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Metabolic Syndrome And Insulin Resistance Pdf

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To identify molecular defects contributing to metabolic dysregulation in DS in the undifferentiated state, we generated mesenchymal progenitor cells MPCs from induced pluripotent stem cells derived from a 4-week-old female with DS and a healthy newborn male control. However, alterations in receptor expression and pathway-specific defects in insulin signaling, even in undifferentiated cells, can alter cellular oxidative metabolism, potentially via transcriptional mechanisms.

Metabolic Syndrome

To identify molecular defects contributing to metabolic dysregulation in DS in the undifferentiated state, we generated mesenchymal progenitor cells MPCs from induced pluripotent stem cells derived from a 4-week-old female with DS and a healthy newborn male control. However, alterations in receptor expression and pathway-specific defects in insulin signaling, even in undifferentiated cells, can alter cellular oxidative metabolism, potentially via transcriptional mechanisms. Type 2 diabetes T2D is a major public health problem worldwide.

Intimately linked with the rise in diabetes prevalence is the burgeoning epidemic of obesity 1. Unfortunately, these alarming patterns are also increasingly observed in children and will likely translate into increases in cardiovascular and other health risks associated with insulin resistance and diabetes.

The underlying molecular defects that confer diabetes risk remain unknown. Longitudinal studies in high-risk individuals indicate that insulin resistance is a very early marker of diabetes risk and also predicts the development of T2D 2 , 3. Therefore, elucidating mechanisms by which cellular insulin resistance is linked to T2D is an essential step to develop new approaches for prevention and treatment.

Inherited syndromes of insulin resistance, although rare, have provided useful insights into insulin signaling and mechanisms of genetically determined insulin resistance 4 — 7. One example is Donohue syndrome DS previously known as leprechaunism , a syndrome of severe insulin resistance caused by homozygous or compound heterozygous mutations in the insulin receptor INSR gene and accompanied by selective postreceptor defects 8 — Clinically, this syndrome also includes growth retardation, decreased sc adipose tissue, acanthosis nigricans, ovarian enlargement with hyperandrogenism, fasting hypoglycemia, and early death 15 — We hypothesized that severe insulin resistance results in not only defects in insulin action but also in dysregulation of cellular metabolism.

To approach this question, we generated mesenchymal progenitor cells MPCs from a DS patient with severe insulin resistance due to an INSR mutation, and analyzed these cells in comparison with cells derived from a healthy control child. Such MPCs are relatively undifferentiated but are no longer pluripotent and are committed toward mesodermal lineages We demonstrate that severe, genetically defined insulin resistance, even in the absence of differentiation, alters cellular metabolism.

Dermal fibroblasts were obtained from the foreskin of a healthy newborn male control; American Type Culture Collection Cell Repository Line and from a skin biopsy of a 1-month-old female with severe insulin resistance and DS Coriell Cell Repository, Genetically modified due to a known nonsense mutation AX in exon 14 of the INSR and an accompanying cis -acting mutation inherited from the mother, which together reduce INSR mRNA and cell-surface protein expression 2 , 8 , 9 , This patient was previously termed Minn1.

Clinically, this patient was a small for gestational age Caucasian female with multiple phenotypic abnormalities hirsutism, depressed nasal bridge, lack of sc fat and severe insulin resistance 2. Medium was changed every other day.

Morphology of MPC was assessed using phase contrast microscopy. Cells were treated with trypsin, washed with PBS and centrifuged at g for 5 minutes. Ten thousand events per cell type were acquired on a BD fluorescence-activated cell sorting Aria flow cytometer.

Data were analyzed using FlowJo software Treestar. Proteins were resolved by sodium dodecyl sulfate-PAGE and transferred to nitrocellulose. HepG2 lysate stimulated with nM insulin, 5 min was used as control. Equal numbers of cells were seeded in gelatin-coated extracellular flux analyzer microplates Seahorse Bioscience and incubated with krebs ringer buffer nM NaCl, 4.

