Visceral fat and insulin resistance as predictors of non-alcoholic steatohepatitis

AIM： To examine whether visceral fat is associated with non-alcoholic steatohepatitis （NASH）, to assess for parameters associated with visceral adiposity and to investigate for factors associated with fibrotic severity in NASH. METHODS： Thirty NASH and 30 control subjects underwent biochemical tests, anthropometric assessment, bioelectrical impedance, dual energy X-ray absorptiometry and abdominal fat study by CT scan. Liver biopsies were graded according to the Brunt criteria. RESULTS： NASH subjects had elevated blood pressure, body mass index, waist circumference and waist-to-hip ratio. A greater number of diabetes rnellitus, impaired glucose tolerance test and HOMA-IR 〉 3.5 were found in NASH patients. HOMA-IR 〉 2.8 （OR 20.98, 95% CI 3.22-136.62; P 〈 0.001） and visceral fat area 〉 158 cm^2 （OR 18.55, 95% CI 1.60-214.67; P = 0.019） were independent predictors for NASH. Advanced stage of NASH was found in 15 （50%） patients. HOMA-IR 〉 3.5 （OR 23.12, 95% CI 2.00-266.23; P = 0.012） and grading of portal inflammation （OR 7.15, 95% CI 1.63-31.20; P = 0.009） were determined as independent risk factors for advanced stage of NASH. CONCLUSION： Obesity （especially central obesity） and metabolic syndrome are common in Thai NASH. Insulin resistance and elevated visceral fat are risk factors for the presence of NASH. The advanced stage of thedisease is related to insulin resistance.     

The influence of dietary fat on insulin resistance

Dietary fat has been implicated in the development of insulin resistance in both animals and humans. Most, although not all, studies suggest that higher levels of total fat in the diet result in greater whole-body insulin resistance. Although, in practice, obesity may complicate the relationship between fat intake and insulin resistance, clinical trials demonstrate that high levels of dietary fat can impair insulin sensitivity independent of body weight changes. In addition, it appears that different types of fat have different effects on insulin action. Saturated and certain monounsaturated fats have been implicated in causing insulin resistance, whereas polyunsaturated and omega-3 fatty acids largely do not appear to have adverse effects on insulin action. Given the importance of insulin resistance in the development of diabetes and heart disease, establishing appropriate levels of fat in the diet is an important clinical goal.     

Impaired beta-cell function in human aging: response to nicotinic acid-induced insulin resistance

CONTEXT: Glucose tolerance declines with age and may involve impaired beta-cell sensitivity to glucose and beta-cell compensation for insulin resistance. OBJECTIVE: We investigated beta-cell sensitivity to glucose and beta-cell compensation for nicotinic acid-induced insulin resistance in young (age <35 yr) people with normal glucose tolerance (NGT) and old (age >60 yr) people with NGT and impaired glucose tolerance (IGT). DESIGN/PATIENTS/SETTING/INTERVENTION: Fifteen young NGT, 16 old NGT, and 14 old IGT were randomized to 2-wk treatment with nicotinic acid or placebo in a double-blind, crossover study in a university medical setting. At the end of each treatment period, participants had a frequently sampled iv glucose tolerance test and ramp clamp, in which insulin secretion rates (ISR) were determined in response to a matched 5-10 mm glucose stimulus. MAIN OUTCOME MEASURES: Insulin sensitivity (S(I)), acute insulin response to iv glucose (AIRg), and disposition index (AIRg x S(I), or beta-cell compensation for insulin resistance) from frequently sampled iv glucose tolerance testing, and ISR area under the curve (or beta-cell sensitivity to glucose) from ramp clamp were determined. RESULTS: Progressive impairments in insulin secretion as assessed by AIRg, disposition index, and ISR area under the curve were identified in older people with NGT, with more marked defects in older people with IGT. Nicotinic acid treatment significantly reduced S(I) in all groups. beta-Cell compensation for nicotinic acid-induced insulin resistance was incomplete in all three groups, with greater defects in the two older groups. CONCLUSIONS: Human aging is associated with impaired beta-cell sensitivity to glucose and impaired beta-cell compensation to insulin resistance.     

