeks of age and subsequently returned to approximately 0.9 at 22 weeks of age. The changes in RER were concurrent with the alterations in body weight and blood glucose level. However, other metabolic indicators such as glucose tolerance, changes in body fat mass, and urinary glucose levels, did not change with age. The results suggested that the energy source utilized in db/db mice changed with the age-related progression of diabetes.