Concomitant Insulin Resistance Research Articles

Pancreatitis in pregnancy: The complex interplay with triglycerides and diabetes

Pancreatitis in pregnancy: The complex interplay with triglycerides and diabetes

Pulmonary hypertension and metabolic disorders

This review presents current data regarding the relationship between hyperuricemia, obesity, diabetes mellitus, lipid disorders and pulmonary arterial hypertension (PAH), chronic thromboembolic pulmonary hypertension (CTEPH). Hyperuricemia is associated with a higher risk of developing of PAH, worse prognosis of PAH and greater severity of the patient's condition. Obesity leads to the development of pro-inflammatory and vasoconstrictor effects, hypoxia, which contributes to the progression of PH, however, the survival rate of patients with PH and overweight or obesity is higher than with normal or reduced body weight. Diabetes mellitus and concomitant insulin resistance are associated with a high risk of hospitalization for right ventricular heart failure and mortality. The presence of PAH is associated with lower values of total cholesterol, low-density lipoprotein cholesterol (LDL-C), triglycerides, and probably high-density lipoprotein cholesterol (HDL-C). At the same time, higher levels of LDL-С and HDL-С in PAH and CTEPH determine a better prognosis of the disease.All metabolic disorders considered have common mechanisms of influence on PH. Further study of their pathogenetic basis will make it possible to develop unified approaches to methods of their correction in patients with various types of pulmonary hypertension.

The effects of Dapagliflozin in type 2 diabetes mellitus patients with complications of cardiovascular disease

Type 2 diabetes mellitus (T2DM) is a complex metabolic disorder in which concomitant insulin resistance and beta-cell impairment lead to hyperglycemia. Cardiovascular problems are more common in T2DM but after the discovery of the dapagliflozin class of SGLT2 (Sodium-glucose co-transporter 2) inhibitor, the rate of cardiovascular disease (CVD) reduced slightly including heart failure (HF). Numerous recent clinical studies emphasized that dapagliflozin as monotherapy and combined therapy with another hypoglycemic agent help to improve glycaemic control and decrease blood pressure and body weight. In the present review, the safety and efficacy of dapagliflozin have been highlighted in patients with HFrEF(Heart failure with reduced ejection fraction), after comparison with placebo and dapagliflozin. It decreased the risk of total HF hospitalizations and cardiovascular death with a low-hypoglycaemic effect. Recurrent hospitalizations are a common problem in patients with HFrEF and it is also preventable. This review article also emphasized the comparative effects of drugs and placebo to prove the effectiveness of drugs and a further reduction in the rate of heart failure. The mild adverse effect is observed in clinical trials where urinary tract infection is most common.

Plasma levels of mannan-binding lectin-associated serine proteases are increased in type 1 diabetes patients with insulin resistance.

Activation of the lectin pathway of the complement system, as demonstrated by elevated levels of mannan-binding lectin proteins (MBL), contributes to vascular pathology in type 1 diabetes (T1D). Vascular complications are greatest in T1D individuals with concomitant insulin resistance (IR), however, whether IR amplifies activiation of the lectin pathway in T1D is unknown. We pooled pretreatment data from two RCTs and performed a cross-sectional analysis on 46 T1D individuals. We employed estimated glucose disposal rate (eGDR), a validated IR surrogate with cut-points of: <5.1, 5.1-8.7, and > 8.7 mg/kg/min to determine IR status, with lower eGDR values conferring higher degrees of IR. Plasma levels of MBL-associated proteases (MASP-1, MASP-2, and MASP-3) and their regulatory protein MAp44 were compared among eGDR classifications. In a subset of 14 individuals, we assessed change in MASPs and MAp44 following improvement in IR. We found that MASP-1, MASP-2, MASP-3, and MAp44 levels increased in a stepwise fashion across eGDR thresholds with elevated MASPs and MAp44 levels conferring greater degrees of IR. In a subset of 14 patients, improvement in IR was associated with significant reductions in MASPs, but not MAp44, levels. In conclusion, IR in T1D amplifies levels of MASP-1/2/3 and their regulator MAp44, and improvement of IR normalizes MASP-1/2/3 levels. Given that elevated levels of these proteins contribute to vascular pathology, amplification of the lectin pathway of the complement system may offer mechanistic insight into the relationship between IR and vascular complications in T1D.