Pathogenesis of age-related glucose intolerance in man: insulin resistance and decreased beta-cell function

To identify the pathogenic factors responsible for glucose intolerance of aging, we measured a variety of metabolic parameters, including insulin sensitivity and islet cell function, in 10 young (18-36 yr old) and 10 older (57-82 yr old) men of normal body weight. Subject groups had equivalent fasting plasma glucose and fat cell size values. Frequently sampled iv glucose tolerance tests were performed, and the data were analyzed by computer using the minimal model approach. This technique yields the following measures: SI, the insulin sensitivity index; phi 1 and phi 2, indices of first and second phase beta-cell responsiveness to glucose; n, fractional insulin clearance, and SG, a measure of dynamic glucose disappearance dependent on glucose per se. We also evaluated beta-cell responsiveness independently by measuring the plasma insulin response to arginine injections at three levels of glycemia and calculated potentiation slope from the relationship between the acute insulin response to arginine and the prestimulus glucose level. The older men were glucose intolerant (glucose disappearance rate, 1.32% min-1) compared to the younger men (glucose disappearance rate, 2.21% min-1; P less than 0.01). This intolerance was the result of both a beta-cell defect and insulin resistance. The potentiation slope (r = -0.67; P less than 0.02) and phi 2 (r = -0.47; P less than 0.05) both decreased with age. In addition, SI in the older group was diminished 63% (2.4 vs. 6.5; 10(-4) min-1/microU/ml; P less than 0.001) and was unrelated to differences in body fat. No differences were found in either n or SG. These studies suggest that the diminished glucose tolerance of aging in normal weight men has multifactorial causality. Both beta-cell dysfunction and insulin resistance are important. In contrast, we found little evidence for changes in insulin clearance or insulin-independent glucose disappearance contributing to age-related glucose intolerance.     

Visceral fat accumulation and insulin resistance are important factors in nonalcoholic fatty liver disease

Background Nonalcoholic fatty liver diseases are often associated with obesity, insulin resistance, and excessive visceral fat accumulation. The aims of this study were (1) to evaluate the relationship between the severity of fatty liver and visceral fat accumulation in nonalcoholic fatty liver diseases, and (2) to investigate the relationships of fatty liver with biochemical data and insulin resistance. Methods One hundred twenty-nine subjects (63 women) with fatty liver diagnosed by ultrasonography were enrolled. Subjects positive for hepatitis B virus, hepatitis C virus, or autoimmune antibodies and those whose alcohol intake was over 20 g/day were excluded. The visceral fat area at the umbilical level and the liver–spleen ratio were evaluated by computed tomography. Results The severity of fatty liver evaluated by ultrasonography showed a significant positive relationship with the visceral fat area and waist circumstance (fatty liver severity: mild, 92.0 ± 30.9 cm²; moderate, 122.1 ± 32.6 cm²; severe, 161.0 ± 48.4 cm²; P < 0.0001). The visceral fat area and liver–spleen ratio were negatively correlated (r = −0.605, P < 0.0001). The severity of fatty liver showed strong positive relationships with serum aspartate aminotransferase, alanine aminotransferase, fasting plasma glucose, fasting plasma insulin, and insulin resistance. The severity of fatty liver was positively related to the visceral fat area in 49 nonobese subjects (body mass index <25). Conclusions The severity of fatty liver was positively correlated with visceral fat accumulation and insulin resistance in both obese and nonobese subjects, suggesting that hepatic fat infiltration in nonalcoholic fatty liver disease may be influenced by visceral fat accumulation regardless of body mass index.     

Comparison between beta-cell function and insulin resistance indexes in prepubertal and pubertal obese children

