Nonalcoholic fatty liver disease and diabetes mellitus: pathogenesis and treatment

Nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM) frequently coexist as they share the pathogenic abnormalities of excess adiposity and insulin resistance. Although type 1 diabetes mellitus (T1DM) is due to a relative lack of insulin, an increased prevalence of obesity and insulin resistance in this population means that NAFLD also commonly coexists with this condition. Both T2DM and NAFLD are associated with adverse outcomes of the other; T2DM is a risk factor for progressive liver disease and liver-related death in patients with NAFLD, whereas NAFLD may be a marker of cardiovascular risk and mortality in individuals with T2DM. Nonalcoholic steatohepatitis-a histological subtype of NAFLD characterized by hepatocyte injury and inflammation-is present in approximately 10% of patients with T2DM and is associated with an increased risk for the development of cirrhosis and liver-related death. Current treatment strategies aim to improve insulin resistance via weight loss and exercise, improve insulin sensitivity by the use of insulin-sensitizing agents (for example, pioglitazone) and reduce oxidative stress by the use of antioxidants, such as vitamin E. Pioglitazone and vitamin E supplementation show the most promise in improving hepatic steatosis and inflammation but have not yet been demonstrated to improve fibrosis, and concern remains regarding the toxicity of long-term use of both of these agents.     

Insulin resistance in type 1 diabetes: what is ‘double diabetes’ and what are the risks?

In this review, we explore the concept of ‘double diabetes’, a combination of type 1 diabetes with features of insulin resistance and type 2 diabetes. After considering whether double diabetes is a useful concept, we discuss potential mechanisms of increased insulin resistance in type 1 diabetes before examining the extent to which double diabetes might increase the risk of cardiovascular disease (CVD). We then go on to consider the proposal that weight gain from intensive insulin regimens may be associated with increased CV risk factors in some patients with type 1 diabetes, and explore the complex relationships between weight gain, insulin resistance, glycaemic control and CV outcome. Important comparisons and contrasts between type 1 diabetes and type 2 diabetes are highlighted in terms of hepatic fat, fat partitioning and lipid profile, and how these may differ between type 1 diabetic patients with and without double diabetes. In so doing, we hope this work will stimulate much-needed research in this area and an improvement in clinical practice.     

Non-alcoholic fatty liver disease and type 2 diabetes mellitus: The liver disease of our age?

Non-alcoholic fatty liver disease (NAFLD) is a chronic liver disease that might affect up to one-third of the adult population in industrialised countries. NAFLD incorporates histologically and clinically different non-alcoholic entities; fatty liver (NAFL, steatosis hepatis) and steatohepatitis (NASH-characterised by hepatocyte ballooning and lobular inflammation ± fibrosis) might progress to cirrhosis and rarely to hepatocellular cancer. NAFL increasingly affects children (paediatric prevalence is 4.2%-9.6%). Type 2 diabetes mellitus (T2DM), insulin resistance (IR), obesity, metabolic syndrome and NAFLD are particularly closely related. Increased hepatic lipid storage is an early abnormality in insulin resistant women with a history of gestational diabetes mellitus. The accumulation of triacylglycerols in hepatocytes is predominantly derived from the plasma nonesterified fatty acid pool supplied largely by the adipose tissue. A few NAFLD susceptibility gene variants are associated with progressive liver disease, IR, T2DM and a higher risk for hepatocellular carcinoma. Although not approved, pharmacological approaches might be considered in NASH patients.     