Insulin and aging - a disappointing relationship.

Experimental studies in animal models of aging such as nematodes, fruit flies or mice have observed that decreased levels of insulin or insulin signaling promotes longevity. In humans, hyperinsulinemia and concomitant insulin resistance are associated with an elevated risk of age-related diseases suggestive of a shortened healthspan. Age-related disorders include neurodegenerative diseases, hypertension, cardiovascular disease, and type 2 diabetes. High ambient insulin concentrations promote increased lipogenesis and fat storage, heightened protein synthesis and accumulation of non-functional polypeptides due to limited turnover capacity. Moreover, there is impaired autophagy activity, and less endothelial NO synthase activity. These changes are associated with mitochondrial dysfunction and oxidative stress. The cellular stress induced by anabolic activity of insulin initiates an adaptive response aiming at maintaining homeostasis, characterized by activation of the transcription factor Nrf2, of AMP activated kinase, and an unfolded protein response. This protective response is more potent in the long-lived human species than in short-lived models of aging research resulting in a stronger pro-aging impact of insulin in nematodes and fruit flies. In humans, resistance to insulin-induced cell stress decreases with age, because of an increase of insulin and insulin resistance levels but less Nrf2 activation. These detrimental changes might be contained by adopting a lifestyle that promotes low insulin/insulin resistance levels and enhances an adaptive response to cellular stress, as observed with dietary restriction or exercise.

Metal Homeostasis and Exposure in Distinct Phenotypic Subtypes of Insulin Resistance among Children with Obesity.

Trace elements and heavy metals have proven pivotal roles in childhood obesity and insulin resistance. However, growing evidence suggests that insulin resistance could encompass distinct phenotypic subtypes. Herein, we performed a comprehensive metallomics characterization of plasma samples from children and adolescents with obesity and concomitant insulin resistance, who were stratified as early (N = 17, 11.4 ± 2.4 years), middle (N = 16, 11.8 ± 1.9 years), and late (N = 33, 11.7 ± 2.0 years) responders according to the insulin secretion profile in response to an oral glucose tolerance test. To this end, we employed a high-throughput method aimed at determining the biodistribution of various essential and toxic elements by analyzing total metal contents, metal-containing proteins, and labile metal species. Compared with the early responders, participants with delayed glucose-induced hyperinsulinemia showed a worsened insulin resistance (HOMA-IR, 4.5 vs. 3.8) and lipid profile (total cholesterol, 160 vs. 144 mg/dL; LDL-cholesterol, 99 vs. 82 mg/dL), which in turn was accompanied by sharpened disturbances in the levels of plasmatic proteins containing chromium (4.8 vs. 5.1 µg/L), cobalt (0.79 vs. 1.2 µg/L), lead (0.021 vs. 0.025 µg/L), and arsenic (0.077 vs. 0.17 µg/L). A correlation analysis demonstrated a close inter-relationship among these multielemental perturbations and the characteristic metabolic complications occurring in childhood obesity, namely impaired insulin-mediated metabolism of carbohydrates and lipids. These findings highlight the crucial involvement that altered metal homeostasis and exposure may have in regulating insulin signaling, glucose metabolism, and dyslipidemia in childhood obesity.

Microvascular and macrovascular complications of type 2 diabetes mellitus: Exome wide association analyses.

