Lack of overt FGF21 resistance in two mouse models of obesity and insulin resistance

Circulating levels of fibroblast growth factor 21 (FGF21), a metabolic regulator of glucose, lipid, and energy homeostasis, are elevated in obese diabetic subjects, raising questions about potential FGF21 resistance. Here we report tissue expression changes in FGF21 and its receptor components, and we describe the target-organ and whole-body responses to FGF21 in ob/ob and diet-induced obese (DIO) mice. Plasma FGF21 concentrations were elevated 8- and 16-fold in DIO and ob/ob mice, respectively, paralleling a dramatic increase in hepatic FGF21 mRNA expression. Concurrently, expression levels of βKlotho, FGF receptor (FGFR)-1c, and FGFR2c were markedly down-regulated in the white adipose tissues (WAT) of ob/ob and DIO mice. However, dose-response curves of recombinant human FGF21 (rhFGF21) stimulation of ERK phosphorylation in the liver and WAT were not right shifted in disease models, although the magnitude of induction in ERK phosphorylation was partially attenuated in DIO mice. Whole-body metabolic responses were preserved in ob/ob and DIO mice, with disease models being more sensitive and responsive than lean mice to the glucose-lowering and weight-loss effects of rhFGF21. Endogenous FGF21 levels, although elevated in diseased mice, were below the half-maximal effective concentrations of rhFGF21, suggesting a state of relative deficiency. Hepatic and WAT FGF21 mRNA expression levels declined after rhFGF21 treatment in the absence of the increased expression levels of βKlotho and FGFR. We conclude that overt FGF21 resistance was not evident in the disease models, and increased hepatic FGF21 expression as a result of local metabolic changes is likely a major cause of elevated circulating FGF21 levels.     

Experimental models of insulin resistance and obesity: lessons learned

For better understanding the role of each element involved in the physiopathology of obesity and insulin resistance, researchers can use experimental models, which may in controlled manner evaluate the participation of each element on the obesity and insulin resistance and provide information for better understanding the physiopathology and treatment of obesity and insulin resistance. Experimental obesity and insulin resistance can be due to a deficient response to leptin, secondary to hypoleptinemia and/or mutations on leptin receptor, by modifications on insulin receptor, deletion or diminished insulin signal transduction, enhancement of the effects of orexigen peptides and/or diminution of anorexigen peptides actions on hypothalamus, as well as secondary to arterial hypertension, as in the spontaneously hypertension. Obesity and insulin resistance can also be induced by glucocorticoid excess, frutose enriched and cafeteria diet and due to hypothalamus lesions induced by neonatal administration of monossodium glutamate.     

Prevalence of insulin resistance and cardiometabolic risk in Korean children and adolescents: A population-based study

Aims

We aimed to establish normal reference values of serum insulin and the homeostasis model assessment of insulin resistance (HOMA-IR). We also aimed to verify HOMA-IR “cut-off values” in predicting cardiometabolic risk among Korean children and adolescents.

Methods

Data from 2716 Korean subjects (1421 male and 1295 female, aged 10–20 years) were evaluated. Insulin resistance was defined as HOMA-IR >95th percentile. The odds ratios of cardiometabolic risk were assessed based on the state of insulin resistance.

Results

Reference values of insulin and HOMA-IR were determined according to sex and age, based on data obtained from normal-weight subjects with normal fasting glucose levels. HOMA-IR values appeared to peak at the age of 14–15 years in male subjects and at the age of 12–13 years in female subjects. The prevalence of insulin resistance in the subjects was 9.8% (male = 10.9%, female = 8.6%). The prevalence of insulin resistance in normal-weight, overweight, and obese subjects were 4.7%, 25.6%, and 47.1% respectively. Subjects with insulin resistance had a higher prevalence of metabolic syndrome (odds ratios = 18.33; 95% confidence interval, 9.62–34.94) and its components, especially hyperglycemia and hypertriglyceridemia.

Conclusion

We established reference values of serum insulin and HOMA-IR according to age and sex. Obesity is the most important risk factor for insulin resistance and metabolic syndrome. However, insulin resistance independently increases cardiometabolic risk. This information may be useful for Korean as well as other Asian in planning programs for the prevention of type 2 diabetes.     