Insulin resistance as a predictor for restenosis after coronary stenting

PURPOSE: The rationale of this study was to determine whether insulin resistance is an independent risk factor for restenosis after coronary stenting. BACKGROUND: Previous studies suggested that hyperinsulinemia may be an important risk factor for ischemic heart disease. Restenosis after coronary stenting is neointimal tissue proliferation and de-novo stenosis is atherosclerosis from the point of view of histology. However, it has not been determined whether insulin resistance is independently related to restenosis after coronary stenting. METHODS: Clinical variables of unselected population of 110 patients were analyzed in multivariate logistic regression analyses for both restenosis and de-novo stenosis. Clinical, lesion-related, and procedural variables were analyzed by chi-square analysis, and relative risk. RESULTS: Multivariate logistic regression analysis showed that homeostasis model assessment insulin resistance (HOMA-IR) and HbA1c were associated with restenosis after coronary stenting (HOMA-IR; P=0.0447, HbA1c; P=0.0462), and HbA1c and low-density lipoprotein cholesterol (LDL-C) were associated with de-novo stenosis (HbA1c; P=0.0201, LDL-C; P=0.0204). Restenosis was influenced by insulin resistance [Relative Risk (RR) 2.06; 95 percent confidence interval (95%CI) 1.20 to 3.56], diabetes mellitus (DM: RR 1.92; 95%CI 1.25 to 2.95), and final minimal lumen diameter (RR 2.83; 95%CI 1.32 to 6.06). CONCLUSIONS: HOMA-IR and DM are the predictors of restenosis after coronary stenting, and HbA1c and LDL-C are the predictors of de-novo stenosis. These results may be reflected in histological differences between neointimal tissue proliferation as restenosis and atherosclerosis as de-novo stenosis.     

182个2型糖尿病家系865人调查分析

目的 建立一个可用于系统研究2型糖尿病的高发家系人群,对2型糖尿病家系的发病情况、临床及生化指标进行分析.方法 按美国糖尿病学会标准,已诊断有糖尿病家族史的糖尿病先证者进行三代家族史和血统成员的调查研究,全部非患者采血做口服葡萄糖耐量试验确认,并对新老患者用免疫学方法,系谱分析和分子生物学方法排除1型糖尿病、青少年发病的成年型糖尿病(MODY)和线粒体遗传阳性家系,最终筛选出具有2个或2个以卜2型糖尿病患者的家系182个(实际调查共865人)并进行分析.全部家系成员均检查血糖、血脂、胰岛素C肽释放试验.结果 受调查的865名成员中2型糖尿病、单纯空腹血糖受损、单纯葡萄糖耐量减退、空腹血糖受损合并葡萄糖耐量减退总患病率为59.88%,2型糖尿病患病率为45.43%.新榆出2型糖尿病患者94例,单纯空腹血糖受损者14例,单纯葡萄糖耐量减退者61例,空腹血糖受损合并葡萄糖耐量减退者27例.先证者父、母、同胞、子女的患病率明显高于普通人群.糖尿病组收缩压、舒张压、总胆固醇、低密度脂蛋白胆固醇、甘油二酯、体重指数、胰岛素抵抗指数明显高于空腹血糖受损和(或)葡萄糖耐量减退组或未发病者.在2型糖尿病发病前的葡萄糖耐量减退阶段,收缩压、舒张压、总胆固醇、低密度脂蛋白胆固醇、甘油三酯、体重指数、胰岛素抵抗指数也高于正常人群.结论 2型糖尿病发病具有明显的家族聚集性,高血压、高血脂、肥胖是2型糖尿病的高危因素,胰岛素抵抗在糖尿病发病前已存在.     

Type 2 diabetes mellitus--current therapies and the emergence of surgical options

Patients with type 2 diabetes mellitus (T2DM) are usually treated with pharmacologic agents in combination with lifestyle modification. The development of new antidiabetic agents, such as insulin analogs and incretin-based therapies, has led to treatment strategies that enable many patients with T2DM to achieve target HbA(1c) levels (≤7.0%). However, many factors-including those related to the patient or the health-care provider, drug inadequacies and adverse effects-can interfere with the ability of some patients to reach metabolic targets. Clinical data from the USA indicate that HbA(1c) concentration, blood pressure and serum levels of lipids in patients with T2DM are progressively decreasing toward the target goals set by the American Diabetes Association. These improvements in metabolic regulation have led to a 30-40% decrease in reported microvascular and macrovascular complications of diabetes mellitus in the USA. Gastric bypass surgery in morbidly obese individuals with T2DM leads to remission of the diabetes mellitus in the majority of patients and improvement in the rest. A major contributor to this improvement is an alteration in gastrointestinal hormone secretions. Interventional surgery might, therefore, be considered a reasonable therapeutic alternative for overweight and obese (BMI <35 kg/m2) patients with T2DM who do not respond to medical therapy.     