Type 2 diabetes mellitus (T2DM) is a chronic, metabolic disorder in which concomitant insulin resistance and β-cell impairment lead to hyperglycemia, influenced by genetic and environmental factors. T2DM is associated with long-term complications that have contributed to the burden of morbidity and mortality worldwide. The objective of this manuscript is to conduct an Exome-Wide Association Study (EWAS) on T2DM Emirati individuals to improve our understanding on diabetes-related complications to improve early diagnostic methods and treatment strategies. This cross-sectional study recruited 310 Emirati participants that were stratified according to their medically diagnosed diabetes-related complications: diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, and cardiovascular complications. The Illumina's Infinium Exome-24 array was used and 39,840 SNPs remained for analysis after quality control. The analysis revealed the associations of various genes with each complication category: 1) diabetic retinopathy was associated to SHANK3 gene in locus 22q13.33 (SNP rs9616915; p=5.18 x10-4), ZSCAN5A gene in locus 19q13.43 (SNP rs7252603; p=7.55 x10-4), and DCP1B gene in locus 12p13.33 (SNPs rs715146, rs1044950, rs113147414, rs34730825; p=7.62 x10-4); 2) diabetic neuropathy was associated to ADH4 gene in locus 4q23 (SNP rs4148883; p=1.23 x10-4), SLC11A1 gene in locus 2q35 (SNP rs17235409; p=1.85 x10-4), and MATN4 gene in locus 20q13.12 (SNP rs2072788; p=2.68 x10-4); 3) diabetic nephropathy was associated to PPP1R3A gene in locus 7q31.1 (SNP rs1799999; p=1.91 x10-4), ZNF136 gene in locus 19p13.2 (SNP rs140861589; p=2.80 x10-4), and HSPA12B gene in locus 20p13 (SNP rs6076550; p=2.86 x10-4); and 4) cardiovascular complications was associated to PCNT gene in locus 21q22.3 (SNPs rs7279204, rs6518289, rs2839227, rs2839223; p=2.18 x10-4,3.04 x10-4,4.51 x10-4,5.22 x10-4 respectively), SEPT14 gene in locus 7p11.2 (SNP rs146350220; p=2.77 x10-4), and WDR73 gene in locus 15q25.2 (SNP rs72750868; p=4.47 x10-4). We have identified susceptibility loci associated with each category of T2DM-related complications in the Emirati population. Given that only 16% of the markers from the Illumina's Infinium Exome chip passed quality control assessment, this demonstrates that multiple variants were, either, monomorphic in the Arab population or were not genotyped due to the use of a Euro-centric EWAS array that limits the possibility of including targeted ethnic-specific SNPs. Our results suggest the alarming possibility that lack of representation in reference panels could inhibit discovery of functionally important loci associated to T2DM complications. Further effort must be conducted to improve the representation of diverse populations in genotyping and sequencing studies.

Ectopic lipid metabolism in anterior pituitary dysfunction.

Over the past decades, adapted lifestyle and dietary habits in industrialized countries have led to a progress of obesity and associated metabolic disorders. Concomitant insulin resistance and derangements in lipid metabolism foster the deposition of excess lipids in organs and tissues with limited capacity of physiologic lipid storage. In organs pivotal for systemic metabolic homeostasis, this ectopic lipid content disturbs metabolic action, thereby promotes the progression of metabolic disease, and inherits a risk for cardiometabolic complications. Pituitary hormone syndromes are commonly associated with metabolic diseases. However, the impact on subcutaneous, visceral, and ectopic fat stores between disorders and their underlying hormonal axes is rather different, and the underlying pathophysiological pathways remain largely unknown. Pituitary disorders might influence ectopic lipid deposition indirectly by modulating lipid metabolism and insulin sensitivity, but also directly by organ specific hormonal effects on energy metabolism. In this review, we aim to I) provide information about the impact of pituitary disorders on ectopic fat stores, II) and to present up-to-date knowledge on potential pathophysiological mechanisms of hormone action in ectopic lipid metabolism.

Altered Metal Homeostasis Associates with Inflammation, Oxidative Stress, Impaired Glucose Metabolism, and Dyslipidemia in the Crosstalk between Childhood Obesity and Insulin Resistance.

