Childhood obesity and insulin resistance

Insulin resistance (IR) in childhood has importance to the understanding and prevention of the growing epidemic of insulin resistance syndrome (IRS) in adults with attendant obesity, type 2 diabetes (T2DM), atherosclerotic diseases, hypertension, gout, non-alcoholic, steato-hepatitis (NASH), gall bladder disease, nephropathy, polycystic ovarian disease (PCOS), infertility and premature senility. The severity of IR and its’ complications in children unfortunately and usually progresses in their pubertal transition to adulthood; affected young children are more likely than adults to have underlying causal monogenic disorders; the sequence of natural history and events give insights into disease pathogeneses, and optimal life style choices that last are best made during the early formative years. Some features of IR in children discussed herein are: a strong tendency to low birth weight for gestational age, adverse effects of adrenarche and therapeutic steroid therapy, predisposition to premature pubarche, acanthosis nigricans, tall stature despite pituitary GH suppression, allergic diathesis, hyperandrogenism and PCOS, dyslipidemia and fatty liver disease, and diagnosis by clinical and biochemical markers of IR including insulin regulated hepatic hormonal binding proteins such as IGFBP-1. The national preoccupation with the “metabolic syndrome” T2DM and obesity, should be appropriately directed to an improved understanding of IR in children and their management, if the looming health crisis in affected adults is to be seriously addressed. The nation is facing its’ first generation of children who will be less healthy and die younger than the previous generation (Marks (2005) Presentation to the American Association of Diabetes Educators 32nd Annual Meeting and Exhibition, August 10–13, Washington, DC).     

Molecular mechanism of insulin resistance and obesity

Obesity and insulin resistance have been recognized as leading causes of major health issues. We have endeavored to depict the molecular mechanism of insulin resistance, focusing on the function of adipocyte. We have investigated a role of PPARgamma on the pathogenesis of Type II diabetes. Heterozygous PPARgamma-deficient mice were protected from the development of insulin resistance due to adipocyte hypertrophy under a high-fat diet. Moreover, a Pro12Ala polymorphism in the human PPARgamma2 gene was associated with decreased risk of Type II diabetes in Japanese. Taken together with these results, PPARgamma is proved to be a thrifty gene mediating Type II diabetes. Pharmacological inhibitors of PPARgamma/RXR ameliorate high-fat diet-induced insulin resistance in animal models of Type II diabetes. We have performed a genome-wide scan of Japanese Type 2 diabetic families using affected sib pair analysis. Our genome scan reveals at least 9 chromosomal regions potentially harbor susceptibility genes of Type II diabetes in Japanese. Among these regions, 3q26-q28 appeared to be very attractive one, because of the gene encoding adiponectin, the expression of which we had found enhanced in insulin-sensitive PPARgamma-deficient mice. Indeed, the subjects with the G/G genotype of SNP276 in the adiponectin gene were at increased risk for Type II diabetes compared with those having the T/T genotype. The plasma adiponectin levels were lower in the subjects with the G allele, suggesting that genetically inherited decrease in adiponectin levels predispose subjects to insulin resistance and Type II diabetes. Our work also confirmed that replenishment of adiponectin represents a novel treatment strategy for insulin resistance and Type II diabetes using animal models. Further investigation will be needed to clarify how adiponectin exerts its effect and to discover the molecular target of therapies.     

Pathogenesis of insulin resistance in metabolic obesity

This review considers molecular mechanisms of insulin resistance developed under conditions of metabolic inflammation; special attention is paid to analysis of the results of experimental and clinical studies work aimed at identifying molecular targets for the development of new methods for prevention and treatment of insulin resistance.     

