Obesity, insulin resistance and the implication of thiazolidinediones

The mechanism of insulin resistance in obesity is not fully understood. In muscle cells, the number of insulin receptor, the function of glucose transporter 4 and the activity of tyrosine kinase decrease. The rink of body fat accumulation and insulin resistance in muscle is thought through free fatty acid and tumor necrosis factor alpha secreted in adipose tissue. Thiazolidinediones (TZDs) are useful to reduce insulin resistance especially in obesity. TZDs seem to cause small weight gain, but to reduce visceral fat in 12-24 weeks. In longer period, it hasn't been studied very much. There are some unsolved problems. So now, targets of TZDs are obese diabetes failed in other medicines. When using TZDs, be cautious of excess eating and physical inactivity.     

Obesity, inflammation and insulin resistance: which role for adipokines

Adipose tissue is now recognized as an endocrine organ involved in regulating physiologic and pathologic processes including inflammation. It synthesizes and secretes hormones such as leptin and adiponectin. It can secrete other products namely adipokines including cytokines and chemokines. The release of adipokines by either adipocytes or adipose tissue-infiltrated macrophages leads to a chronic sub-inflammatory state that likely plays a major role in cardiovascular complications linked to obesity and insulin resistance.     

Obesity/insulin resistance is associated with endothelial dysfunction. Implications for the syndrome of insulin resistance.

To test the hypothesis that obesity/insulin resistance impairs both endothelium-dependent vasodilation and insulin-mediated augmentation of endothelium-dependent vasodilation, we studied leg blood flow (LBF) responses to graded intrafemoral artery infusions of methacholine chloride (MCh) or sodium nitroprusside (SNP) during saline infusion and euglycemic hyperinsulinemia in lean insulin-sensitive controls (C), in obese insulin-resistant subjects (OB), and in subjects with non-insulin-dependent diabetes mellitus (NIDDM). MCh induced increments in LBF were approximately 40% and 55% lower in OB and NIDDM, respectively, as compared with C (P < 0.05). Euglycemic hyperinsulinemia augmented the LBF response to MCh by - 50% in C (P < 0.05 vs saline) but not in OB and NIDDM. SNP caused comparable increments in LBF in all groups. Regression analysis revealed a significant inverse correlation between the maximal LBF change in response to MCh and body fat content. Thus, obesity/insulin resistance is associated with (a) blunted endothelium-dependent, but normal endothelium-independent vasodilation and (b) failure of euglycemic hyperinsulinemia to augment endothelium-dependent vasodilation. Therefore, obese/insulin-resistant subjects are characterized by endothelial dysfunction and endothelial resistance to insulin's effect on enhancement of endothelium-dependent vasodilation. This endothelial dysfunction could contribute to the increased risk of atherosclerosis in obese insulin-resistant subjects.     

Obesity, plasma high sensitivity C-reactive protein levels and insulin resistance status among school children in Taiwan