Metals are redox-active substances that participate in central biological processes and may be involved in a multitude of pathogenic events. However, considering the inconsistencies reported in the literature, further research is crucial to disentangle the role of metal homeostasis in childhood obesity and comorbidities using well-characterized cohorts and state-of-the-art analytical methods. To this end, we studied an observational population comprising children with obesity and insulin resistance, children with obesity without insulin resistance, and healthy control children. A multi-elemental approach based on the size-fractionation of metal species was applied to quantify the total content of various essential and toxic elements in plasma and erythrocyte samples, and to simultaneously investigate the metal fractions conforming the metalloproteome and the labile metal pool. The most important disturbances in childhood obesity were found to be related to elevated circulating copper levels, decreased content of plasmatic proteins containing chromium, cobalt, iron, manganese, molybdenum, selenium, and zinc, as well as the sequestration of copper, iron, and selenium within erythrocytes. Interestingly, these metal disturbances were normally exacerbated among children with concomitant insulin resistance, and in turn were associated to other characteristic pathogenic events, such as inflammation, oxidative stress, abnormal glucose metabolism, and dyslipidemia. Therefore, this study represents one-step further towards a better understanding of the involvement of metals in the crosstalk between childhood obesity and insulin resistance.

Hyperglycemia with or without insulin resistance triggers different structural changes in brain microcirculation and perivascular matrix.

Both type-1 and type-2 DM are related to an increased risk of cognitive impairment, neurovascular complications, and dementia. The primary triggers for complications are hyperglycemia and concomitant insulin resistance in type-2 DM. However, the diverse mechanisms in the pathogenesis of diabetes-related neurovascular complications and extracellular matrix (ECM) remodeling in type-1 and 2 have not been elucidated yet. Here, we investigated the high fat-high sucrose (HFHS) feeding model and streptozotocin-induced type-1 DM model to study the early effects of hyperglycemia with or without insulin resistance to demonstrate the brain microcirculatory changes, perivascular ECM alterations in histological sections and 3D-reconstructed cleared brain tissues. One of the main findings of this study was robust rarefaction in brain microvessels in both models. Interestingly, the HFHS model leads to widespread non-functional angiogenesis, but the type-1 DM model predominantly in the rostral brain. Rarefaction was accompanied by basement membrane thickening and perivascular collagen accumulation in type-1 DM; more severe blood-brain barrier leakage, and disruption of perivascular ECM organization, mainly of elastin and collagen fibers' structural integrity in the HFHS model. Our results point out that the downstream mechanisms of the long-term vascular complications of hyperglycemia models are structurally distinctive and may have implications for appropriate treatment options.

Glucose variability is associated with an adverse vascular profile but only in the presence of insulin resistance in individuals with type 1 diabetes: An observational study.

Aims/HypothesisWe hypothesised that the detrimental effect of high glucose variability (GV) in people with type 1 diabetes is mainly evident in those with concomitant insulin resistance.MethodsWe conducted secondary analyses on continuous glucose monitoring (CGM) using baseline observational data from three randomised controlled trials and assessed the relationship with established vascular markers. We used standard CGM summary statistics and principal component analysis to generate individual glucose variability signatures for each participant. Cluster analysis was then employed to establish three GV clusters (low, intermediate, or high GV, respectively). The relationship with thrombotic biomarkers was then investigated according to insulin resistance, assessed as estimated glucose disposal rate (eGDR).ResultsOf 107 patients, 45%, 37%, and 18% of patients were assigned into low, intermediate, and high GV clusters, respectively. Thrombosis biomarkers (including fibrinogen, plasminogen activator inhibitor-1, tissue factor activity, and tumour necrosis factor-alpha) increased in a stepwise fashion across all three GV clusters; this increase in thrombosis markers was evident in the presence of low but not high eGDR and at a threshold of eGDR <5.1 mg/kg/min.ConclusionHigher GV is associated with increased thrombotic biomarkers in type 1 diabetes but only in those with concomitant insulin resistance.

