肝源性糖尿病发病机制研究进展*

肝源性糖尿病是继发于慢性肝功能损伤后发生的糖尿病。近年来,多项研究表明胰岛素抵抗与肝源性糖尿病之间的关系密切,但肝源性糖尿病的发病机制尚未完全阐明,了解肝源性糖尿病发病机制有助于提高临床对肝源性糖尿病的认识和防治水平。本文阐述了胰岛素分泌与代谢障碍、肝炎病毒感染、肝纤维化和肝硬化引起的肝脏损害、血清胰岛素样生长因子-1、肿瘤坏死因子-α和游离脂肪酸等体液因子代谢紊乱、瘦素和脂联素等脂肪细胞因子的影响以及其他方面的最新研究发现。     

肝源性糖尿病发病机制的最新进展

肝源性糖尿病(HD)是终末期肝病的常见并发症,对患者预后的不良影响已得到大量研究证实。近十年国内外对HD的发病机制进行了大量研究,取得了一些进展。系统综述了HD的发病机制研究进展,为临床医生的诊断与治疗HD提供参考。     

Clinical implications of hepatogenous diabetes in liver cirrhosis

BACKGROUND: Hepatogenous diabetes is a common complication of liver cirrhosis. The aim of the present study was to examine the clinical and therapeutic implications and the prognostic significance of hepatogenous diabetes in patients with liver cirrhosis. METHODS: The prospective cohort study was conducted in 52 patients with histologically confirmed liver cirrhosis (44% Child A, 37% Child B, 19% Child C). The examination included a history, determination of basal C-peptide and glycosylated hemoglobin (HbA(1c)) and, in some cases, a 3 h oral glucose tolerance test with 100 g glucose. Patients were also examined for signs of diabetic retinopathy and information on the further course of illness was obtained. RESULTS: Seventy-one percent of patients with liver cirrhosis had manifest diabetes, 25% had impaired glucose tolerance and only 4% had normal glucose tolerance. In most cases, the hepatogenous diabetes was clinically asymptomatic. Sixteen percent of patients with hepatogenous diabetes had a family history of diabetes; only 8% had retinopathic complications. Within 5.6 +/- 4.5 years after diagnosis of liver cirrhosis, 52% of the diabetics had died, mainly of complications of the cirrhosis. There were no diabetes-associated or cardiovascular deaths. CONCLUSIONS: Hepatogenous diabetes differs from type 2 diabetes in that there is less often a positive family history and that the cardiovascular and retinopathic risk is low. The prognosis of cirrhotic patients with diabetes is more likely to be negatively affected by the underlying hepatic disease and its complications than by the diabetes. Antihyperglycemic treatment of hepatogenous diabetes should always be carefully weighed up in each individual case.     

Increased insulin sensitivity is associated with reduced insulin and glucagon secretion and increased insulin clearance in man

Insulin secretion is increased in insulin resistance. In this study, we examined whether high insulin sensitivity results in low insulin secretion. Twelve male master athletes [age 25.6 +/- 4.1 (mean +/- SD) yr] and seven male sedentary students (age 25.0 +/- 2.0 yr) underwent a hyperinsulinemic, euglycemic clamp and a glucose-dependent arginine stimulation test. Athletes had high insulin sensitivity [230 +/- 18 vs. 92 +/- 12 (nmol glucose/kg.min)/(pmol insulin/liter), P < 0.001] and low insulin response to arginine (at fasting glucose 135 +/- 22 vs. 394 +/- 60 pmol/liter, P < 0.001), which resulted in unaltered disposition index (32.8 +/- 3.8 vs. 33.5 +/- 3.3 micro mol glucose/kg.min, NS). Also, the C-peptide response to arginine was reduced (at fasting glucose 0.71 +/- 0.09 vs. 0.89 +/- 0.09 nmol/liter, P = 0.034). However, the C-peptide reduction was not as large as the insulin reduction yielding increased disposition index in athletes when calculated from C-peptide data (184 +/- 9 vs. 76 +/- 11 micro mol glucose/kg.min, P < 0.001). This difference is explained by increased insulin clearance among the athletes during the first 5 min after arginine (81.1% +/- 1.8% vs. 53.6% +/- 4.7%, P < 0.001). Also, the glucagon response to arginine was reduced in the athletes (58.8 +/- 6.7 vs. 90.1 +/- 9.9 ng/liter at fasting glucose, P = 0.009). We conclude that high insulin sensitivity results in low islet hormone secretion and increased insulin clearance.     