芪黄胶囊对2型糖尿病患者胰岛素抵抗及TNF-α影响的临床研究

目的研究芪黄胶囊对2型糖尿病患者胰岛素抵抗(IR)及肿瘤坏死因子-α(TNF-α)的影响,观察芪黄胶囊延缓2型糖尿病及其并发症的疗效和机制。方法气阴两虚型2型糖尿病患者80例,随机分为治疗组(芪黄胶囊+二甲双胍治疗组)和对照组(二甲双胍组)。两组均以2个月为1疗程,治疗前后中医证候疗效判定,观察治疗前后TNF-α、体重指数(BMI)、血脂、糖化血红蛋白(HbA1c)、空腹血糖(FBG)、餐后2h血糖(2hPBG)、空腹胰岛素(FINS),计算胰岛素敏感指数(IAI)、IR指数(HOMA-IR)。结果芪黄胶囊可显著降低气阴两虚型2型糖尿病患者TNF-α水平,改善患者的中医证候,同时具有良好的降糖、降脂作用,增加胰岛素敏感性,改善IR的作用,与对照组比较有统计学意义。结论芪黄胶囊治疗可明显降低气阴两虚型2型糖尿病患者TNF-α水平,增加胰岛素敏感性,改善IR。     

非酒精性脂肪肝血尿酸水平与胰岛素抵抗的相关性

目的:研究非酒精性脂肪肝(non-alcoholic fatty liver,NAFL)患者血尿酸水平及其与胰岛素抵抗程度的相关性.方法:选取单纯NAFL患者40例,NAFL合并2型糖尿病患者(type2diabetes mellitus,T2DM)72例,健康体检者62名为研究对象.测定体重指数(body mass index,BMI),检测空腹血糖(fasting blood glucose,FBG)、尿酸(serum uric acid,SUA)、丙氨酸氨基转移酶(alanine aminotransferase,ALT)、门冬氨酸氨基转移酶(aspartate aminotransferase,AST)、胆固醇(cholesterol,TC)、甘油三酯(triglyceride,TG)、糖化血红蛋白(glycated hemoglobin,HbA1C)、尿微量白蛋白/尿肌酐(Ualb/UCr)等生化指标并行肝脏B超检查.放射免疫法测定空腹胰岛素(fasting insulin,FINS),计算胰岛素抵抗指数(HOMA IR).结果:NAFL合并T2DM组BMI、SUA、ALT、AST、TG、FBG、FINS、HOMA IR、HbA1C、Ualb/UCr、SF均高于对照组;与单纯NAFL比较,NAFL合并T2DM组胰岛素抵抗及SUA水平更重;相关性研究表明FBG、HOMA IR、HbA1C与SUA呈正相关.结论:NAFL患者存在明显的胰岛素抵抗及高血尿酸血症,且两者具有一定的相关性.降低胰岛素抵抗联合纠正尿酸代谢紊乱对防止NAFL的发生发展具有重要的临床意义.     

Adiponectin and sE-selectin concentrations in relation to inflammation in obese type 2 diabetic patients with coronary heart disease

Adipose tissue can release proinflammatory mediators, namely C-reactive protein (CRP), interleukin 1β (IL-1β), and monocyte chemotactic protein 1 (MCP-1), contributing to vascular injury and insulin resistance (IR). Other mediators namely, adiponectin and nitric oxide (NO) are protective. We enrolled type 2 diabetes mellitus (T2DM) obese male patients without coronary heart disease ([CHD] group II, n = 25) and T2DM obese patients with CHD (group III, n = 25). They were compared with 20 age- and body mass index (BMI)-matched nondiabetic control males (group I). Fasting blood glucose (FBG), glycated hemoglobin (HbA(1c)%), lipids, insulin, malondialdehyde ([MDA]; lipid peroxidation product), NO, high-sensitivity CRP (hsCRP), IL-1β, MCP-1, adiponectin as well as sE-selectin concentration were significantly different in patients with T2DM and CHD compared with patients without CHD and nondiabetic controls (P = .01). There was a significant negative correlation between adiponectin and E-selectin (P = .0001). Adipose tissue in T2DM obese patients may contribute to the pathogenesis of CHD.     