Peculiarities of hormonal regulation of the blood antioxidant system of adolescents with obesity

The study is designed to establish the relationship between the rate of the induced blood lipid peroxidation and production of some hormones in adolescents. The investigations have not shown any significant alteration in the blood insulin content as well as in the daily catecholamines and melatonin excretion in the urine of adolescents in early puberty with the I–II degree of neuroendocrine obesity and without insulin resistance. The rate of the induced blood lipid peroxidation in them remains to be at the initial level. In adolescents of the same age group hyperinsulinemia and an increased urinary excretion of catecholamines and melatonin occur against the background of the concomitant insulin resistance. The rate of the induced blood lipid peroxidation in such cases remains at the level of control values. Formation of hyperinsulinemia and an increased urinary excretion of norepinephrine and melatonin have been registered in late puberty in adolescents with neuroendocrine obesity of the I–II degree without insulin resistance. The emergence of these changes is accompanied by the maintenance of control values of the induced blood lipid peroxidation. The similar changes in the endocrine parameters with attendant increase in the rate of the induced blood lipid peroxidation are occurred in adolescents of the above-mentioned age group with neuroendocrine obesity against the background of insulin resistance.

Enhancement of select cognitive domains with rosiglitazone implicates dorsal hippocampus circuitry sensitive to PPARγ agonism in an Alzheimer's mouse model

IntroductionSeveral clinical studies have tested the efficacy of insulin‐sensitizing drugs for cognitive enhancement in Alzheimer's disease (AD) patients, as type 2 diabetes (T2D) is a well‐recognized risk factor for AD. Pilot studies assessing FDA‐approved diabetes drugs in subjects with early‐stage disease have found cognitive benefit in subjects comorbid for insulin resistance. In AD mouse models with concomitant insulin resistance, we have shown that 4 weeks of RSG can reverse peripheral and central insulin resistance concomitant with rescue of hippocampus‐dependent fear learning and memory and hippocampal circuitry deficits in 9‐month‐old (9MO) Tg2576 mice with no effect in wild‐type (WT) mice. Bioinformatics analysis of genomic and proteomic data reveals an intimate link between PPARγ and MAPK/ERK signaling in the hippocampus. We then demonstrated a direct interaction between PPARγ and phospho‐ERK in vitro and in vivo during memory consolidation. The translational value of this discovery is evidenced by the positive correlational relationship between human AD postmortem brain levels of pERK‐PPARγ nuclear complexes with cognitive reserve.MethodsWe tested whether insulin sensitizer therapy could rescue spatial navigation, context discrimination, and object recognition learning and memory in aged wild‐type and Tg2576 mice in addition to hippocampus‐dependent contextual fear learning and memory, as we have previously reported.ResultsWe found that rosiglitazone treatment improved cognitive domains that predominantly rely upon the dorsal hippocampus rather than those that additionally engage the ventral hippocampus.ConclusionThese results suggest that insulin sensitizer therapy with rosiglitazone improved age‐ and AD‐related learning and memory deficits in circuit selective ways.

Diet to Reduce the Metabolic Syndrome Associated with Menopause. The Logic for Olive Oil.

The rates of metabolic syndrome are increasing in parallel with the increasing prevalence of obesity, primarily due to its concomitant insulin resistance. This is particularly concerning for women, as the years around menopause are accompanied by an increase in visceral obesity, a strong determinant of insulin resistance. A fall in estrogens and increase in the androgen/estrogen ratio is attributed a determining role in this process, which has been confirmed in other physiological models, such as polycystic ovary syndrome. A healthy lifestyle, with special emphasis on nutrition, has been recommended as a first-line strategy in consensuses and guidelines. A consistent body of evidence has accumulated suggesting that the Mediterranean diet, with olive oil as a vital component, has both health benefits and acceptable adherence. Herein, we provide an updated overview of current knowledge on the benefits of olive oil most relevant to menopause-associated metabolic syndrome, including an analysis of the components with the greatest health impact, their effect on basic mechanisms of disease, and the state of the art regarding their action on the main features of metabolic syndrome.