All data were normalized to 36B4 and expressed relative to control. Statistical analysis was performed using 2-tailed Student's t test. As seen in Supplemental Figure 1 , MPCs have fibroblast-like morphology, with relatively large nucleus, and prominent nucleolus; this pattern did not differ between cells derived from DS vs control. Although fluorescence-activated cell sorting analysis indicated a trend for lower expression of CD73 and CD in DS, there were no significant differences in expression of these antigens by PCR.

C, Quantification of protein level from 3 independent experiments 3 wells per cell line. We next examined phosphorylation of the insulin and IGF-1 receptors. Because we did not observe a robust signal using an antibody which recognizes tyrosine phosphorylation of both the insulin and IGF-1 receptor, except at the nM insulin dose Figure 3A , we assessed both insulin and IGF-1 receptor phosphorylation independently using immunoprecipitation with specific anti-INSR and anti-IGF-1R antibodies and immunoblotting with antiphosphotyrosine antibodies for antibodies, please see Table 2.

As expected, insulin stimulated phosphorylation of the INSR in control cells 1. We observed a doublet at 95 kDa, with upper band corresponding to the INSR Figure 3B , indicated by black arrowhead and a lower nonspecific band open arrowhead. The upper band emerged in response to insulin in control cells, but not in DS cells quantified in Figure 3C.

Black and open arrowheads indicate INSR and nonspecific bands, respectively. C, Quantification from 2 independent experiments. We next examined insulin signaling downstream of the insulin and IGF-1 receptors. C, Time course of AKT phosphorylation. Confluent MPCs were serum starved for 4 hours and treated with insulin for dose response 0nM—nM insulin for 10 min and time course nM insulin for 0, 1, 5, and 10 min analysis.

To determine whether genetically determined insulin resistance affected metabolism in MPC, we assessed cellular bioenergetics. Moreover, we observed no differences in mitochondrial membrane potential, as assessed by MitoTracker Red staining Supplemental Figure 5.

We next analyzed ECAR, a surrogate measure for glycolytic flux. Because this suggested increased lactate production, we directly measured lactate in conditioned medium.

B, Assay of lactate in conditioned medium. All data normalized to 36B4 and expressed relative to control. Both iPS cells and mesenchymal progenitors derived from them are relatively undifferentiated 21 , and few epigenetic marks are retained during reprogramming Thus, these cells permit dissection of the impact of genetic mutations on cellular function, largely independent of environmentally mediated and differentiation-dependent mechanisms.

We have used MPC derived from a patient with DS to assess the impact of genetically determined insulin resistance on cellular signaling and metabolism. Several possibilities may account for these findings. As seen in the immunoprecipitation experiments, the anti-C-terminal antibody may have enriched for the small amount of nonmutated INSR protein. Given that ERK-dependent pathways are critical for cellular growth 30 , such reductions in ERK activation could contribute to the growth retardation observed clinically in patients with DS.

Altered insulin signaling has also been observed in other cell models of DS, such as induced pluripotent stem cells and fibroblasts from which they were originally derived However, differences in transcriptional profiles were also observed between iPSC and fibroblasts, suggesting cell type-specific regulation.

Our data indicating disturbances in downstream signaling and regulation of metabolism are broadly consistent with previous studies of fibroblasts derived from patients with DS, which reported substantial heterogeneity in INSR autophosphorylation or kinase activity in individual patients, paralleling the diversity of mutations 23 — Reddy et al 8 demonstrated that INSR autophosphorylation and receptor-associated tyrosine kinase activity were reduced in Minn1 fibroblasts.

Additional studies evaluating the full spectrum of insulin signaling defects and their modulation during progression from pluripotency to differentiated state in multiple individuals with DS and across a spectrum of mutations will be required to address this important question. DS MPCs also have alterations in cellular metabolism. This is unlikely due to increased global mitochondrial mass, as we observed no alterations in mitochondrial DNA content, MitoTracker Green staining, or citrate synthase protein.