Several methods have been developed to assess insulin resistance (IR), insulin secretion, and sensitivity: some of them, such as the homeostasis model assessment (HOMA) for IR (HOMA IR) and for insulin secretion (HOMA beta cell) and the quantitative insulin sensitivity check index (QUICKI) are based on fasting levels of glucose (fasting G) and insulin (fasting I); others, such as the pancreatic insulin response to glucose (IRG) and the insulin sensitivity index (ISI) are derived from the glycemic and insulinemic responses to the oral glucose tolerance test (OGTT). The aim of the study was to compare these indexes in a large group of prepubertal and pubertal obese subjects and verify whether the data from fasting samples were enough for evaluating IR and insulin secretion or if OGTT was mandatory. A total of 405 obese subjects (221 boys and 184 girls) was studied. Ninty-three were prepubertal (Tanner stage I), 98 early pubertal (stage II to III) and 214 late pubertal (stage IV to V). In each subject, a 120-minute OGTT was performed, and the glycemic (mean blood glucose [MBG]) and insulinemic (mean serum insulin [MSI]) responses, expressed as AUC/120, as well as IRG and ISI were calculated. The fasting I/fasting G ratio (FIGR), HOMA IR, HOMA beta cell, and QUICKI were then measured. FIGR and HOMA IR increased in both sexes during puberty, but in girls, the increase was already evident from stage I to stage II to III, while in boys, it was evident only from stage II to III to stage IV to V. QUICKI decreased in girls at the onset of puberty and was lower than in boys in stage II to III; on the other hand, HOMA beta cell did not show any variation. IRG increased throughout puberty, although it was higher in boys than in girls in stages II to III and IV to V, while ISI decreased at the onset of puberty in boys; HOMA IR correlated with MSI and IRG, and HOMA beta cell with MSI in pubertal subjects only. In conclusion, the indexes deriving from fasting samples, such as FIGR and HOMA IR, proved to be enough for evaluating IR in prepubertal and pubertal obese subjects, as did QUICKI for insulin sensitivity, However, OGTT is still useful for assessing insulin secretion, because IRG is more sensitive in depicting the pubertal variations of IR than HOMA beta cell.     

伴代谢综合征高血压病患者胰岛素抵抗的简易评估

目的利用“金标准”钳夹技术评价伴代谢综合征(MS)的高血压病人中评价HOMA胰岛素抵抗指数(HOMAIR)、Cederholm胰岛素敏感指数(ISIced)、Defronzo胰岛素敏感指数(ISIcom)等的相关性和适用性。方法根据口服75g葡萄糖耐量试验(OGTT)结果在MS高血压病人群中分成正常糖耐量组(224例)、空腹血糖受损组(11例)和糖耐量异常组(228例)。均用胰岛素敏感指数(ΔI30/ΔG30)及新的细胞功能指数(MBCI)分析其在MS高血压病人群的适用性。结果(1)在MS高血压病人中ISIced,ISIcom与钳夹技术相关,相关系数分别为063和078(P=00001),而HOMAIR与钳夹技术不相关(P>005)。(2)单纯高血压病组除了血压外,其余各项指标均与正常人组差异无统计学意义(P>005);而MS高血压病组胰岛素敏感性及β细胞功能明显差于正常人组及单纯高血压病组患者。(3)MS高血压病组中,钳夹技术判定胰岛素抵抗为6910%,以ISIced为标准有7637%存在胰岛素抵抗,以ISIcom为标准有5213%。结论利用OGTT资料得到的ISIced和ISIcom适用于MS高血压病人群中评价胰岛素抵抗,并且ISIced更优越于ISIcom,而HOMAIR不适用于这部分人群。MS高血压病正常糖耐量人群相对于单纯高血压病人群β细胞功能呈代偿性高胰岛素分泌状态。MS高血压病人群糖负荷后胰岛素分泌高峰延迟,MBCI更适合评     

Crucial role of insulin receptor substrate-2 in compensatory beta-cell hyperplasia in response to high fat diet-induced insulin resistance