Noncoding RNAs in Nonalcoholic Fatty Liver Disease: Potential Diagnosis and Prognosis Biomarkers.

Nonalcoholic fatty liver disease (NAFLD) is currently the most common chronic liver disease worldwide in part due to the concomitant obesity pandemic and insulin resistance (IR). It is increasingly becoming evident that NAFLD is a disease affecting numerous extrahepatic vital organs and regulatory pathways. The molecular mechanisms underlying the nonalcoholic steatosis formation are poorly understood, and little information is available on the pathways that are responsible for the progressive hepatocellular damage that follows lipid accumulation. Recently, much research has focused on the identification of the epigenetic modifications that contribute to NAFLD pathogenesis. Noncoding RNAs (ncRNAs) are one of such epigenetic factors that could be implicated in the NAFLD development and progression. In this review, we summarize the current knowledge of the genetic and epigenetic factors potentially underlying the disease. Particular emphasis will be put on the contribution of microRNAs (miRNAs), long noncoding RNAs (lncRNAs), and circular RNAs (circRNAs) to the pathophysiology of NAFLD as well as their potential use as therapeutic targets or as markers for the prediction and the progression of the disease.

Overweight Individuals with Type 1 Diabetes Are Less Likely to Present with Diabetic Ketoacidosis—Data from the After Diabetes Diagnosis Research Support System (ADDRESS-2) Cohort

Introduction: Insulin resistance has been proposed to accelerate progression to type 1 diabetes (T1D) in antibody positive relatives of affected individuals. We hypothesised that overweight individuals with confirmed T1D would be less likely to present with diabetic ketoacidosis (DKA), signifying an earlier onset of T1D, due to concomitant insulin resistance. Methods: The ADDRESS-2 study recruits incident clinician-assigned T1D cases within 6-months of diagnosis and systematically assesses pancreatic autoimmunity by GAD-65, IA-2 and ZnT8 antibodies. People with at least two positive antibodies were selected to confirm diagnosis of T1D and categorised for adiposity according to BMI (adults) or Z-scores (children). Odds ratios (OR) for presentation with DKA were compared, adjusted for potential confounders and sub-analysed by whether adult or child at recruitment. Results: 31% (969/ 3132) were positive for two or more pancreatic antibodies. Of these 44% (424/969) presented with DKA. The proportions with DKA varied significantly by adiposity: 59% underweight (16/27), 47% normal (280/601), 39% overweight (103/263), 30% obese (19/63) and 40% severely obese (6/15) (p=0.02). When adjusted for age, being overweight or obese was associated with lower risk of DKA in adults (OR 0.58, p=0.006; 0.44, p=0.03, respectively) not children (OR 0.9, p=0.81; 0.51, p=0.12, respectively). Higher adiposity category was associated with higher daily insulin-requirements independent of age, with obesity associated with a 4 unit/day increase (p=0.03) and severe obesity, 11 units/day increase (p=0.008). Conclusion: Adults with T1D are less likely to present with DKA if overweight or obese. Despite smaller proportions of DKA, insulin requirements are higher. These data suggest that, in adults, T1D presentation is unmasked by the insulin resistance of obesity prior to absolute insulin deficiency and ketoacidosis. Disclosure S. Misra: None. A. Kaur: None. I.F. Godsland: None. H.C. Walkey: None. D.G. Johnston: None. N. Oliver: Advisory Panel; Self; Dexcom, Inc., Roche Diabetes Care Health and Digital Solutions, Medtronic. Research Support; Self; Dexcom, Inc., Roche Diabetes Care Health and Digital Solutions. Other Relationship; Self; Novo Nordisk A/S, Takeda Development Centre Europe Ltd..