Increased oxygen consumption could also reflect uncoupling. We observed no alterations in expression of the uncoupling proteins UCP1—UCP3 and found no differences in mitochondrial membrane potential, as assessed by MitoTracker Red staining. Interestingly, expression of antioxidant response genes were also significantly altered in DS MPC, with marked suppression of catalase expression and up-regulation of superoxide dismutase 2.

Dysregulation of antioxidant response pathways, as noted in DS fibroblasts 32 , 33 , could also contribute to uncoupling observed in DS MPC. Given the importance of glycolytic pathways in stem cells for maintenance of energetic homeostasis 34 , it is particularly interesting that extracellular acidification and lactate production are increased in DS cells, suggesting underlying cellular energetic stress.

Whether this could be due to reductions in glucose uptake and metabolism associated with reduced hexokinase expression, or alterations in net ATP production due to dysregulation of OXPHOS complex function, will be assessed in future studies. More broadly, our data provide important evidence addressing the relationship between insulin resistance and control of metabolic homeostasis. In recent years, abnormal mitochondrial metabolism has been linked to insulin resistance For example, magnetic resonance spectroscopy has demonstrated decreased ATP synthesis in muscle from patients with T2D, with similar patterns in insulin resistant individuals with family history of diabetes Similarly, analysis of muscle biopsies from insulin resistant subjects has demonstrated decreases in mRNA expression of both nuclear-encoded mitochondrial genes and mitochondrial DNA, lower protein expression of respiratory chain subunits, and reduced mitochondrial size, density, and oxidative enzyme activities 36 — In addition, interventions such as exercise and caloric restriction, which improve insulin sensitivity, also enhance mitochondrial function 41 , In mice, defects in insulin signaling can cause mitochondrial dysfunction In this context, studies in humans with INSR mutations can provide important insights into the relationship between insulin resistance and metabolism.

Nuclear magnetic resonance spectroscopy studies in patients with milder forms of insulin resistance due to distinct INSR mutations have revealed reductions in muscle phosphocreatine resynthesis, indicating energetic stress However, these in vivo relationships are difficult to unravel at a molecular level, and are made even more complex by the epigenetic changes that may result from chronic environmental exposures.

Our studies in mesenchymal precursor cells derived from DS fibroblasts provide further support for the concept that primary, genetically determined insulin resistance can contribute to disordered regulation of cellular metabolism. Given that few epigenetic marks are retained during the reprogramming process, it is likely that observed differences between control and insulin resistant cells reflect genetically determined insulin resistance. We acknowledge that intrinsic differences in genetic background between individuals, clonal variation, or residual epigenetic differences that persist during the cellular reprogramming process could also contribute.

In turn, these defects are likely mediated by INSR-dependent perturbations in transcriptional regulation of metabolic and mitochondrial protein complexes. Analysis of additional patient-derived lines will be required to define the specific molecular mechanisms which link INSR mutations and defective regulation of cellular metabolism.

Our results may also help guide further studies of cells from individuals with less severe forms of insulin resistance associated with human prediabetes and T2D. This work was supported in part by a Pediatric Endocrine Society grant B. Global prevalence of diabetes: estimates for the year and projections for Diabetes Care. Google Scholar. Taylor SI. Lilly lecture: molecular mechanisms of insulin resistance.

Lessons from patients with mutations in the insulin receptor gene. Role of glucose and insulin resistance in development of type 2 diabetes mellitus: results of a year follow-up study. Genotype-phenotype correlation in inherited severe insulin resistance. Hum Mol Genet. Cell culture studies on patients with extreme insulin resistance. Receptor defects on cultured fibroblasts. J Clin Endocrinol Metab. Donahue WL , Uchida I. Leprechaunism: a euphemism for a rare familial disorder.

J Pediatr. Eur J Pediatr. Insulin receptor function in fibroblasts from patients with leprechaunism.

