脂联素与肝源性糖尿病

脂联素（adiponectin）是脂肪组织特异分泌的一种血浆激素蛋白，具有胰岛素增敏和拮抗胰岛素抵抗作用。研究证实胰岛素抵抗是肝源性糖尿病发病的主要机制之一。因此，脂联素与肝源性糖尿病的发生机制密切相关。对脂联素予以深入的研究将对胰岛素抵抗和肝源性糖尿病的防治带来积极的影响。现就脂联素与肝源性糖尿病的最新研究进展进行综述。     

胰岛素抵抗与高血压的关系

研究表明胰岛素抵抗与高血压密切相关,胰岛素抵抗是高血压的一个独立危险因子,二者存在理论上的因果关系.胰岛素抵抗在高血压的发病机制中起至关重要的作用,而高血压也可影响胰岛素的代谢,造成胰岛素抵抗,两者相辅相成,导致一系列严重慢性并发症的发生.同时,多种降压药物可通过影响糖代谢从而改善胰岛素抵抗,另一方面,部分改善胰岛素抵抗的药物可用于治疗原发性高血压.因此,了解胰岛素抵抗与高血 压之间的关系对于胰岛素抵抗及高血压的防治有重要意义.     

胰岛素抵抗与认知障碍

近年来一些研究表明，胰岛素抵抗可以通过各种机制改变脑组织的神经生理功能，加速大脑老化的进程，在认知功能障碍的发生发展中起了重要作用。本文就目前有关胰岛素抵抗与认知功能障碍的相关性及作用机制的研究作一综述。     

修正的最小模型在分析胰岛素敏感性和分泌功能中的应用

胰岛素抵抗(即胰岛素敏感性降低)和胰岛β细胞功能衰减在糖尿病发生发展过程中起着重要作用,因此,正确地评价人群的胰岛素敏感性和胰岛β细胞功能在临床工作中越来越受到关注。胰岛素敏感性包括外周胰岛素敏感性(在胰岛素作用下,机体在外周组织摄取和清除葡萄糖的能力)和肝胰岛     

抵抗素与肝脏胰岛素抵抗的关系

抵抗素是一种脂肪细胞因子,研究发现高抵抗素水平可诱导肝脏胰岛素抵抗发生,其机制可能是抑制腺苷酸活化蛋白激酶(AMPK)磷酸化,上调糖异生关键酶PEPCK和G6Pase的表达促进糖异生,从而使肝糖输出增多。肝脏是胰岛素作用的重要靶点,也是机体代谢的关键器官。肝脏胰岛素抵抗时,糖脂代谢紊乱加重机体胰岛素抵抗,促进2型糖尿病的发生。AMPK是物质代谢的关键激酶,通过磷酸化作用调节糖脂代谢相关酶的活性以及调节机体的能量平衡。抵抗素通过AMPK调节肝糖代谢这一观点为探讨抵抗素在胰岛素抵抗中的作用提供了新的思路。     

重视非酒精性脂肪性肝病胰岛素抵抗的防治

胰岛素抵抗广泛存在于非酒精性脂肪性肝病发生、发展的各个环节.胰岛素抵抗的存在不仅影响非酒精性脂肪性肝病的进展,还提高肝细胞对损肝因素的敏感性,影响药物治疗的效果.重视非酒精性脂肪性肝病胰岛素抵抗的诊断和治疗,将有益于改善非酒精性脂肪性肝病的预后,提高药物治疗效果.中医药治疗胰岛素抵抗已经显示了一些特色和优势,在加强患者科学管理,重视生活方式干预的基础上,开展对非酒精性脂肪性肝病胰岛素抵抗证候病机的研究,加强对有效方药的科学评价并积极探索其作用机制,将有助于提高中医药防治胰岛素抵抗的研究水平.     