The relationship between testosterone and dehydroepiandrosterone sulfate concentrations, insulin resistance and visceral obesity in elderly men

INTRODUCTION: Sex hormones deficiency--hypotestosteronemia (20-30% of men) and dehydroepian-drosterone sulfate deficiency (60-70% of men) are often observed in elderly men. In these men also changes of body composition (visceral obesity, increasing of fat mass), and metabolic disturbances (hypercholesterolemia, hyperinsulinism and insulin resistance) are common disorders. Visceral obesity and insulin resistance may be either reasons or effects of testosterone deficiency. Probably also DHEA-S deficiency is the risk factor of visceral obesity and insulin resistance, but it is not clear, whether this possible influence is independent from testosterone deficiency. OBJECTIVES: The aim of this study was to analyze the association between testosterone and DHEA deficiency and waist/hip ratio (WHR), levels of glucose and insulin resistance (HOMA and FG/FI) in elderly men as well as analysis, whether these sex hormones influent on measured parameters separately. MATERIAL AND METHODS: Together 85 men with age from 60 to 70 years men (mean 66.3+/-1.5 years; mean+/-SEM) was analyzed. Testosterone levels<4 ng/ml or DHEA levels<2000 ng/ml and BMI<30 kg/m2 were including criteria. Patients were divided into three groups: 52 with testosterone deficiency (L-T), 32 with DHEA deficiency (L-DHEA-S) and 67 with deficiency of both sex hormones (L-T/DHEA-S). Statistical analysis was made using Student-t, Kruskal-Wallis, and Mann-Whitney tests. RESULTS: Testosterone levels in L-T, L-DHEA and L-T/DHEA groups were respectively 3.19+/-0.23 ng/ml, 4.89+/-0.45 ng/ml and 3.25+/-0.34 g/ml (p<0.002). While DHEA-S levels were respectively 2498+/-98 ng/ml, 1435+/-1010 ng/ml and 1501+/-89 ng/ml). BMI values do not differ between groups. WHR ratio values were the highest in L-T/DHEA-S group (p<0.05 vs. L-T) group, significant lower in L-T group (p<0.005 vs. L-DHEA-S) and the lowest in L-DHEA-S group. Insulin fasting levels were lowest in L-DHEA-S group, higher in L-T group (p<0.01) and the highest in L-T/DHEA-S group (p<0.001 vs, L-T group). FG/FI values were the highest in L-DHEA-S group, lower in L-T group (NS) and lowest in L-T/DHEA group (p<0.002 vs. L-T group). HOMA ratio values similarly did not change significantly between L-T (6.6+/-3.21) and L-DHEA-S group (5.5+/-2.92), although tendency to higher values in L-T group was noticed, while WHR ratio values were significantly higher in L-T/DHEA group (7.3+/-2.45; p<0.002 vs. L-T group). CONCLUSIONS: DHEA-S and testosterone deficiency were independently associated with higher insulin resistance and obesity. WHR ratio seems to be more sensitive then BMI ratio to reflect the androgen deficiency on obesity and body composition in elderly men.     

Angiopoietin-related growth factor antagonizes obesity and insulin resistance

Angiopoietin-related growth factor (AGF), a member of the angiopoietin-like protein (Angptl) family, is secreted predominantly from the liver into the systemic circulation. Here, we show that most (>80%) of the AGF-deficient mice die at about embryonic day 13, whereas the surviving AGF-deficient mice develop marked obesity, lipid accumulation in skeletal muscle and liver, and insulin resistance accompanied by reduced energy expenditure relative to controls. In parallel, mice with targeted activation of AGF show leanness and increased insulin sensitivity resulting from increased energy expenditure. They are also protected from high-fat diet-induced obesity, insulin resistance and nonadipose tissue steatosis. Hepatic overexpression of AGF by adenoviral transduction, which leads to an approximately 2.5-fold increase in serum AGF concentrations, results in a significant (P < 0.01) body weight loss and increases insulin sensitivity in mice fed a high-fat diet. This study establishes AGF as a new hepatocyte-derived circulating factor that counteracts obesity and related insulin resistance.     

Regulation of obesity and insulin resistance by nitric oxide

Obesity is a risk factor for developing type 2 diabetes and cardiovascular disease and has quickly become a worldwide pandemic with few tangible and safe treatment options. Although it is generally accepted that the primary cause of obesity is energy imbalance, i.e., the calories consumed are greater than are utilized, understanding how caloric balance is regulated has proven a challenge. Many “distal” causes of obesity, such as the structural environment, occupation, and social influences, are exceedingly difficult to change or manipulate. Hence, molecular processes and pathways more proximal to the origins of obesity—those that directly regulate energy metabolism or caloric intake—seem to be more feasible targets for therapy. In particular, nitric oxide (NO) is emerging as a central regulator of energy metabolism and body composition. NO bioavailability is decreased in animal models of diet-induced obesity and in obese and insulin-resistant patients, and increasing NO output has remarkable effects on obesity and insulin resistance. This review discusses the role of NO in regulating adiposity and insulin sensitivity and places its modes of action into context with the known causes and consequences of metabolic disease.     