Abstract 81: Absence of Macrophage microRNA-155 Affects Cardiac Metabolic and Inflammatory Remodeling Following Diabesotension and Protects Against Development of Heart Failure

The co-existence of diabetes, obesity, hypertension - diabesotension - is a major burden in western societies and often culminates into heart failure (HF). Diabesotension is associated with a chronic status of low-grade inflammation, involving macrophage infiltration into adipose and cardiac tissues, local activation of inflammatory pathways and concomitant insulin-resistance. We showed that the microRNA miR-155 is a powerful modulator of hypertension-induced cardiac inflammation and HF. Here we hypothesize that absence of miR-155 in macrophages protects against adipose tissue and cardiac inflammation during diabesotension and thereby prevents insulin resistance and cardiac dysfunction. Male C57Bl/6J mice received a bone marrow transplantation of miR-155 WT (n=30) or miR-155 KO (n=30) donors with same genetic background. High fat (HFD; n=22/gr) or chow diet (n=8/gr) was given for 20 weeks. An HFD subgroup was subjected to pressure overload by angiotensin II (1.5mg/kg/d) for 4 weeks (HFD+PO; n=12/gr). Glycaemia, glucose tolerance test, cardiac MRI were performed after 16 and/or 20 weeks. Organs were stored for histology, RNA and FACS analysis. After 16 weeks of HFD, body weight (+11% WT; +14% KO; p&lt;0.05) and glycaemia (+16% WT; +18% KO; p&lt;0.05) increased compared to chow diet animals in both genotypes, confirming the status of obesity and pre-diabetes. Absence of macrophage miR-155 protected HFD-mice from glucose intolerance (at T15: WT 25.08; KO 18.15 mmol/L; p&lt;0.05), suggesting that adipose tissue macrophages might contribute to insulin resistance. In addition, HFD+PO caused mild systolic dysfunction in WT but not in miR-155 KO animals compared to control (ejection fraction: -19% WT, p&lt;0.05; -7% KO, n.s.). While cardiac interstitial fibrosis was not affected by absence of macrophage miR-155, cardiac CD45-positive leukocyte infiltration upon HFD+PO was abrogated. HFD+PO-induced cardiac expression of two PPAR-dependent metabolic genes, angiopoietin-like 4 and uncoupling protein 3, is repressed in the absence of macrophage miR-155. Our data suggest that macrophage miR-155 plays a role in the development of insulin resistance and cardiac dysfunction, possibly by affecting local immune cell function and metabolic programming.

Body mass index, waist circumference and HOMA-IR correlate with the Psoriasis Area and Severity Index in patients with psoriasis receiving phototherapy

Funding sources: This work was funded by an unrestricted research grant from Merck Serono Ltd and Abbott Laboratories Ltd and the Postgraduate Medical and Dental Board of Ireland. Conflicts of interest: none declared. Dear Editor, An increased incidence of obesity in patients with psoriasis has been documented in cross‐sectional studies of large healthcare databases and case–control studies.1 2 3 4 5 6 7 Obesity, and in particular centripetal obesity, confers a risk of developing insulin resistance and type 2 diabetes, which in turn increases the risk of cardiovascular disease. Since 1978 it has been known that patients with psoriasis have higher rates of type 2 diabetes and cardiovascular disease and it is likely that this is driven by obesity and concomitant insulin resistance. We undertook a study to establish the effect of body mass index (BMI), abdominal obesity and insulin resistance on psoriasis severity and Framingham risk. Following ethical approval, consecutive patients with psoriasis, aged ≥ 18 years, were recruited prior to commencing phototherapy or photochemotherapy (TL‐01 or psoralen plus ultraviolet A) between October 2008 and July 2011. Patients had a full physical examination and the Psoriasis Area and Severity Index (PASI) score was recorded. Height, weight and waist circumference were measured for each patient. The BMI was calculated using the formula: weight in kg/(height in m)2. Obesity was defined as a BMI > 30, overweight as BMI 25–30 and lean as a BMI < 25 according to the World Health Organization definition of obesity. Systolic blood pressure was measured using a sphygmomanometer on the left brachial artery. Fasting blood samples were taken for the measurement of insulin, glucose and serum cholesterol. Insulin resistance was measured using the homeostasis model with the formula: insulin × glucose/22·5 (HOMA‐IR, homeostatic model assessment–insulin resistance). Framingham risk was calculated using MedCalc® (MedCalc Software, Ostend, Belgium). Results were analysed using GraphPad Prism (GraphPad Software Inc., La Jolla, CA, U.S.A.), using Student's t‐test, anova and Pearson's rank correlation.