OBJECTIVE: To evaluate the degree of obesity and plasma high sensitivity C-reactive protein (hs-CRP) levels in relation to insulin resistance status among school children in Taiwan. METHODS: After multistage sampling, we randomly selected 1438 children (701 boys and 737 girls) with the mean age of 13.4 years (from 12 to 16) in Taipei in 2003. Anthropometric measures and plasma biochemical variables (including lipid profiles, glucose and insulin) were measured using standard methods. Plasma hs-CRP levels were measured using nephelometric methods. We calculated insulin resistance (IR) index using HOMA methods and further calculated a gender-specific insulin resistance syndrome (IRS) summary score by adding the quartile ranks from the distribution of systolic blood pressure (SBP), triglyceride (TG), high density lipoprotein-cholesterol (HDL-C) and insulin levels of each children. A high IRS summary score corresponds to higher levels of SBP, TG and insulin levels and lower levels of HDL-C. RESULTS: Boys were taller, heavier, had larger BMI, glucose, IRS summary score and hs-CRP than girls; however, there is no difference in plasma TG, insulin levels, and IR index between genders. Plasma hs-CRP levels were positively correlated with anthropometric measures, TG, insulin levels, IR index, and IRS summary score and negatively correlated with HDL-C. Anthropometric measures, plasma TG, insulin levels, IR index and IRS summary score were significantly higher in children with higher plasma hs-CRP levels (test for trend p<0.05). After adjustment for age, heart rate, smoking and drinking, hs-CRP continued to be positively associated with anthropometric variables (weight and BMI), insulin levels, and IR index and negatively correlated with HDL-C in both genders. Plasma hs-CRP levels were also positively associated with TG and IRS summary score in boys and glucose in girls. However, after further adjusting for BMI, the association of hs-CRP on TG, insulin levels, IR index and IRS summary score disappeared in boys and on body weight, HDL-C, insulin level and IR index disappeared in girls. CONCLUSION: Plasma hs-CRP levels are positively related to anthropometric variables, such as body weight and BMI, insulin levels, IR index and IRS summary score and negatively related to HDL-C in Taiwanese children. Moreover, the degree of body fat status (as measured by BMI) plays a more significantly role on insulin resistance status than hs-CRP levels among Taiwanese children.     

Inflammation and insulin resistance

Over a hundred years ago, high doses of salicylates were shown to lower glucose levels in diabetic patients. This should have been an important clue to link inflammation to the pathogenesis of type 2 diabetes (T2D), but the antihyperglycemic and antiinflammatory effects of salicylates were not connected to the pathogenesis of insulin resistance until recently. Together with the discovery of an important role for tissue macrophages, these new findings are helping to reshape thinking about how obesity increases the risk for developing T2D and the metabolic syndrome. The evolving concept of insulin resistance and T2D as having immunological components and an improving picture of how inflammation modulates metabolism provide new opportunities for using antiinflammatory strategies to correct the metabolic consequences of excess adiposity.     

Insulin signaling and insulin resistance

Insulin controls carbohydrate and lipid metabolism. Among other things, it stimulates glucose storage as glycogen and lipid storage as triglycerides. Insulin acts through a membrane receptor which is a tyrosine kinase. When activated by insulin binding, the tyrosine kinase will recruit and phosphorylate intracellular substrates called IRS (insulin receptor substrate). Phosphorylated IRS will be used as docking sites for proteins which will transmit the insulin signal through several systems (e.g. PI3-kinase). The insulin resistance which is concomitant with type 2 diabetes and obesity is linked to an increased intracellular availability of fatty acids which are precursors of lipid mediators inducing a decreased efficiency of insulin signal transmission. Therapies aimed at improving insulin sensitivity could then target proteins involved in the regulation of intacellular fatty acid availibility.     

Adipocyte function and insulin resistance

The importance of free fatty acids (FFA) and adipocytokines released from adipocytes in the development of insulin resistance is discussed in this review article. FFA may cause insulin resistance through so-called Rundle cycle and may also inhibit glucose uptake by skeletal muscles. Adipocytokines, bioactive substances secreted from adipose tissue may have important roles in occurrence of insulin resistance. For example, TNF-alpha from adipocytes reduces tyrosine kinase activity of the insulin receptor in obesity. A novel collagen-like protein, adiponectin inhibits TNF-alpha induced cell phenomena and its reduction at obesity may be one of molecular mechanism of insulin resistance.     

异位脂肪与胰岛素抵抗

异位脂肪是引起胰岛素抵抗的重要原因,脂质异位沉积于肝脏、肌肉均与胰岛素抵抗密切相关.异位脂肪形成的原因目前尚不清楚,脂肪组织储脂能力下降、线粒体功能低下及组织内脂肪酸β氧化减少,脂肪炎症及内分泌学说,以及CD36在组织细胞膜中分布不同均可能导致异位脂肪沉积.炎症因子、内质网压力、脂质因子等在肝脏及骨骼肌的胰岛素抵抗形成中有重要作用,但是不发生于体质量正常的胰岛素抵抗的年轻人及老年人中.而二酰甘油所诱发的胰岛素抵抗可出现在肥胖、先天性脂肪营养不良、2型糖尿病的正常体质量的后代等人群,以及随着年龄的增加也可出现.     