TSC2在胰岛素抵抗中的作用研究进展

胰岛素抵抗（IR）是一类复杂的异质性病理过程,是指体内周围组织对胰岛素的敏感性降低,即肌肉、脂肪等组织对胰岛素促进葡萄糖摄取产生抵抗作用。其中胰岛素信号转导障碍是IR形成的主要机制,IRS-2／P13K／Akt途径是胰岛素的主要信号通路。近年研究发现,TSC2／mTOR是这条信号路径中一种主要下游通路,在IR的发生与发展中起着重要作用。本文对其研究进展综述如下。     

Obestatin与胰岛素抵抗

脑肠肽obestatin是南ghrelin基因编码,经过翻译后不同剪切和修饰,产生的一种含有23个氨基酸的生物活性肽.研究发现obestatin具有调节食欲、延缓胃排空、抑制体重增加、影响胰岛素分泌、增强β细胞功能等作用,并可能在肥胖、胰岛素抵抗的发生中起重要作用.Obestatin与胰岛素分泌、胰岛素抵抗及其相关疾病的关系及机制目前尚未明确,其可能成为治疗肥胖和糖尿病的新靶点.     

胰岛素抵抗细胞核水平的研究

胰岛素抵抗是非胰岛素依赖型糖尿病和糖耐量减低的一个重要特征。晚近研究证实，在细胞核水平上基因表达控制的改变可以是人类疾病中存在激素抵抗的一种机制。近期研究显示：（１）载脂蛋白Ｃ－Ⅲ启动子变异引起单基因水平上的胰岛素抵抗，胰岛素可调节ａｐｏＣ－Ⅲ基因。通过对其下调节，而起到抑制ａｐｏＣ－Ⅲ基因过度表达作用。（２）ａｐｏＣ－Ⅲ启动子的遗传性变异－－胰岛素反应序列（ＩＲＳ）发生突变，使胰岛素对ａｐｏＣ－     

胰岛素抵抗的炎症机制

研究证明胰岛素抵抗是一个慢性亚临床炎症过程 ,细胞因子肿瘤坏死因子 (TNF)α和白介素 (IL) 6都能减低机体组织细胞对胰岛素的敏感性 ,来自脂肪等组织的细胞因子和炎症敏感蛋白如IL 8、抵抗素、脂联素、C反应蛋白和纤溶酶原激活物抑制剂 (PAI) 1等对胰岛素抵抗的发生也有重要作用。另一方面 ,在胰岛素抵抗时脂肪组织、骨骼肌细胞、肝脏和动脉血管组织都不同程度地增加一些细胞因子的表达 ,这些细胞因子通过内分泌、旁分泌和自分泌机制进一步减低组织细胞对胰岛素的敏感性。通过对胰岛素抵抗炎症机制的认识 ,有助于对这些代谢性疾病的发生和发展进行预测、动态观察和干预治疗。     

A proposed new paradigm for insulin resistance

The perspective presented here is a working hypothesis suggesting a new paradigm for insulin resistance where, analogous to the cause of type 1 diabetes being attributed to lack of insulin, type 2 diabetes is due to lack of action of a hepatic insulin sensitizing substance (HISS). In both cases, the major metabolic dysfunction is with post-meal nutrient processing. In the immediate postprandial state, insulin causes the release of the putative hormone, HISS, from the liver. HISS stimulates glucose uptake in skeletal muscle. The hepatic parasympathetic nerves determine, in a permissive manner, the ability of insulin to cause HISS release maximally in the postprandial state. HISS release in response to insulin is progressively reduced with fasting. The glucose disposal effect of insulin in the fed state is decreased by approximately 55% by blocking HISS release. HISS release is blocked by fasting, surgical parasympathetic denervation of the liver, blockade of hepatic cholinergic muscarinic receptors, blockade of hepatic nitric oxide production, or blockade of hepatic cyclooxygenase, and results in a condition referred to as HISS-dependent insulin resistance (HDIR). HDIR is physiologically and appropriately produced in the fasted state and, pathologically, in chronic liver disease, sucrose fed, fetal alcohol exposed, spontaneously hypertensive, and aging rats. Therapeutic approaches to correct the metabolic imbalance in processing the meal nutrients that occur in type 2 diabetes can be approached through this paradigm.     