Failure to adequately adapt reduced insulin sensitivity with increased insulin secretion in women with impaired glucose tolerance

Summary To study the islet adaptation to reduced insulin sensitivity in normal and glucose intolerant post-menopausal women, we performed a euglycaemic, hyperinsulinaemic clamp in 108 randomly selected women, aged 58–59 years. Of the 20 women with the lowest insulin sensitivity, 11 had impaired glucose tolerance (IGT) whereas 9 had normal glucose tolerance (NGT). These women together with 15 women with medium insulin sensitivity and 16 women with high insulin sensitivity and NGT were further examined with arginine stimulation at three glucose levels (fasting, 14 and >25 mmol/l). In NGT, the acute insulin response (AIR) to 5 g i. v. arginine at all three glucose levels and the slope_AIR, i. e. the glucose potentiation of insulin secretion, were markedly increased in the women with the lowest insulin sensitivity and NGT compared to those with medium or high insulin sensitivity. In contrast, in low insulin sensitivity, AIR was significantly lower in IGT than in NGT (at glucose 14 mmol/l p=0.015, and at >25 mmol/l p=0.048). The potentiation of AIR induced by low insulin sensitivity in women with NGT was reduced by 74% (AIR at 14 mmol/l glucose) and 57% (AIR at >25 mmol/l glucose), respectively, in women with IGT. Also the slope_AIR was lower in IGT than in NGT (p=0.025); the increase in slope_AIR due to low insulin sensitivity was abolished in IGT. In contrast, glucagon secretion was not different between women with IGT as opposed to NGT. We conclude that as long as there is an adequate beta-cell adaptation to low insulin sensitivity with increased insulin secretory capacity and glucose potentiation of insulin secretion, NGT persists.Abbreviations NIDDM Non-insulin-dependent diabetes mellitus - AIR acute insulin response - AGR acute glucagon response     

Insulin secretion, insulin sensitivity and diabetes in black children.

Historically, type 2 diabetes has been considered rare in the pediatric population. However, over the last decade, there has been a disturbing upswing in the rate of non-type 1 diabetes in the pediatric age group, particularly adolescents, with a greater proportion of Black children being affected. In this review, the following questions will be addressed: (1) what are the clinical characteristics of youth-onset atypical diabetes, (2) how common is it, (3) what are the risk factors, and (4) how should it be treated?     

肝硬化伴肝源性糖尿病临床分析

目的分析肝硬化伴肝源性糖尿病的临床特征。方法回顾性分析45例肝硬化伴肝源性糖尿病患者的临床资料。结果 45例患者中,乙型肝炎肝硬化31例（68.9%）;空腹血糖7.3±2.9mmol/L,餐后2h血糖16.2±4.7mmol/L,空腹血糖水平与Child-Pugh分级呈正相关（Spearman等级相关系数rs=0.48,P〈0.01）;通过饮食控制、口服α葡萄糖苷酶抑制剂或皮下注射胰岛素,大部分患者血糖控制在正常水平或接近正常水平;7例死亡病例均死于肝硬化并发症。结论肝硬化伴肝源性糖尿病患者的糖尿病症状多不典型,以餐后高血糖为特征,血糖水平与肝功能的损害程度密切相关,应用胰岛素治疗效果较好,不良预后主要与肝硬化相关。     

Contribution of insulin deficiency and insulin resistance to the development of type 2 diabetes: nature of early stage diabetes