Management of diabetes mellitus: is the pump mightier than the pen?

Continuous subcutaneous insulin infusion (CSII, or insulin pump therapy) reduces HbA1c levels and hypoglycaemia in patients with type 1 diabetes mellitus (T1DM) compared with multiple daily insulin injections (MDI). The greatest reduction in HbA(1c) levels with CSII occurs in patients with the worst glycaemic control; therefore, the most appropriate and cost-effective use of CSII in adults with T1DM is in those who have continued, elevated HbA(1c) levels or disabling hypoglycaemic episodes with MDI (including the use of long-acting insulin analogues and structured patient education). The disadvantages of CSII include higher costs than MDI and the risk of ketosis in the event of pump failure. In children with T1DM, CSII may be used when MDI is considered impractical or inappropriate. Pumps are not generally recommended for patients with type 2 diabetes mellitus but may improve control in some subgroups. A new generation of smaller insulin infusion pumps with an integrated cannula, called patch pumps, could improve uptake of CSII in general. The important clinical question is not whether CSII is more efficacious than MDI in general adult T1DM, but whether CSII further improves glycaemic control when this control continues to be poor with MDI, and evidence exists that in most cases it does.     

血糖波动与氧化应激对2型糖尿病微血管病变的影响

目的探讨血糖波动与氧化应激对2型糖尿病微血管病变的关系。方法选择2型糖尿病患者109例,根据尿白蛋白排泄率(UAER)分为3组:正常白蛋白尿组(A组)、微量白蛋白尿组(B组)和大量白蛋白尿组(C组)。健康体检者30例为对照组。糖尿病患者给予胰岛素治疗12周,检测干预前后血压、空腹血糖(FPG)、空腹胰岛素、胰岛素抵抗指数(HOMA-IR)、血脂、糖化血红蛋白(HbA1c)、平均血糖波动幅度(MAGE)、超氧化物歧化酶(SOD)、丙二醛和UAER。结果胰岛素干预后,A组、B组和C组FPG、HbA1c、HOMA-IR、TG较治疗前明显下降(P<0.05);B组和C组SOD较治疗前明显增高,丙二醛、UAER、MAGE较治疗前明显下降(P<0.05,P<0.01)。MAGE与HOMA-IR、UAER、丙二醛呈正相关,与SOD呈负相关(P<0.05,P<0.01);logistic回归分析显示,年龄、病程、收缩压、HbA1c、HOMA-IR、MAGE、丙二醛是导致2型糖尿病患者蛋白尿严重程度的独立危险因素,SOD是保护因素。结论血糖波动与体内氧化应激密切相关,氧化应激参与糖尿病微血管病变的发生、发展。     

Positive association of branched-chain amino acids with triglyceride and glycated haemoglobin in Indian patients with type 2 diabetes mellitus

Background and aimsOver the past few years, branched-chain amino acids (BCAAs) are increasingly being linked to insulin resistance and type 2 diabetes mellitus (T2DM), but their relevance for metabolic dyslipidaemia in T2DM is unclear. This study aims to determine the plasma and urinary BCAAs and their association with insulin resistance, lipid profile and glycated haemoglobin in patients with T2DM among Indian adults.MethodsIn this analytical cross-sectional study, a total of eighty subjects were recruited, 40 T2DM cases and 40 healthy controls. Blood samples collected were subjected to fasting blood sugar (FBS), lipid profile, HbA1c, insulin and BCAAs analysis and urine samples were assessed for BCAAs. All associations were assessed using Spearman Rank Correlation.ResultsThe plasma levels of BCAAs were significantly higher (p < 0.05) in subjects with T2DM than in control subjects. Spearman Rank Correlation analyses revealed a non-significant (p = 0.21) but positive association between BCAAs and homeostasis model assessment of insulin resistance (HOMA-IR) in patients with T2DM (Rho: 0.27). Among lipid profile parameters, only triglycerides had a significant positive correlation to plasma BCAAs in cases (Rho: 0.5971) but not in control subjects. Findings also revealed a significant positive (p < 0.05) association between plasma BCAAs and HbA1c in patients with T2DM (Rho: 0.5325). Urinary BCAAs levels had a non-significant increase in T2DM subjects and did not show any significant correlation with other parameters assessed.ConclusionElevated levels of plasma BCAAs are positively associated with triglyceride and HbA1c. They could serve as an effective marker for the assessment of metabolic dyslipidaemia in subjects with T2DM. Further, large scale studies are needed for confirmation of the same.     