Increased insulin resistance in obese, glucose-intolerant Southwestern American Indians: evidence for a defect not explained by obesity

Increased in vivo resistance to insulin-mediated glucose disposal has been observed in obese subjects with normal glucose tolerance and in nonobese subjects with glucose intolerance. To determine whether the insulin resistance of glucose-intolerant obese subjects can be accounted for by obesity alone, insulin-mediated glucose disposal was measured in 14 glucose-intolerant and 21 nondiabetic. Southwestern American Indians with similar degrees of obesity. A mixture of insulin, glucose, and somatostatin was infused which delivered the same quantity of glucose and achieved similar plasma insulin concentrations in all subjects. Despite similar steady state plasma insulin levels, the mean steady state plasma glucose concentration was higher in the glucose-intolerant subjects than in weight-matched subjects with normal glucose tolerance (226 +/- 10 vs. 136 +/- 13 mg/dl; P < 0.0001). This increased resistance to insulin action was found in the presence of similar insulin binding to mononuclear cells (measured in 8 glucose-intolerant subjects and 9 subjects with normal glucose tolerance). In obese Southwestern American Indians with glucose intolerance, abnormalities beyond the site of insulin binding to its receptor may explain the observed increase in in vivo insulin resistance.     

Derivation and validation of diabetes risk score for urban Asian Indians

OBJECTIVE: Simple risk scores for identifying people with undiagnosed diabetes have been developed, mostly in Caucasian groups. This may not be suitable for Asian Indians, therefore this study was undertaken to develop and validate a simple diabetes risk score in an urban Asian Indian population with a high prevalence of diabetes. We also tested whether this score was applicable to South Asian migrants living in a different cultural context. RESEARCH DESIGN AND METHODS: A population based Cohort of 10,003 participants aged >or=20 years was divided into two equal halves (Cohorts 1 and 2), after excluding people with known diabetes. Cohort 1 (n=4993) was used to derive the risk score. Validation of the score was performed in the other half of the survey population (Cohort 2) (n=5010). The validation was also done in a separate survey population in Chennai, India (Cohort 3) (n=2002) (diagnosis of diabetes was based on OGTT) and in the South Asian Cohort of the 1999 Health Survey for England (n=676) (fasting glucose value>or=7 mmol/l and HbA1c>or=6.5% were used for diagnosis). A logistic regression model was used to compute the beta coefficients for risk factors. The risk score value was derived from a receiver operating characteristic curve. RESULTS: The significant risk factors included in the risk score were age, BMI, waist circumference, family history of diabetes and sedentary physical activity. A risk score value of >21 gave a sensitivity, specificity, positive predictive value and negative predictive value of 76.6%, 59.9%, 9.4% and 97.9% in Cohort 1, 72.4%, 59%, 8.3% and 97.6% in Cohort 2 and 73.7%, 61.0%, 12.2% and 96.9% in Cohort 3, respectively. The higher distribution of risk factors in the UK Cohort means that at the same cut point the score was much more sensitive but also less specific. (sensitivity 92.2%, specificity 25.7%, positive predictive value of 21.6% and negative predictive value of 93.7%). CONCLUSIONS: A diabetes risk score involving simple non-biochemical measurements was developed and validated in a native Asian Indian population. This easily applicable simple score could play an important role as the first step in the process of identifying individuals with an increased likelihood of having prevalent but undiagnosed diabetes. The different distribution of risk factors with the migrant Asian Indians living in England and the different relationship between sensitivity and specificity for the same score demonstrate that risk scores and cut-points developed and tested even within one ethnic group cannot be generalized to individuals of the same ethnic group living in a different cultural setting where the distribution of risk factors for diabetes is different.     