In type 2 diabetes, there is a defect in the regulation of functional beta-cell mass to overcome high-fat (HF) diet-induced insulin resistance. Many signals and pathways have been implicated in beta-cell function, proliferation and apoptosis. The co-ordinated regulation of functional beta-cell mass by insulin signalling and glucose metabolism under HF diet-induced insulin-resistant conditions is discussed in this article. Insulin receptor substrate (IRS)-2 is one of the two major substrates for the insulin signalling. Interestingly, IRS-2 is involved in the regulation of beta-cell proliferation, as has been demonstrated using knockout mice models. On the other hand, in an animal model for human type 2 diabetes with impaired insulin secretion because of insufficiency of glucose metabolism, decreased beta-cell proliferation was observed in mice with beta-cell-specific glucokinase haploinsufficiency (Gck(+/) (-)) fed a HF diet without upregulation of IRS-2 in beta-cells, which was reversed by overexpression of IRS-2 in beta-cells. As to the mechanism underlying the upregulation of IRS-2 in beta-cells, glucose metabolism plays an important role independently of insulin, and phosphorylation of cAMP response element-binding protein triggered by calcium-dependent signalling is the critical pathway. Downstream from insulin signalling via IRS-2 in beta-cells, a reduction in FoxO1 nuclear exclusion contributes to the insufficient proliferative response of beta-cells to insulin resistance. These findings suggest that IRS-2 is critical for beta-cell hyperplasia in response to HF diet-induced insulin resistance.     

Insulin resistance and beta-cell function in different ethnic groups in Kenya: the role of abdominal fat distribution

Little is known about the pathophysiology of diabetes in Africans. Thus, we assessed whether insulin resistance and beta-cell function differed by ethnicity in Kenya and whether differences were modified by abdominal fat distribution. A cross-sectional study in 1,087 rural Luo (n = 361), Kamba (n = 378), and Maasai (n = 348) was conducted. All participants had a standard 75-g oral glucose tolerance test (OGTT). Venous blood samples were collected at 0, 30, and 120 min. Serum insulin was analysed at 0 and 30 min. From the OGTT, we assessed the homoeostasis model assessment of insulin resistance by computer model, early phase insulin secretion, and disposition index (DI) dividing insulin secretion by insulin resistance. Abdominal subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) thickness were carried out by ultrasonography. Linear regression analyses were done to assess ethnic differences in insulin indices. The Maasai had 32 and 17 % higher insulin resistance than the Luo and Kamba, respectively (p < 0.001). Early phase insulin secretion was 16 % higher in the Maasai compared to the Luo (p < 0.001). DI was 12 % (p = 0.002) and 10 % (p = 0.015) lower in the Maasai compared to the Luo and Kamba, respectively. Adjustments of SAT (range 0.1–7.1 cm) and VAT (range 1.5–14.2 cm) largely explained these inter-group differences with the Maasai having the highest combined abdominal fat accumulation. The Maasai had the highest insulin resistance and secretion, but the lowest relative beta-cell function compared to the Luo and Kamba. These differences were primarily explained by abdominal fat distribution.     

Short-term exercise improves beta-cell function and insulin resistance in older people with impaired glucose tolerance

BACKGROUND: There is a high prevalence of diabetes and impaired glucose tolerance (IGT) in the older population. Normal aging is associated with insulin resistance and impaired insulin secretion, with greater defects in people with IGT. Short-term exercise has been found to increase insulin sensitivity, but little is known about acute exercise effects on beta-cell function in older people with IGT. METHODS: We assessed the effects of 7 consecutive days of supervised aerobic exercise (1 h/d at 60-70% heart rate reserve) in 12 sedentary older people with IGT. Screening included oral glucose tolerance test, stress/maximal O(2) uptake test, and dual-energy x-ray absorptiometry scan. Participants had a frequently sampled iv glucose tolerance test at baseline and 15-20 h after the seventh exercise session. Insulin sensitivity (S(I)), glucose disappearance constant (Kg, a measure of iv glucose tolerance), acute insulin response to glucose (AIRg), and disposition index (AIRg x S(I)), a measure of beta-cell function in relation to insulin resistance, were calculated. RESULTS: Exercise was well tolerated. Body weight, fasting glucose, fasting insulin, and iv glucose tolerance were unchanged with exercise. S(I) increased by 59%, AIRg decreased by 12%, and disposition index increased by 31%. There was no significant change in fasting lipid, catecholamine, leptin, or adiponectin levels. CONCLUSIONS: Short-term exercise not only improved insulin resistance but also significantly enhanced beta-cell function in older people with IGT. These effects of short-term exercise on beta-cell function cannot be explained by changes in body weight or circulating levels of lipids, leptin, adiponectin, or catecholamines.     

Association between smoking, insulin resistance and beta-cell function in a North-western First Nation.