Glucose-lowering treatment and clinical results in 163 121 patients with type 2 diabetes: an observational study from the Swedish national diabetes register

Aims: To analyse clinical characteristics and treatment results in unselected type 2 diabetes mellitus (T2DM) patients, with non‐pharmacological treatment as well as the most commonly used pharmacological glucose‐lowering treatment regimens, in everyday clinical practice. Methods: In this population‐based cross‐sectional study, information was linked from the Swedish National Diabetes Register, Prescribed Drug Register and Patient Register. T2DM patients with non‐pharmacological treatment and T2DM patients continuously using the 12 most common pharmacological treatment regimens were included in the study (n = 163121). Results: There were statistically significant differences in clinical characteristics between the groups. Patients with insulin‐based treatment regimens had the longest duration of diabetes and more cardiovascular risk factors than the T2DM‐population in general. The proportion of patients reaching HbA1c ≤7% varied between 70.1% (metformin) and 25.0% [premixed insulin (PMI) + SU) in patients with pharmacological treatment. 84.8% of the patients with non‐pharmacological treatment reached target. Compared to patients on metformin, patients on other pharmacological treatments had a lower likelihood, with hazard ratios ranging from 0.58; 95% confidence interval (CI), 0.54–0.63 to 0.97;0.94–0.99, of having HbA1c ≤7% (adjusted for covariates). Patients on insulin‐based treatments had the lowest likelihood, while non‐pharmacological treatment was associated with an increased likelihood of having HbA1c ≤7%. Conclusion: This nation‐wide study shows insufficiently reached treatment goals for haemoglobin A1c (HbA1c) in all treatment groups. Patients on insulin‐based treatment regimens had the longest duration of diabetes, more cardiovascular risk factors and the highest proportions of patients not reaching HbA1c target.     

胰升血糖素与肝源性胰岛素抵抗

肝源性IR是T2DM重要发病基础之一,机制主要为受体缺陷及信号转导异常。作为对抗胰岛素的重要激素,胰升血糖素在糖尿病发病中起重要作用。与健康人群比,糖尿病患者或动物存在胰岛素异常分泌,也存在胰升血糖素异常高分泌。胰升血糖素在肝源性IR中的作用主要为抑制肝糖原合成及糖酵解,促进肝糖原分解、糖异生及脂肪分解。     

SNP in microRNA sequences or binding sites of miRNAs: association with type 2 diabetes mellitus susceptibility and in silico analysis

Type 2 diabetes mellitus (T2DM) is characterized with defects in insulin secretion, increased hepatic glucose production, and resistance to the action of insulin. The Iranian population is genetically predisposed to T2DM similar to other Asian populations. Therefore, it is imperative to search the genetic variations in T2DM susceptibility unique to the Iranian population. Three hundred patients with type 2 diabetes mellitus and 300 healthy subjects were selected. Peripheral venous blood samples were collected from all subjects. SNPs of mir-605 and the 3′-UTR of ESR1 gene were genotyped by PCR-RFLP. Also, in silico analysis was performed to evaluate potential effects of two SNPs. A significant association was found between all genotypes of ESR1 and T2DM. The data analysis identified an increased risk of T2DM associated with rs9341070 CT genotype among case subjects in relation to control subjects (p value?=?0.005; OR?=?2.05; 95% CI?=?1.24–3.28). The rs2043556 genotypes in miR-605 were significantly correlated with T2DM and there were correlations between GG genotypes of mir-605 rs2043556 with decreased risk for T2DM (p value?=?0.01; OR?=?0.38; 95% CI?=?0.18–0.80). The rs9341070 CT acted as a non-protective factor to increase the risk of T2DM, while the rs2043556 GG genotype is identified as protective factor in diabetes mellitus type 2. According to bioinformatics analysis, it was predicted that rs9341070 in 3′-UTR of ESR1 gene and rs2043556 in mir-605 possibly participate in the regulation of mature miRNA and mRNA targets.     