Knockout models are useful tools to dissect the pathophysiology and genetics of insulin resistance

OBJECTIVE: The development of type 2 diabetes is linked to insulin resistance coupled with a failure of pancreatic beta-cells to compensate by adequate insulin secretion. DESIGN: Here, we review studies obtained from genetically engineered mice that provide novel insights into the pathophysiology of insulin resistance. RESULTS: Knockout models with monogenic impairment in insulin action have highlighted the potential role for insulin signalling molecules in insulin resistance at a tissue-specific level. Polygenic models have strengthened the idea that minor defects in insulin secretion and insulin action, when combined, can lead to diabetes, emphasizing the importance of interactions of different genetic loci in the production of diabetes. Knockout models with tissue-specific alterations in glucose or lipid metabolism have dissected the individual contributions of insulin-responsive organs to glucose homeostasis. They have demonstrated the central role of fat as an endocrine tissue in the maintenance of insulin sensitivity and the development of insulin resistance. Finally, these models have shown the potential role of impaired insulin action in pancreatic beta-cells and brain in the development of insulin deficiency and obesity.     

Waist circumference cutoff points and action levels for Asian Indians for identification of abdominal obesity

OBJECTIVE: To test the validity of internationally accepted waist circumference (WC) action levels for adult Asian Indians. DESIGN: Analysis of data from multisite cross-sectional epidemiological studies in north India.Subjects:In all, 2050 adult subjects >18 years of age (883 male and 1167 female subjects). MEASUREMENTS: Body mass index (BMI), WC, waist-to-hip circumference ratio, blood pressure, and fasting samples for blood glucose, total cholesterol, serum triglycerides, and high-density lipoprotein cholesterol. RESULTS: In male subjects, a WC cutoff point of 78 cm (sensitivity 74.3%, specificity 68.0%), and in female subjects, a cutoff point of 72 cm (sensitivity 68.7%, specificity 71.8%) were appropriate in identifying those with at least one cardiovascular risk factor and for identifying those with a BMI >21 kg/m(2). WC levels of > or =90 and > or =80 cm for men and women, respectively, identified high odds ratio for cardiovascular risk factor(s) and BMI level of > or =25 kg/m(2). The current internationally accepted WC cutoff points (102 cm in men and 88 cm in women) showed lower sensitivity and lower correct classification as compared to the WC cutoff points generated in the present study. CONCLUSION: We propose the following WC action levels for adult Asian Indians: action level 1: men, > or =78 cm, women, >/=72 cm; and action level 2: men, > or =90 cm, women, > or =80 cm.     

Insulin resistance, insulin response, and obesity as indicators of metabolic risk

CONTEXT: Insulin resistance (IR) and obesity, especially abdominal obesity, are regarded as central pathophysiological features of a cluster of cardiovascular risk factors (CVRFs), but their relative roles remain undefined. Moreover, the differential impact of IR viz. insulin response has not been evaluated. OBJECTIVE: The objective of this study was to dissect out the impact of obesity, abdominal obesity, and IR/insulin response on CVRF. DESIGN: This was a cross-sectional study. SETTING: The study was conducted at 21 research centers in Europe. SUBJECTS: The study included a cohort of 1308 nondiabetic subjects [718 women and 590 men, age 30-60 yr, body mass index (BMI) 17-44 kg.m(-2)]. MAIN OUTCOME MEASURES: We measured IR (by a standardized euglycemic insulin clamp), waist girth, insulin response to an oral glucose tolerance test, and major CVRF, and analyzed their associations by multivariate models and factor analysis. RESULTS: BMI was positively related to all CVRFs. Waist circumference was related to higher blood pressure and serum triglycerides and lower high-density lipoprotein-cholesterol, IR to reduced glucose tolerance, higher free fatty acids, triglyceride and low-density lipoprotein-cholesterol, and lower high-density lipoprotein-cholesterol, and insulin response to higher heart rate, blood pressure and fasting glucose, and the same dyslipidemic profile as IR (P < or = 0.05 for all). By factor analysis, three main factors (related to IR, age, and fatness, respectively) appeared to underlie this pattern of associations. Each of BMI, waist girth, IR, and insulin response was independently associated with total CVRF load (all P < 0.001). CONCLUSIONS: When IR, fat mass and distribution, and insulin response are measured simultaneously in a large cohort, no one factor stands out as the sole driving force of the CVRF cluster, each being associated with one or more physiological pathways according to known cause-effect relationships.     