At the time of diagnosis of type 2 diabetes (T2D), patients already have varying degrees of beta-cell dysfunction and insulin resistance and the defects continue to deteriorate despite treatment. We examined insulin secretion impairment and insulin resistance in overweight patients with T2D who had metformin failure, with elevated HbA1c at maximal metformin dose. Patients (N = 1,039) were examined at entry to the European Exenatide (EUREXA) clinical trial of add-on exenatide versus sulphonylurea. Mean (±SD) age was 57 ± 10 years, and BMI was 32.4 ± 4.1 kg/m². All patients underwent an oral glucose tolerance test; HOMA-IR, HOMA-B, ?I ₃₀/?G ₃₀, disposition index and pro-insulin/insulin ratio were evaluated in relation to stratified HbA1c levels (≤7.3, >7.3–8.2, >8.2%) and duration of diabetes (<3, ≥3–<6, ≥6 years) using non-parametric analysis of variance. Patients overall had a wide range of impaired insulin secretion (HOMA-B: median 50.4, interquartile range 32.8–78.8) and insulin resistance (HOMA-IR: 4.8, 3.0–7.4). With increasing HbA1c levels, there was a statistically significant decrease in HOMA-B (P < 0.001), ?I ₃₀/?G ₃₀ (P = 0.003) and disposition index (P < 0.001), and increase in pro-insulin/insulin (P < 0.001) and HOMA-IR (P < 0.001). With increasing duration since diabetes diagnosis, there was a significant decrease in HOMA-B (P < 0.001), but no significant trend in HOMA-IR, ?I ₃₀/?G ₃₀, disposition index or pro-insulin/insulin. Metformin failure in these patients was associated with beta-cell dysfunction to a greater extent than insulin resistance. Loss of the first-phase insulin release, indicated by a low ?I ₃₀/?G ₃₀, would indicate that this patient cohort requires add-on therapy that can maintain beta-cell function.     

Adiponectin in relation to insulin sensitivity and insulin secretion in the development of type 2 diabetes: a prospective study in 64-year-old women

Abstract. Fagerberg B, Kellis D, Bergström G, Behre CJ (Sahlgrenska Academy at Gothenburg University, Gothenburg, Sweden). Adiponectin in relation to insulin sensitivity and insulin secretion in the development of type 2 diabetes: a prospective study in 64‐year‐old women. J Intern Med 2011; 269 : 636–643. Objectives. To examine how serum adiponectin levels predict the incidence of type 2 diabetes, from different prediabetic states, in relation to insulin sensitivity and β‐cell function during 5.5 years of follow‐up. Methods. In a population‐based cohort of 64‐year‐old Caucasian women, we assessed glucose tolerance, insulin sensitivity as homeostasis model assessment, insulin secretion as acute insulin response, lifestyle factors and serum concentrations of adiponectin and high‐sensitivity C‐reactive protein. After 5.5 years of follow‐up, 167 women with normal glucose tolerance (NGT) and 174 with impaired glucose tolerance (IGT) at baseline were re‐examined and incidence of diabetes was assessed. Results. A total of 69 new cases of diabetes were detected during follow‐up. Diabetes incidence was independently predicted by low levels of serum adiponectin, insulin resistance and insulin secretion, cigarette smoking, impaired fasting glucose (IFG) and IGT at baseline. Serum adiponectin below 11.54 g L^?1 was associated with an odds ratio of 3.6 (95% confidence interval 1.4–8.6) for future type 2 diabetes. At baseline, a high serum adiponectin concentration correlated positively with high levels of insulin sensitivity and insulin secretion. Women with incident diabetes had lower serum adiponectin levels in the NGT, IFG and IGT groups at baseline compared to those who did not develop diabetes during follow‐up. Conclusions. Low adiponectin concentrations were associated with future diabetes independently of insulin secretion and sensitivity, as well as IGT, IFG, smoking and abdominal obesity.     

The dynamic insulin sensitivity and secretion test--a novel measure of insulin sensitivity

The objective was to validate the methodology for the dynamic insulin sensitivity and secretion test (DISST) and to demonstrate its potential in clinical and research settings. One hundred twenty-three men and women had routine clinical and biochemical measurements, an oral glucose tolerance test, and a DISST. For the DISST, participants were cannulated for blood sampling and bolus administration. Blood samples were drawn at t = 0, 10, 15, 25, and 35 minutes for measurement of glucose, insulin, and C-peptide. A 10-g bolus of intravenous glucose at t = 5 minutes and 1 U of intravenous insulin immediately after the t = 15 minute sample were given. Fifty participants also had a hyperinsulinemic-euglycemic clamp. Relationships between DISST insulin sensitivity (SI) and the clamp, and both DISST SI and secretion and other metabolic variables were measured. A Bland-Altman plot showed little bias in the comparison of DISST with the clamp, with DISST underestimating the glucose clamp by 0.1·10⁻²·mg·L·kg⁻¹·min⁻¹·pmol⁻¹ (90% confidence interval, −0.2 to 0). The correlation between SI as measured by DISST and the clamp was 0.82; the c unit for the receiver operating characteristic curve analysis for the 2 tests was 0.96. Metabolic variables showed significant correlations with DISST SI and the second phase of insulin release. The DISST also appears able to distinguish different insulin secretion patterns in individuals with identical SI values. The DISST is a simple, dynamic test that compares favorably with the clamp in assessing SI and allows simultaneous assessment of insulin secretion. The DISST has the potential to provide even more information about the pathophysiology of diabetes than more complicated tests.     