Increased insulin requirement may contribute to risk of obesity in children and young people with Type 1 Diabetes Mellitus

IntroductionType 1 diabetes mellitus (T1DM) is an autoimmune disorder that interferes with the function of the beta cells in the pancreas. Reports show that the incidence of T1DM is increasing throughout England and Wales, along with the Body Mass Index (BMI) of this patient group. The association between type 2 diabetes mellitus (T2DM) and obesity is recognised, but literature describing the association between T1DM and high BMI is more limited.The aim of this paper is to identify factors affecting BMI and the impact that this increasing trend has on children and young people with T1DM.MethodsInformation was obtained from the medical records of patients with T1DM at the local paediatric centre. BMI standard deviation scores (SDS) were calculated and compared to other factors, which include insulin requirement, HbA1c, pubertal status and age at diagnosis.ResultsThis study involved 102 patients (43 male and 59 female). The mean age at diagnosis was 7.79 years (range from 0.16 to 16.91 years). Our results showed a significant association between insulin requirement and BMI SDS (r = 0.23, p = 0.02) and a significant association between insulin requirement and mean HbA1c (r = 0.59, p=<0.01). A multivariable regression analysis of factors affecting BMI SDS showed that insulin requirement was an independent factor affecting BMI SDS.ConclusionThere were significant associations between increased insulin requirement, high BMI SDS and poorer glycaemic control. Further research is required to fully understand the risk factors that may contribute to obesity in T1DM.     

Managing diabetes and liver disease association

There is strong association between liver diseases and diabetes (DM) which is higher than expected by a chance association of two very common disorders. It can be classified into three categories: Liver disease related to diabetes, hepatogenous diabetes (HD), and liver disease occurring coincidentally with DM. The criteria for the diagnosis of diabetes associating liver disease are the same for primary diabetes. Two hours post glucose load is a better screening test for HD. HbA1c may not be suitable for diagnosis or monitoring of diabetes associating advanced liver disease. Apart from the increased cardiovascular risk in patients with type 2 DM (T2 DM) and NAFLD, the cardiovascular and retinopathy risk is low in HD. Patients with metabolic derangement should be screened for NAFLD which in turn may predict T2 DM development. Similarly, patients with established T2 DM should also be screened for NAFLD which further contributes to diabetes worsening.Diabetes is a significant risk factor for progression of the chronic liver disease. It is associated with poor patient survival.Treatment of diabetes associating liver disease appears beneficial. Metformin, if tolerated and not contraindicated, is recommended as a first-line therapy for patients with diabetes and chronic liver disease (CLD). If the hepatic disease is severe, insulin secretagogues should be avoided because of the increased risk of hypoglycaemia. Pioglitazone may be useful in patients with fatty liver disease. DPP-4 inhibitors showed effectiveness and safety for the treatment of T2 DM in CLD patients up to those with child B stage. GLP-1 receptor agonists and SGLT-2 inhibitors exhibit positive effects on weight and are associated with minimal risk of hypoglycaemia. Insulin must be used with caution, as hypoglycaemia may be a problem. Insulin analogues are preferred in the context of hypoglycaemiaStatins can be used to treat dyslipidaemia in NAFLD, also the use of angiotensin II receptor antagonist for hypertension is safe and beneficialGiven the clear association between diabetes mellitus and hepatocellular carcinoma, the strict control of glycaemia with insulin sensitizers can be essential in its prevention.The addition of DM to the currently used scores (Child-Pugh and MELD scores) may enhance the sensitivity and the specificity for prediction of morbidity and mortality rates in cirrhotic patients.In the new era of directly acting antiviral agents (DAAs) for HCV treatment, it is recommended to follow up lipid profile and blood sugar levels following SVR in order to adjust doses of medications used in diabetic (SVR is associated with reduction in insulin requirements) and dyslipidaemic patients (rebound increase in the lipid profile after clearing the virus may increase risk of cardiovascular disease (CVD)). The issues of post liver transplant diabetes and relation between DM and chronic HBV are highlighted.This narrative review and Consensus-based practice guidance (under revision and criticism) are based on a formal review and analysis of the recently published world literature on the topic (Medline search up to September 2017); and the experience of the authors and independent reviewers.     