Abdominal obesity, insulin resistance, and the risk of colonic adenoma.]

BACKGROUND/AIMS: Abdominal obesity and hyperinsulinemia or insulin resistance are of interest in connection with colon carcinogenesis. We conducted a prospective case controlled study for the evaluation of relationship between abdominal obesity, insulin resistance, and colorectal adenoma. METHODS: Fifty patients with colorectal adenoma and fifty healthy subjects were included in this study. Total colonoscopic examinations were performed in all the subjects. Fasting blood sugar (FBS), insulin, homeostasis model assessment (HOMA-IR), triglyceride (TG), cholesterol (CROL), BMI (body mass index), WHR (waist hip ratio), percent body fat (PBF) and obesity degree (OD) were measured. HOMA-IR was considered to represent insulin resistance. Diabetic patients were excluded from this study. RESULTS: There were no differences in sex, serum insulin, FBS, HOMA-IR, TG, CROL between adenoma and control group. Subjects with high BMI, WHR, percent body fat, and obesity were more likely to have colonic adenoma. Multiple logistic regression analysis after adjusting confounding factors, had revealed that WHR was the most important independent risk factor for colon adenoma. CONCLUSIONS: Abdominal obesity was most closely related to colonic adenoma. However, insulin resistance was not related to colonic adenoma. A larger case controlled study is needed.     

Ethnicity modifies the effect of obesity on insulin resistance in pregnancy: a comparison of Asian, South Asian, and Caucasian women

CONTEXT: Women of Asian and South Asian descent are at increased risk of developing gestational diabetes mellitus compared with Caucasians, despite lower body mass index (BMI). Nevertheless, there has been limited study of insulin action during pregnancy in these ethnic groups. OBJECTIVE: The objective of the study was to compare insulin sensitivity in pregnancy in Asian, South Asian, and Caucasian subjects and to determine whether the impact of obesity on insulin action is modified by ethnicity. DESIGN AND PARTICIPANTS: A cross-sectional study was performed in outpatients undergoing oral glucose tolerance testing in late pregnancy. Participants were stratified into three groups: 1) Caucasian (n = 116); 2) South Asian (n = 31); and 3) Asian (n = 28). MAIN OUTCOME MEASURE: Insulin sensitivity was measured using the oral glucose tolerance test (IS(OGTT)) index of M. Matsuda and R. DeFronzo, previously validated in pregnancy. Results: There were no significant ethnic differences in insulin sensitivity despite variation in prepregnancy BMI (Caucasians, 25.2 kg/m(2); South Asians, 23.3 kg/m(2); Asians, 21.4 kg/m(2); overall P = 0.0001). On multiple linear regression analysis, the strongest independent determinants of IS(OGTT) were gestational diabetes mellitus (t = -5.71; P < 0.0001) and BMI (t = -5.43; P < 0.0001). Importantly, both Asian (t = -2.87; P = 0.0047) and South Asian (t = -2.46; P = 0.015) ethnicity also emerged as negative, independent determinants of IS(OGTT). Furthermore, Asian ethnicity significantly modified the association of prepregnancy BMI with IS(OGTT) (interaction term, t = -2.29; P = 0.0231). CONCLUSIONS: Asian and South Asian ethnicity are both independently associated with increased insulin resistance in late pregnancy. Prepregnancy BMI has a much greater effect on insulin resistance in pregnancy in Asian women than in Caucasians. Ethnicity thus emerges as a factor that modulates the effect of obesity on insulin resistance in pregnancy.     

Genetics of human obesity: lessons from mouse models and candidate genes

Obesity is a common disorder with potentially serious negative implications on health and quality of life and a rising prevalence worldwide, warranting effective treatments. The disorder runs in families, and important knowledge is expected to follow the identification of human obesity genes. Although statistical analysis of inheritance of obesity in humans suggests a large genetic component in obesity, up to 80%, few actual obesity genes have been identified so far. However, a number of obesity causing genes have successfully been cloned from rodents with monogenic forms of obesity, and it is probable that new knowledge in the field of human obesity will result from these findings.     