Yohimbine increases plasma insulin concentrations of dogs

Recent evidence suggests that catecholamines inhibit insulin release by stimulating alpha 2-adrenoreceptors in beta-cells of the pancreatic islets. In the present study, iv injections of 0.1 and 0.3 mg/kg of yohimbine, an alpha 2-adrenoreceptor antagonist, resulted in increased plasma insulin and decreased plasma glucose concentrations in the dog. The use of alpha 2-adrenoreceptor antagonists may be of value in non-insulin-dependent diabetic patients by counteracting the inhibitory influence of endogenous catecholamines.     

Ceramide kinase deficiency improves diet-induced obesity and insulin resistance

Ceramide kinase (CERK) is an enzyme that phosphorylates ceramide to produce ceramide 1-phosphate. Recently, evidence has emerged that CERK has a role in inflammatory signaling of immune cells. Since obesity is accompanied by chronic, low-grade inflammation, we examined whether CERK might be involved using CERK-null mice. We determined that CERK deficiency suppresses diet-induced increases in body weight, and improves glucose intolerance. Furthermore, we demonstrated that CERK deficiency attenuates MCP-1/CCR2 signaling in macrophages infiltrating the adipose tissue, resulting in the suppression of inflammation in adipocytes, which might otherwise lead to obesity and diabetes.     

Increased insulin translation from an insulin splice-variant overexpressed in diabetes, obesity, and insulin resistance

Type 2 diabetes occurs when pancreatic beta-cells become unable to compensate for the underlying insulin resistance. Insulin secretion requires beta-cell insulin stores to be replenished by insulin biosynthesis, which is mainly regulated at the translational level. Such translational regulation often involves the 5'-untranslated region. Recently, we identified a human insulin splice-variant (SPV) altering only the 5'-untranslated region and conferring increased translation efficiency. We now describe a mouse SPV (mSPV) that is found in the cytoplasm and exhibits increased translation efficiency resulting in more normal (prepro)insulin protein per RNA. The RNA stability of mSPV is not increased, but the predicted secondary RNA structure is altered, which may facilitate translation. To determine the role of mSPV in insulin resistance and diabetes, mSPV expression was measured by quantitative real-time RT-PCR in islets from three diabetic and/or insulin-resistant, obese and nonobese, mouse models (BTBRob/ob, C57BL/6ob/ob, and C57BL/6azip). Interestingly, mSPV expression was significantly higher in all diabetic/insulin-resistant mice compared with wild-type littermates and was dramatically induced in primary mouse islets incubated at high glucose. This raises the possibility that the mSPV may represent a compensatory beta-cell mechanism to enhance insulin biosynthesis when insulin requirements are elevated by hyperglycemia/insulin resistance.     

From insulin receptor signalling to Glut 4 translocation abnormalities in obesity and insulin resistance

Insulin resistance is commonly associated with obesity in rodents. Using mice made obese with goldthioglucose (GTG-obese mice), we have shown that insulin resistance results from defects at the level of the receptor and from intracellular alterations in insulin signalling pathway, without major alteration in the number of the Glut 4 glucose transporter. Activation of phosphatidylinositol 3-kinase (PI 3-kinase) was found to be profoundly affected in response to insulin. This defect appears very early in the development of obesity, together with a marked decrease in IRS 1 tyrosine phosphorylation. In order to better understand the abnormalities in glucose transport in insulin resistance, we have studied the pathway leading from the insulin receptor kinase stimulation to the translocation of the Glut 4 containing vesicles. This stimulation involves the activation of PI 3-kinase, which in turns activates protein kinase B. We have then focussed at the mechanism of vesicle exocytosis, and more specifically at the role of the small GTPase Rab4 in this process. We have shown that Rab4 participates, first in the intracellular retention of the Glut 4 containing vesicles, second in the insulin signalling pathway leading to glucose transporter translocation.     