Effects of bezafibrate on insulin secretion and peripheral insulin sensitivity in hyperlipidemic patients with and without diabetes

Although it has been reported that bezafibrate influences carbohydrate metabolism, this possibility has never been properly evaluated in a controlled clinical trial. In this study we attempted to evaluate the effects of bezafibrate on plasma lipoproteins, glucose tolerance, insulin secretion and peripheral insulin sensitivity in a group of hypertriglyceridemic patients with and without diabetes. Sixteen hyperlipidemic patients (10 males and 6 females) participated in the study. Eight had type IIB and 8 type IV hyperlipoproteinemia; 6 of them also had non-insulin dependent diabetes mellitus. The study was performed according to a double blind, crossover design: after 1 month wash-out period in which patients were on diet alone, they underwent, in a random order, a period of placebo therapy and another period in which they received a single daily dose of a long-acting bezafibrate preparation (400 mg) administered in the evening. Each treatment lasted 2 months. Total plasma and VLDL triglyceride concentrations were consistently reduced by bezafibrate (-46%, P less than 0.001; and -50%, P less than 0.001). Total and VLDL-cholesterol were also reduced by bezafibrate. The effects of bezafibrate on lipoproteins were similar in diabetic and non-diabetic subjects. Bezafibrate treatment did not influence fasting blood glucose concentration, glucose tolerance, peripheral insulin sensitivity or insulin secretion. In conclusion, the results of this controlled trial clearly indicate that bezafibrate can be successfully employed to lower plasma lipid levels in patients with non-insulin dependent diabetes mellitus and hyperlipidemia.     

短期胰岛素泵强化治疗对新诊断2型糖尿病患者胰岛素分泌和敏感性的影响

目的 探讨短期胰岛素泵强化治疗对新诊断2型糖尿病患者胰岛素敏感性和胰岛素分泌功能的影响.方法 选取2006年6月至2007年2月在本院就诊的新诊断2型糖尿病患者10例进行为期2周的胰岛素泵强化治疗,在治疗前和停泵24 h后分别进行两次静脉葡萄糖耐量试验(IVGTT)和高胰岛素-正葡萄糖钳夹试验.结果 (1)在治疗前所有糖尿病患者均缺乏急性胰岛素分泌(AIR),经2周强化治疗使血糖正常后,所有患者AIR均有了不同程度地恢复[(7.63±4.73 vs 0.83±1.96)mU/L,P＜0.01)].AIR恢复较好的患者略为年轻和肥胖.(2)糖耐量正常志愿者平均葡萄糖输注率(GIR)为(8.26±2.48)mg·kg-1·min-1,而初发2型糖尿病患者在胰岛素泵强化治疗前GIR为(2.30±0.81)mg·kg-1·min-1(与正常者比,P＜0.01),胰岛素泵强化治疗后GIR升高到(5.33±1.43)mg·kg-1·min-1(P＜0.01).GIR升高显著的患者腰围和体重指数低、治疗前的平均血糖高.结论 短期胰岛素泵强化治疗使血糖"正常化",同时可改善胰岛细胞功能,提高胰岛素敏感性.     

The role of impaired early insulin secretion in the pathogenesis of Type II diabetes mellitus

Patients with Type II (non-insulin-dependent) diabetes mellitus manifest abnormalities in insulin action and insulin secretion. It is widely accepted that insulin resistance is an early finding, evident before the onset of hyperglycaemia and predictive of the subsequent development of diabetes. Whether abnormalities in insulin secretion also precede and predict diabetes has been debated. However, recent studies clearly indicate that early insulin secretion plays a critical role in maintaining normal glucose homeostasis. Cross-sectional analyses show that acute insulin secretory responses (AIR) to intravenous glucose are lower in subjects with impaired glucose tolerance and those at high risk for developing diabetes. Prospectively, a low AIR predicts the development of diabetes in several populations. In longitudinal studies, AIR declines dramatically as patients progress from normal to impaired glucose tolerance and ultimately to diabetes. Early insulin secretion is important for the rapid and efficient suppression of endogenous glucose production after a meal. Thus, loss of early insulin secretion initially leads to post-prandial hyperglycaemia which, as the disease progresses, worsens to clinical hyperglycaemia. Strategies that enhance early insulin secretion improve glucose tolerance and represent a novel and more physiologic approach to improving glycaemic control in patients with Type II diabetes mellitus. [Diabetologia (2001) 44: 929–945] Received: 27 December 2000 and in revised form: 8 April 2001     