Insulin Resistance and Metabolic Syndrome in Young Men With Acne

Skip to search form Skip to main content You are currently offline. Some features of the site may not work correctly. DOI: Kilpatrick and A. Rigby and S.

Adiponectin is an adipokine that is specifically and abundantly expressed in adipose tissue and directly sensitizes the body to insulin. Hypoadiponectinemia, caused by interactions of genetic factors such as SNPs in the Adiponectin gene and environmental factors causing obesity, appears to play an important causal role in insulin resistance, type 2 diabetes, and the metabolic syndrome, which are linked to obesity. The adiponectin receptors, AdipoR1 and AdipoR2, which mediate the antidiabetic metabolic actions of adiponectin, have been cloned and are downregulated in obesity-linked insulin resistance. Upregulation of adiponectin is a partial cause of the insulin-sensitizing and antidiabetic actions of thiazolidinediones. Therefore, adiponectin and adiponectin receptors represent potential versatile therapeutic targets to combat obesity-linked diseases characterized by insulin resistance. This Review describes the pathophysiology of adiponectin and adiponectin receptors in insulin resistance, diabetes, and the metabolic syndrome.

Study record managers: refer to the Data Element Definitions if submitting registration or results information. The Metabolic Syndrome is a high prevalence disease worldwide. About a quarter of the adult population suffers the disease. Resveratrol is a substance found in many plants, including grapes, nuts and wine, but it's also found in Polygonum cuspidatum. There is evidence that resveratrol consumption has beneficial effects on glucose and lipids metabolism, blood pressure and body weight. The aim of this study was to evaluate the effect of resveratrol on metabolic syndrome, insulin sensitivity and insulin secretion.


Metabolic syndrome is a clinical entity characterized by abdominal obesity, atherogenic dyslipidemia, impaired glucose tolerance, and.


Insulin Resistance, the Metabolic Syndrome, and Complication Risk in Type 1 Diabetes

The constellation of metabolic abnormalities tightly correlates with cardiovascular dysfunction, resulting in high morbidity and mortality rates Reaven a. An estimated million people had diabetes worldwide in , and this number is predicted to rise to million by , with a high economic cost for disease management Whiting et al. Table 1 Clinical criteria for the diagnosis of metabolic syndrome. However, patients with type 2 diabetes are non-insulin-dependent, in these patients intensive insulin therapy lowers blood glucose levels, but increases body weight and cardiovascular risk, as demonstrated in the Action to Control Cardiovascular Risk in Diabetes ACCORD trial Wilson Intensive insulin therapy does not provide much cardioprotective benefit in adults, and two-thirds of patients with type 2 diabetes die of heart failure.

JAMA Dermatol. Postadolescent patients were recruited only to negate the effects of physiologic insulin resistance that are seen at the time of puberty and adolescence. Twenty-five patients were included in each of the 4 individual severity groups according to the Global Acne Grading System and were age matched to male controls without acne. Prevalence of insulin resistance and metabolic syndrome did not differ significantly among the acne severity groups. This resistance may be a stage of prediabetes, and the patients may develop hyperinsulinemia or type 2 diabetes in the future.

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People who have metabolic syndrome typically have apple-shaped bodies, meaning they have larger waists and carry a lot of weight around their abdomens. It's thought that having a pear-shaped body — that is, carrying more of your weight around your hips and having a narrower waist — doesn't increase your risk of diabetes, heart disease and other complications of metabolic syndrome. Metabolic syndrome is a cluster of conditions that occur together, increasing your risk of heart disease, stroke and type 2 diabetes. These conditions include increased blood pressure, high blood sugar, excess body fat around the waist, and abnormal cholesterol or triglyceride levels. Having just one of these conditions doesn't mean you have metabolic syndrome. But it does mean you have a greater risk of serious disease. And if you develop more of these conditions, your risk of complications, such as type 2 diabetes and heart disease, rises even higher.

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