Development of insulin resistance and obesity in mice overexpressing cellular glutathione peroxidase

Insulin resistance, a hallmark of type 2 diabetes, is associated with oxidative stress. However, the role of reactive oxygen species or specific antioxidant enzymes in its development has not been tested under physiological conditions. The objective of our study was to investigate the impact of overexpression of glutathione peroxidase 1 (GPX1), an intracellular selenoprotein that reduces hydrogen peroxide (H(2)O(2)) in vivo, on glucose metabolism and insulin function. The GPX1-overexpressing (OE) and WT male mice (n = 80) were fed a selenium-adequate diet (0.4 mg/kg) from 8 to 24 weeks of age. Compared with the WT, the OE mice developed (P < 0.05) hyperglycemia (117 vs. 149 mg/dl), hyperinsulinemia (419 vs. 1,350 pg/ml), and elevated plasma leptin (5 vs. 16 ng/ml) at 24 weeks of age. Meanwhile, these mice were heavier (37 vs. 27 g, P < 0.001) and fatter (37% vs. 17% fat, P < 0.01) than the WT mice. At 30-60 min after an insulin challenge, the OE mice had 25% less (P < 0.05) of a decrease in blood glucose than the WT mice. Their insulin resistance was associated with a 30-70% reduction (P < 0.05) in the insulin-stimulated phosphorylations of insulin receptor (beta-subunit) in liver and Akt (Ser(473) and Thr(308)) in liver and soleus muscle. Here we report the development of insulin resistance in mammals with elevated expression of an antioxidant enzyme and suggest that increased GPX1 activity may interfere with insulin function by overquenching intracellular reactive oxygen species required for insulin sensitizing.     

Adapting to insulin resistance in obesity: role of insulin secretion and clearance

Aims/hypothesis

The aim of this study was to quantify the relative contributions of increased insulin secretion rate (ISR) and decreased insulin clearance rate (ICR) in the compensatory hyperinsulinaemia characteristic of insulin-resistant individuals without diabetes.

Methods

Obese (BMI ≥30 kg/m²) individuals without diabetes (n?=?91) were identified from a registry of volunteers. Volunteers underwent the following measurements: oral glucose tolerance; insulin resistance (steady-state plasma glucose [SSPG] concentration during the insulin suppression test [IST]); ISR (using the graded glucose infusion test [GGIT]); and ICR (using the IST and GGIT). Participants were stratified into tertiles based on SSPG concentration: SSPG-1(insulin-sensitive); SSPG-2 (intermediate); and SSPG-3 (insulin-resistant).

Results

There were no differences in BMI and waist circumference among the SSPG tertiles. Serum alanine aminotransferase concentrations were higher in the SSPG-2 and SSPG-3 groups compared with the SSPG-1 group (p?=?0.02). Following an oral glucose challenge, there was a progressive increase in the total integrated insulin response from the most insulin-sensitive to the most insulin-resistant tertiles (p?<?0.001). Following intravenous glucose, the SSPG-3 group had significantly greater integrated glucose (median [interquartile range], 32.9 [30.8–36.3] mmol/l?×?h) and insulin responses (1711 [1476–2223] mmol/l?×?h) compared with the SSPG-1 group (30.3 [28.8–32.9] mmol/l?×?h, p?=?0.04, and 851 [600–1057] pmol/l?×?h, p?<?0.001, respectively). Furthermore, only the SSPG-3 group had significant changes in both ISR and ICR (p?<?0.001). In the SSPG-2 group, only the ICR was significantly decreased compared with the SSPG-1 group. Therefore, ICR progressively declined during the IST with increasing insulin resistance (SSPG-1, 0.48 [0.41–0.59]; SSPG-2, 0.43 [0.39–0.50]; SSPG-3, 0.34 [0.31–0.40]).

Conclusions/interpretation

While both increases in ISR and decreases in ICR compensate for insulin resistance, decreases in ICR may provide the first adaptation to decreased insulin sensitivity.