Influence of severe diabetes mellitus early in pregnancy in the rat: effects on insulin sensitivity and insulin secretion in the offspring

Summary We studied the influence of severe diabetes early in pregnancy on insulin sensitivity and insulin secretion in the offspring. Diabetes (blood glucose >20 mmol/l) was induced in female Sprague-Dawley rats before mating. Diabetic dams were insulin treated during the second half of pregnancy (mean blood glucose 10.6 mmol/l). The offspring were reared by foster mothers. Offspring of both sexes were insulin resistant at four and seven months of age as evidenced by normal glucose tolerance after glucose (2 g/kg body weight intraperitoneally) concomitant with higher than normal rises in insulin levels. Regardless of fetal environment the male rats had higher glucose and insulin levels than the female rats. Insulin responses to glucose (27 mmol/l) in vitro in perfused pancreases were not increased by maternal diabetes, male gender or higher age. Conversely responses to 3-isobutyl-1-methylxanthine (1.0 mmol/l) were enhanced by all three conditions. The pancreatic content of insulin was only marginally affected by maternal diabetes. We conclude that severe diabetes during early pregnancy affects glucose homeostasis in the offspring primarily by diminishing insulin sensitivity and that susceptibility to this effect is not sex- or age-dependent.     

Effect of insulin sensitivity on pulsatile insulin secretion

OBJECTIVE: The aim of the study was to determine whether derangements in insulin pulsatility are related to the presence of insulin resistance or whether these changes occur only in non-insulin-dependent diabetes mellitus (NIDDM). DESIGN AND METHODS: The study included 26 obese, 11 NIDDM and 10 control subjects. The obese group was divided into a low insulin (plasma insulin <20 mU/l, OLI, 14 subjects) and a high insulin (OHI, 12 subjects) group. For pulsatility analysis blood was sampled every 2 min for 90 min. Pulsatility analysis was carried out using the PulsDetekt program. The insulin secretion randomness was quantified using interpulse interval deviation (IpID) and approximate entropy (ApEn). ApEn and ApEn normalized by s.d. of the individual insulin time series (nApEn) were calculated. Lower values of ApEn and IpID indicate more regular secretion. Homeostasis model assessment (HOMA) was used to quantify insulin sensitivity. RESULTS: Insulin pulses were significantly less regular in the OHI and the NIDDM groups compared with the control and the OLI groups (control: ApEn 0.54+/-0.16, nApEn 0.69+/-0.19, IpID 2.53+/-0.99; OLI: ApEn 0.64+/-0.12, nApEn 0. 79+/-0.15, IpID 2.92+/-1.09; OHI: ApEn 0.88+/-0.07, nApEn 0.92+/-0. 07, IpID 3.95+/-0.84; NIDDM: ApEn 0.92+/-0.16, nApEn 0.99+/-0.09, IpID 4.41+/-0.53; means +/- s.d.). There was no difference in the pulse regularity between the OHI and the NIDDM groups. CONCLUSIONS: Decrease in insulin sensitivity was correlated with the reduction of insulin secretion regularity. Therefore irregular insulin secretion is related to a reduction in insulin sensitivity, and it is not unique to NIDDM.     

肝源性糖尿病的诊断与治疗

肝源性糖尿病是指继发于肝实质损害的糖尿病,临床表现以高血糖,葡萄糖耐量减低为特征,其发病率与感染的肝炎病毒类型有关.研究表明肝源性糖尿病患者多存在胰岛素抵抗,血清胰岛素样生长因子(IGF-1)降低及生长激素(GH)水平增高.在诊断与治疗方面与2型糖尿病有所不同,要兼顾肝损害和糖尿病两个方面,本文就此方面加以论述.