Modulation of bone morphogenetic protein-9 expression and processing by insulin, glucose, and glucocorticoids: possible candidate for hepatic insulin-sensitizing substance

Bone morphogenetic protein 9 (BMP-9), a member of the TGF-beta superfamily predominantly expressed in nonparenchymal liver cells, has been demonstrated to improve glucose homeostasis in diabetic mice. Along with this therapeutic effect, BMP-9 was proposed as a candidate for the hepatic insulin-sensitizing substance (HISS). Whether BMP-9 plays a physiological role in glucose homeostasis is still unknown. In the present study, we show that BMP-9 expression and processing is severely reduced in the liver of insulin-resistant rats. BMP-9 expression and processing was directly stimulated by in situ exposition of the liver to the combination of glucose and insulin and oral glucose in overnight fasted rats. Additionally, prolonged fasting (72 h) abrogated refeeding-induced BMP-9 expression and processing. Previous exposition to dexamethasone, a known inductor of insulin resistance, reduced BMP-9 processing stimulated by the combination of insulin and glucose. Finally, we show that neutralization of BMP-9 with an anti-BMP-9 antibody induces glucose intolerance and insulin resistance in 12-h fasted rats. Collectively, the present results demonstrate that BMP-9 plays an important role in the control of glucose homeostasis of the normal rat. Additionally, BMP-9 is expressed and processed in an HISS-like fashion, which is impaired in the presence of insulin resistance. BMP-9 regulation according to the feeding status and the presence of diabetogenic factors reinforces the hypothesis that BMP-9 might exert the role of HISS in glucose homeostasis physiology.     

Hepatic parasympathetic role in insulin resistance on an animal model of hypertension

The hepatic insulin sensitizing substance (HISS) pathway, which includes the hepatic parasympathetic nerves and hepatic nitric oxide (HNO), has been shown to be crucial to the action of insulin on glucose metabolism. Insulin resistance in essential hypertension has been related to parasympathetic dysfunction; thus, we tested the hypothesis that the HISS pathway is impaired in spontaneously hypertensive rats (SHR) when compared with their normotensive controls, Wistar (WIS) and Wistar Kyoto (WKY) rats. A modified euglycemic clamp quantified insulin sensitivity. Differentiation of the HISS-dependent and HISS-independent components of insulin action was achieved by administration of a muscarinic receptor antagonist (atropine, 3 mg/kg) or of a nitric oxide synthase inhibitor (N(g)-methyl-arginine, 0.73 mg/kg). Both SHR and WKY had lower postprandial total insulin action when compared with WIS (209.1 +/- 13.6 for WKY and 217.8 +/- 19.8 for SHR vs 296.1 +/- 16.9 mg glucose/kg body weight for WIS, P < .05). Furthermore, we observed that this is due to a decrease of the HISS-dependent component of insulin action (154.8 +/- 16.4 for WIS vs 87.1 +/- 14.5 for WKY and 55.9 +/- 15.6 mg glucose/kg body weight for SHR; P < .05 and P < .001, respectively; data concerning the atropine protocol). Blockade of HISS action by inhibition of hepatic nitric oxide synthase with N(g)-methyl-arginine showed similar results to those obtained with atropine, suggesting that they indeed act through the same pathway. In conclusion, our results support our hypothesis that impairment of the HISS pathway is responsible for the development of insulin resistance between WIS and SHR.     

Hemorrhage results in hepatic insulin-sensitizing substance-dependent insulin resistance mediated by somatostatin in rats

BACKGROUND/AIMS: Acute hemorrhage results in hyperglycemia regulated in a redundant manner by adrenal catecholamines and hepatic sympathetic nerves. In addition, insulin secretion is suppressed and insulin resistance is accounted for completely by elimination of the hepatic insulin-sensitizing substance (HISS) component of insulin action. Blockade of HISS action secondary to blood loss leads to a state known as HISS-dependent insulin resistance (HDIR) which results in a decrease in the glucose disposal action of insulin by 33 +/- 3%. METHODS: This paper describes nine studies that have explored the neuroendocrine control of HDIR that is produced in response to the stress of blood loss. The rapid insulin sensitivity test (RIST), a transient euglycemic clamp, was used to measure insulin sensitivity. To test the role of the adrenergic system, alpha- and beta-adrenergic receptor antagonists, phentolamine and propranolol, were tested for the ability to block HDIR produced by hemorrhage. RESULTS: Neither intervention was effective (32 +/- 6 and 36 +/- 3%, respectively). Exogenous somatostatin was shown to produce HDIR that could be blocked by the somatostatin receptor antagonist, cyclosomatostatin. Cyclosomatostatin completely blocked the development of HDIR that occurred following hemorrhage (RIST index 214 +/- 9 control, 218 +/- 9 mg glucose/kg body weight after cyclosomatostatin plus hemorrhage). CONCLUSIONS: The adrenergic system is not involved in producing HDIR in response to hemorrhage. Somatostatin appears to be the hormonal regulator of this response and it is suggested that the somatostatin derives from a neural origin within the liver.     