Role of ethnicity in overweight and obese patients with nonalcoholic steatohepatitis

The role of ethnicity in determining disease severity in nonalcoholic steatohepatitis (NASH) remains unclear. We recruited 152 patients with biopsy-proven NASH, 63% of whom were Hispanic and 37% of whom were Caucasian. Both groups were well matched for age, sex, and total body fat. We measured: (1) liver fat by magnetic resonance imaging and spectroscopy; (2) fasting plasma glucose, fasting plasma insulin (FPI), and free fatty acid (FFA) levels; (3) total body fat by dual energy x-ray absorptiometry (DXA); (4) liver and muscle insulin sensitivity (insulin clamp with 3-[(3)H] glucose); (5) insulin resistance at the level of the liver (fasting endogenous glucose production derived from 3-[(3)H] glucose infusion × FPI) and adipose tissue (fasting FFA × FPI). Liver fat was slightly, but not significantly, higher in Hispanic vs. Caucasian patients (27 ± 2% vs. 24 ± 2%, p = 0.16). However, this trend did not translate into worse liver steatosis, necroinflammation or fibrosis. Patients with NASH had severe hepatic, adipose tissue and muscle insulin resistance versus healthy subjects without NASH nonalcoholic fatty liver disease, but there were no differences between both ethnic groups on these parameters. However, Hispanics versus Caucasians with type 2 diabetes mellitus (T2DM) had a trend for worse hepatic/adipose tissue insulin resistance and fibrosis. Conclusion: When Hispanic and Caucasian patients with NASH are well matched for clinical parameters, particularly for adiposity, slightly higher liver fat content is not associated with worse hepatic insulin resistance or more severe NASH on histology. Hispanic ethnicity does not appear to be a major determinant of disease severity in NASH, although those with diabetes may be at greater risk of fibrosis. Given the higher risk of T2DM in Hispanics, long-term studies are needed to define their risk of disease progression.     

Insulin resistance, endocrine function and adipokines in type 2 diabetes patients at different glycaemic levels: potential impact for glucotoxicity in vivo

OBJECTIVE: To evaluate the interplay between hyperglycaemia, insulin resistance, hormones and adipokines in patients with type 2 diabetes mellitus (T2DM). DESIGN AND METHODS: Ten patients with T2DM with good glycaemic control (G), 10 with poor control (P) and 10 nondiabetic control subjects (C) were matched for sex (M/F 6/4), age and body mass index. A hyperinsulinaemic, euglycaemic clamp was performed and cytokines and endocrine functions, including cortisol axis activity were assessed. RESULTS: Patients with diabetes were more insulin resistant than group C, and group P exhibited the highest degree of insulin resistance (P = 0.01, P vs C). Tumour necrosis factor (TNF)-alpha levels were elevated in patients with diabetes (P = 0.05) and group P had the highest levels of fasting serum cortisol (P = 0.05), nonesterified fatty acids (NEFA; P = 0.06) and C-reactive protein (CRP; P = 0.01). Adiponectin levels were lower in the P group. In partial correlation analyses, significant associations were found: glycaemic level (HbA1c) with insulin resistance, TNF-alpha, CRP and basal and ACTH-stimulated cortisol levels, insulin resistance with plasma NEFA, TNF-alpha and stimulated cortisol levels. CONCLUSION: Poor glycaemic control in patients with T2DM was associated with insulin resistance and with elevated TNF-alpha, CRP and basal as well as stimulated cortisol levels. Inflammatory mediators, e.g. TNF-alpha, may contribute to insulin resistance in hyperglycaemic patients with T2DM and this might be a partial explanation for glucotoxicity.