炎症因子与胰岛素抵抗

炎症导致胰岛素抵抗(IR)的分子机制是近年的研究热点。IR使胰岛素维持正常血糖水平的能力下降,其主要发生在肝、骨骼肌和脂肪组织,对于绝大多数肥胖或2型糖尿病患者而言,其发生IR的分子机制是靶细胞胰岛素受体后信号转导通路缺陷。     

Sex steroids and insulin resistance

There is extensive experimental evidence that sex steroids and insulin interact in their actions on tissues. At physiological levels, testosterone and oestradiol are thought to be involved in maintaining normal insulin sensitivity. However, outside this 'physiological window' these steroids may promote insulin resistance. Considerable research has been carried out on polycystic ovarian syndrome, a common disorder associated with excessive androgen production and insulin resistance. Hyperinsulinaemia in patients with this condition is believed to stimulate ovarian androgen production, and there is also evidence that androgens act directly on peripheral tissues to promote insulin resistance. There is the potential for a vicious circle to develop with increasing androgen production and insulin resistance. The molecular basis of this insulin resistance has been reported to involve reduced insulin receptor autophosphorylation, reduced expression and translocation of insulin-responsive glucose transporters and defects of the insulin signalling pathway distal to the insulin receptor. These defects await full characterization. Insulin-sensitizing agents can reverse many of the effects of insulin resistance and may have a future place in the treatment of polycystic ovarian syndrome and other conditions associated with steroid-induced insulin resistance. Recognition and treatment of sex steroid-associated insulin resistance at an early stage in patients may reduce their risk of developing Type II (non-insulin-dependent) diabetes mellitus, hypertension and dyslipidaemia, and so may improve fertility and reduce cardiovascular risk. Here we review the interplay between sex steroids and insulin resistance, and consider the implications this has for clinical conditions.     

Genetic factors and insulin resistance

Diabetes is characterized by impaired insulin secretion from pancreatic beta-cell and/or insulin resistance in peripheral tissues. Genetic factors affecting the insulin sensitivities have been described, including the mutations of genes of insulin receptor, insulin receptor substrate-1, glycogen synthase, uncoupling proteins, beta3-adrenergic receptor, and peroxisome proliferator-activated receptor gamma. Mutant insulin receptors might act as a monogenic factor, but most of the others act as one of the genetic factors of a polygenetic disease.     

Obesity and the development of insulin resistance and impaired fasting glucose in black and white adolescent girls: a longitudinal study

OBJECTIVE: Age at onset of type 2 diabetes has decreased during the past 20 years, especially in black women. Studies of factors associated with insulin resistance and hyperglycemia in preadolescent and adolescent populations are essential to understanding diabetes development. RESEARCH DESIGN AND METHODS: The National Heart, Lung, and Blood Institute (NHLBI) Growth and Health Study (NGHS) is a 10-year cohort study of the development of obesity in black and white girls. Two NGHS centers examined the associations of obesity, puberty, and race with fasting insulin, glucose, and homeostasis model assessment of insulin resistance (HOMA-IR; a calculated index of insulin resistance) measures at 9-10 years of age (baseline) and 10 years later. RESULTS: Black girls had greater baseline and year-10 BMI than white girls, with a greater 10-year incidence of obesity. BMI-insulin correlations were positive in both black and white girls at both visits, but insulin remained higher in black girls after controlling for BMI. In black girls, insulin and HOMA-IR were higher in the prepubertal period (before the emergence of racial differences in BMI), increased more during puberty, and decreased less with its completion. Baseline BMI predicted year-10 glucose and the development of impaired fasting glucose (IFG) in black girls. In white girls, the rate of BMI increase during follow-up predicted these outcomes. The 10-year incidence of diabetes in black girls was 1.4%. CONCLUSIONS: Black-white differences in insulin resistance are not just a consequence of obesity, but precede the pubertal divergence in BMI. The development of IFG appears to be a function of the rate of increase of BMI in white girls and early obesity in black girls.     