AIMS: Aboriginal peoples have a high prevalence of smoking and are at major risk for diabetes. The role of insulin resistance vs. compromised beta-cell function in the link between smoking and glycaemic disease is not clear. This study tested whether relations between insulin resistance and beta-cell function differ between current smokers, former smokers and non-smokers, and if having diabetes modifies smoking-related effects. METHODS: A community-based diabetes screening initiative was mounted for a North-western First Nation (Interior Salishan) in rural British Columbia, Canada. Respondents were on-reserve Aboriginal people (n=156), all adults 18+ years. Glycaemic status was determined by oral glucose tolerance test. Fasting values for glucose and insulin were used to estimate beta-cell function and insulin resistance by homeostasis model assessment (HOMA). Analyses adjusted for age, sex, alcohol intake, education, body mass index and physical activity. RESULTS: For normoglycaemic persons (n=119) current smokers relative to non-smokers had high beta-cell values [difference (95% confidence interval) 19.5 (17.1, 21.9)], while former smokers had low beta-cell values [difference -22.8 (-20.3, -25.3)] (P<0.0001). For diabetic persons (n=37) differences were of equivalent direction but greater magnitude (P<0.0001). Insulin resistance was for normoglycaemic persons highest for current smokers, and for diabetic persons lowest for current smokers (P=0.021). CONCLUSIONS: Former smoking is associated with low beta-cell function, and current smoking with high beta-cell function, independent of diabetes in the North-western First Nation surveyed. Associations between smoking and insulin resistance vary according to glycaemic status. Smoking may have diametric acute and post-cessation effects on beta-cell function and insulin resistance.     

Ectopic fat and insulin resistance

Ectopic fat is defined by the deposition of triglycerides within cells of non-adipose tissue that normally contain only small amounts of fat. Over the past decade, magnetic resonance spectroscopy has been used extensively for noninvasive quantification of intramyocellular, intrahepatocellular, and more recently myocardial and pancreatic lipids. In liver and muscle, triglyceride content usually correlates with whole-body and tissue-specific insulin sensitivity. However, fat mass and oxidative capacity influence this relationship, indicating that ectopic lipid content is not the only factor that explains insulin resistance. Ectopic lipids may rather serve as biomarkers of the balance between metabolic supply and demand in different states of insulin sensitivity. Consequently, ectopic lipid concentrations, particularly in the liver, decrease with lifestyle- or drug-induced improvement of insulin sensitivity.     

Early hypertension is associated with reduced regional cardiac function, insulin resistance, epicardial, and visceral fat

Mild-to-moderate hypertension is often associated with insulin resistance and visceral adiposity. Whether these metabolic abnormalities have an independent impact on regional cardiac function is not known. The goal of this study was to investigate the effects of increased blood pressure, insulin resistance, and ectopic fat accumulation on the changes in peak systolic circumferential strain. Thirty-five male subjects (age: 47+/-1 years; body mass index: 28.4+/-0.6 kg m(-2); mean+/-SEM) included 13 with normal blood pressure (BP: 113+/-5/67+/-2 mm Hg), 13 with prehypertension (BP: 130+/-1/76+/-2 mm Hg), and 9 newly diagnosed with essential hypertension (BP: 150+/-2/94+/-2 mm Hg) who underwent cardiac magnetic resonance tissue tagging (MRI) and MRI quantitation of abdominal visceral and epicardial fat. Glucose tolerance, on oral glucose tolerance test, and insulin resistance were assessed along with the serum lipid profile. All of the subjects had normal glucose tolerance, left- and right-ventricular volumes, and ejection fraction. Across the BP groups, left ventricular mass tended to increase, and circumferential shortening was progressively reduced at basal, midheart, and apical segments (on average, from -17.0+/-0.5% in normal blood pressure to -15.2+/-0.7% in prehypertension to -13.6+/-0.8% in those newly diagnosed with essential hypertension; P=0.004). Reduced circumferential strain was significantly associated with raised BP independent of age (r=0.41; P=0.01) and with epicardial and visceral fat, serum triglycerides, and insulin resistance independent of age and BP. In conclusion, regional left ventricular function is already reduced at the early stages of hypertension despite the normal global cardiac function. Insulin resistance, dyslipidemia, and ectopic fat accumulation are associated with reduced regional systolic function.     