Sexual Dimorphisms in the Associations of BMI and Body Fat with Indices of Pubertal Development in Girls and Boys

The effect of obesity and concomitant insulin resistance on pubertal development is incompletely elucidated. To determine how measures of adiposity and insulin resistance are associated with pubertal maturation in boys and girls. Breast and pubic hair Tanner stage and testicular volume by orchidometry were determined by physical examination in 1066 children. Ovarian volume was estimated by trans-abdominal ultrasound. Fat mass, skeletal age, and fasting serum for insulin and glucose, total T, estradiol, estrone, dehydroepiandrosterone-sulfate, and androstenedione were measured at the National Institutes of Health Clinical Research Center. Convenience sample; 52% obese, 59% female. Logistic regression identified a significant interaction between sex and obesity for prediction of pubertal development (P ≤ .01). There was a negative association between boys' testicular volume and body mass index (BMI)/fat mass but a positive association between girls' breast stage and BMI/fat mass. Ovarian volume in girls was positively associated with insulin resistance but not with BMI/fat mass. There was a positive association between obesity and measures of estrogen exposure (breast development and skeletal age) in both sexes. Positive correlations were seen for girls between BMI and pubic hair development and between insulin resistance and T production, whereas adiposity was negatively associated with pubic hair in boys. Significant sexual dimorphisms in the manifestations of pubertal development are seen in obese girls and boys. Two known effects of obesity, increased peripheral conversion of low-potency androgens to estrogens by adipose tissue-aromatase and increased insulin resistance, may be in large part responsible for these differences.

Comparison of mechanisms underlying changes in glucose utilization in fasted rats anesthetized with propofol or sevoflurane: Hyperinsulinemia is exaggerated by propofol with concomitant insulin resistance induced by an acute lipid load.

The effects of anesthesia with sevoflurane and with propofol on glucose utilization in rats were investigated. Sevoflurane significantly impairs glucose utilization whereas propofol does not. Both insulin secretion and sensitivity affect glucose utilization. Propofol is hydrophobic, and anesthesia with this agent is always accompanied by an acute lipid load, which can exaggerate insulin resistance. The role of the acute lipid load in the effects of anesthesia with sevoflurane and propofol on glucose utilization in fasted rats was investigated. Rats were allocated to groups anesthetized with sevoflurane and infused with physiological saline (group S) or 10% w/v lipid (group SL), or those anesthetized with propofol (group P). Intravenous glucose tolerance tests and insulin tolerance tests were then performed to measure glucose utilization, and blood glucose, plasma insulin, and plasma TNF-α levels were measured. In the intravenous glucose tolerance test, groups SL and P showed significantly higher plasma insulin levels than group S, and group P showed significantly higher plasma insulin levels than group SL. In the insulin tolerance test, groups SL and P showed insulin resistance compared to group S, but no significant difference was observed between groups SL and P. In summary, propofol anesthesia enhances insulin secretion and concomitantly exaggerates insulin resistance, compared with sevoflurane anesthesia. Propofol appears to be the main cause of hyperinsulinemia, and the acute lipid load exaggerates insulin resistance.