Adipose Dipeptidyl Peptidase-4 and Obesity: Correlation with insulin resistance and depot-specific release from adipose tissue in vivo and in vitro

OBJECTIVE

To study expression of the recently identified adipokine dipeptidyl peptidase-4 (DPP4) in subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) of patients with various BMIs and insulin sensitivities, as well as to assess circulating DPP4 in relation to obesity and insulin sensitivity.

RESEARCH DESIGN AND METHODS

DPP4 expression was measured in SAT and VAT from 196 subjects with a wide range of BMIs and insulin sensitivities. DPP4 release was measured ex vivo in paired biopsies from SAT and VAT as well as in vivo from SAT of lean and obese patients. Circulating DPP4 was measured in insulin-sensitive and insulin-resistant BMI-matched obese patients.

RESULTS

DPP4 expression was positively correlated with BMI in both SAT and VAT, with VAT consistently displaying higher expression than SAT. Ex vivo release of DPP4 from adipose tissue explants was higher in VAT than in SAT in both lean and obese patients, with obese patients displaying higher DPP4 release than lean controls. Net release of DPP4 from adipose tissue was also demonstrated in vivo with greater release in obese subjects than in lean subjects and in women than in men. Insulin-sensitive obese patients had significantly lower circulating DPP4 than did obesity-matched insulin-resistant patients. In this experiment, DPP4 positively correlated with the amount of VAT, adipocyte size, and adipose tissue inflammation.

CONCLUSIONS

DPP4, a novel adipokine, has a higher release from VAT that is particularly pronounced in obese and insulin-resistant patients. Our data suggest that DPP4 may be a marker for visceral obesity, insulin resistance, and the metabolic syndrome.Obesity is an increasing health issue worldwide and an economical burden, and as the hallmark of the metabolic syndrome the obese state is frequently associated with the development of chronic diseases, including type 2 diabetes (1,2). The association between the epidemics of obesity and diabetes has promoted research on the endocrine link between lipid and glucose homeostasis, demonstrating that adipose tissue is an endocrine organ releasing various adipokines. A complex interorgan crosstalk scenario between adipose tissue and other central and peripheral organs underlies the progression of obesity-related metabolic disorders, with adipose tissue being a key player in this scenario (3). The current view of the role of expanded adipose tissue in obesity identifies adipokines as a potential link between obesity and insulin resistance (4). This link has stimulated a further characterization of the adipocyte secretome by means of diverse proteomic profiling approaches, leading to the discovery of such novel adipokines as dipeptidyl peptidase-4 (DPP4) (5).DPP4 is a transmembrane glycoprotein and exoprotease that cleaves N-terminal dipeptides from various substrates (6). Most importantly, DPP4 also cleaves and inactivates the incretins glucagon-like peptide 1 (GLP-1) and gastric inhibitory polypeptide. In this context, DPP4-inhibitors are in clinical use as antidiabetic drugs to improve glycemic control by stimulating pancreatic insulin secretion and suppressing glucagon production (7). We recently demonstrated that adipocytes release DPP4 in a differentiation-dependent manner (5). Circulating DPP4 concentrations are increased in obese subjects and correlate with fasting plasma insulin, leptin, and adipocyte size in subcutaneous adipose tissue (SAT); however, the tissue source of circulating DPP4 is not known. This study aimed to assess DPP4 expression and release in paired biopsies of SAT and visceral adipose tissue (VAT) of lean and obese patients and of patients with or without impaired glucose tolerance, as well as DPP4 release from adipose tissue in vivo. Because circulating DPP4 is increased in obese patients with the metabolic syndrome (5), we hypothesized that DPP4 expression and release in VAT are more prominent than in SAT and that VAT DPP4 could be a marker for insulin sensitivity.