Visceral fat and beta cell function in non-diabetic humans

Aims/hypothesis Preferential visceral adipose tissue (VAT) accumulation has been clearly associated with insulin resistance. In contrast, the impact of visceral obesity on beta cell function is controversial.Methods In 62 non-diabetic women and men (age 24–69 years, BMI 21–39 kg/m²), we measured VAT and subcutaneous adipose tissue (SAT) fat mass by magnetic resonance imaging. We also measured insulin secretion and beta cell function by C-peptide deconvolution and physiological modelling of data from a frequently sampled, 75-g, 3-h OGTT, respectively.Results VAT (range 0.1–3.1 kg) was strongly related to sex, age and BMI; SAT was related to sex and BMI. Controlling for sex, age, BMI and SAT by multivariate analysis, excess VAT was associated with a clinical phenotype comprising higher plasma glucose levels, BP, heart rate and serum transaminases. The corresponding metabolic phenotype consisted of insulin resistance (partial r=–0.38) and hyperinsulinaemia (partial r=0.29). The latter, however, was appropriate for the degree of insulin resistance regardless of obesity and abdominal fat distribution. Moreover, none of the model-derived parameters describing beta cell function (glucose sensitivity, rate sensitivity and potentiation) was independently associated with excess VAT.Conclusions/interpretation In non-diabetic Caucasian adults of either sex, preferential visceral fat deposition in itself is part of an insulin-resistant phenotype. The insulin secretory response to a physiological challenge is increased to fully compensate for the insulin resistance, but the dynamics of beta cell function (glucose sensitivity, rate sensitivity and potentiation) are largely preserved.     

2型糖尿病病人的内脏脂肪性肥胖和胰岛素抵抗

目的 探讨2型糖尿病病人内脏型肥胖和胰岛素抵抗的关系。方法 对50例2型糖尿病病人进行内脏脂肪测定,采用CT影像学检查方法;胰岛素抵抗采用高胰岛素—正血糖钳夹试验,得出葡萄糖利用率。根据有无内脏型肥胖将病人分为内脏肥胖组和非内脏肥胖组。结果 (1)内脏肥胖组的内脏脂肪平均值为127.28cm~2,非内脏肥胖组为70.41cm~2;内脏肥胖组比非肥胖型组有更高的甘油三酯水平和收缩压;内脏肥胖组的葡萄糖利用率平均值为3.54mg/(kg·min),非内脏肥胖组的平均值为9.66mg/(kg·min),二组差异有显著意义。(2)内脏脂肪和皮下脂肪与2型糖尿病病人胰岛素介导的葡萄糖利用率显著相关,内脏脂肪是胰岛素抵抗的影响的最强指数,即使与年龄、性别及体重指数校正以后也不影响结果。结论 内脏脂肪肥胖和心血管危险因子密切相关,是2型糖尿病胰岛素抵抗的独立影响因子。     

Targeting insulin resistance and beta-cell dysfunction: the role of thiazolidinediones

Insulin resistance and beta-cell dysfunction are fundamental defects that contribute to the development of type 2 diabetes, and as such are targets for primary prevention of disease progression. The two parameters are linked by several factors, including glucotoxicity and lipotoxicity, and recent research has enlightened understanding of the molecular mechanisms underlying the development and progression of the disease. Historically, type 2 diabetes has been managed by controlling hyperglycemia, using agents that increase insulin levels or reduce hepatic glucose production, as exemplified by the United Kingdom Prospective Diabetes Study. The thiazolidinediones control hyperglycemia by targeting the fundamental defects of the disease, and have shown well-documented improvements in insulin sensitivity and beta-cell function, both in monotherapy and in combination with other oral antidiabetic agents. TRoglitazone In the Prevention Of Diabetes (TRIPOD) has demonstrated the potential for thiazolidinediones to delay progression to type 2 diabetes. Prospective studies such as Diabetes REduction Approaches with ramipril and rosiglitazone Medications (DREAM) are currently evaluating the long-term effects of thiazolidinediones on metabolic status and disease progression.