Nobiletin improves obesity and insulin resistance in high-fat diet-induced obese mice

Nobiletin (NOB) is a polymethoxylated flavone present in citrus fruits and has been reported to have antitumor and anti-inflammatory effects. However, little is known about the effects of NOB on obesity and insulin resistance. In this study, we examined the effects of NOB on obesity and insulin resistance, and the underlying mechanisms, in high-fat diet (HFD)-induced obese mice. Obese mice were fed a HFD for 8 weeks and then treated without (HFD control group) or with NOB at 10 or 100 mg/kg. NOB decreased body weight gain, white adipose tissue (WAT) weight and plasma triglyceride. Plasma glucose levels tended to decrease compared with the HFD group and improved plasma adiponectin levels and glucose tolerance. Furthermore, NOB altered the expression levels of several lipid metabolism-related and adipokine genes. NOB increased the mRNA expression of peroxisome proliferator-activated receptor (PPAR)-γ, sterol regulatory element-binding protein-1c, fatty acid synthase, stearoyl-CoA desaturase-1, PPAR-α, carnitine palmitoyltransferase-1, uncoupling protein-2 and adiponectin, and decreased the mRNA expression of tumor necrosis factor-α and monocyte chemoattractant protein-1 in WAT. NOB also up-regulated glucose transporter-4 protein expression and Akt phosphorylation and suppressed IκBα degradation in WAT. Taken together, these results suggest that NOB improves adiposity, dyslipidemia, hyperglycemia and insulin resistance. These effects may be elicited by regulating the expression of lipid metabolism-related and adipokine genes, and by regulating the expression of inflammatory makers and activity of the insulin signaling pathway.     

Role of PYK2 in the development of obesity and insulin resistance

Non-receptor proline-rich tyrosine kinase-2 (PYK2), which is activated by phosphorylation of one or more of its tyrosine residues, has been implicated in the regulation of GLUT4 glucose transporter translocation and glucose transport. Some data favor a positive role of PYK2 in stimulating glucose transport, whereas other studies suggest that PYK2 may participate in the induction of insulin resistance. To ascertain the importance of PYK2 in the setting of obesity and insulin resistance, we (1) evaluated the regulation of PYK2 in mice fed a high-fat diet and (2) characterized body and glucose homeostasis in wild type (WT) and PYK2(-/-) mice on different diets. We found that both PYK2 expression and phosphorylation were significantly increased in liver and adipose tissues harvested from high-fat diet fed mice. Wild type and PYK2(-/-) mice were fed a high-fat diet for 8 weeks to induce insulin resistance/obesity. Surprisingly, in response to this diet PYK2(-/-) mice gained significantly more weight than WT mice (18.7+/-1.2g vs. 9.5+/-0.6g). Fasting serum leptin and insulin and blood glucose levels were significantly increased in high-fat diet fed mice irrespective of the presence of PYK2 protein. There was a close correlation between serum leptin and body weight. Intraperitoneal glucose tolerance tests revealed that as expected, the high-fat diet resulted in increased blood glucose levels following glucose administration in wild type mice compared to those fed normal chow. An even greater increase in blood glucose levels was observed in PYK2(-/-) mice compared to wild type mice. These results demonstrate that a lack of PYK2 exacerbates weight gain and development of glucose intolerance/insulin resistance induced by a high-fat diet, suggesting that PYK2 may play a role in slowing the development of obesity, insulin resistance, and/or frank diabetes.     

Postnatal deficiency of essential fatty acids in mice results in resistance to diet-induced obesity and low plasma insulin during adulthood

Our objective was to investigate the long-term metabolic effects of postnatal essential fatty acid deficiency (EFAD). Mouse dams were fed an EFAD diet or an isoenergetic control diet 4 days before delivery and throughout lactation. The pups were weaned to standard diet (STD) and were later subdivided into two groups: receiving high fat diet (HFD) or STD. Body composition, energy expenditure, food intake and leptin levels were analyzed in adult offspring. Blood glucose and plasma insulin concentrations were measured before and during a glucose tolerance test. EFAD offspring fed STD were leaner with lower plasma leptin and insulin concentrations compared to controls. EFAD offspring fed HFD were resistant to diet-induced obesity, had higher energy expenditure and lower levels of plasma leptin and insulin compared to controls. These results indicate that the fatty acid composition during lactation is important for body composition and glucose tolerance in the adult offspring.