HISS-dependent insulin resistance (HDIR) in aged rats is associated with adiposity, progresses to syndrome X, and is attenuated by a unique antioxidant cocktail

The hypotheses were: HISS-dependent insulin resistance (HDIR) accounts for insulin resistance that occurs with aging; HDIR is the initiating metabolic defect that leads progressively to type 2 diabetes and the metabolic syndrome; a synergistic antioxidant cocktail in chow confers protection against HDIR, subsequent symptoms of diabetes, and the metabolic syndrome. Male Sprague Dawley rats were tested at 9, 26, and 52 weeks to determine their dynamic response to insulin, the HISS (hepatic insulin sensitizing substance)-dependent component of insulin action, and the HISS-independent (direct) insulin action using a dynamic insulin sensitivity test. In young rats, the HISS component accounted for 52.3+/-2.1% of the response to a bolus of insulin (50mU/kg) which decreased to 29.8+/-3.4% at 6 months and 17.0+/-2.7% at 12 months. HISS action correlated negatively with whole body adiposity and all regional fat depots (r(2) = 0.67-0.87). The antioxidants (vitamin C, vitamin E, and S-adenosylmethionine) conferred protection of HISS action, fat mass at all sites, blood pressure, postprandial insulin and glucose. Data are consistent with the hypotheses. Early detection and therapy directed towards treatment of HDIR offers a novel therapeutic target.     

Pathogenesis of type 2 diabetes: tracing the reverse route from cure to cause

The metabolic abnormalities of type 2 diabetes can be reversed reproducibly by bariatric surgery. By quantifying the major pathophysiological abnormalities in insulin secretion and insulin action after surgery, the sequence of events leading to restoration of normal metabolism can be defined. Liver fat levels fall within days and normal hepatic insulin sensitivity is restored. Simultaneously, plasma glucose levels return towards normal. Insulin sensitivity of muscle remains abnormal, at least over the weeks and months after bariatric surgery. The effect of the surgery is explicable solely in terms of energy restriction. By combining this information with prospective observation of the changes immediately preceding the onset of type 2 diabetes, a clear picture emerges. Insulin resistance in muscle, caused by inherited and environmental factors, facilitates the development of fatty liver during positive energy balance. Once established, the increased insulin secretion required to maintain plasma glucose levels will further increase liver fat deposition. Fatty liver causes resistance to insulin suppression of hepatic glucose output as well as raised plasma triacylglycerol. Exposure of beta cells to increased levels of fatty acids, derived from circulating and locally deposited triacylglycerol, suppresses glucose-mediated insulin secretion. This is reversible initially, but eventually becomes permanent. The essential time sequence of the pathogenesis of type 2 diabetes is now evident. Muscle insulin resistance determines the rate at which fatty liver progresses, and ectopic fat deposition in liver and islet underlies the related dynamic defects of hepatic insulin resistance and beta cell dysfunction. These defects are capable of dramatic reversal under hypoenergetic feeding conditions, completely in early diabetes and to a worthwhile extent in more established disease.     

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。     

Insulin sensitization by voluntary exercise in aging rats is mediated through hepatic insulin sensitizing substance (HISS)

Background

Food in the upper gastrointestinal tract potentiates the glucose uptake response to insulin. Meal-induced insulin sensitization (MIS) occurs as a result of insulin-mediated release of hepatic insulin sensitizing substance (HISS) that increases glucose uptake in peripheral tissues. HISS release decreases with age, and exercise causes metabolic improvements in aging, therefore it is important to analyze the effect of exercise on age-associated decline in HISS-action.

Objectives

The aim of this study is to test the hypothesis that improved insulin sensitivity, by voluntary running-wheel exercise in aging rats, is attained by preserving the HISS response. We also investigate the possible association of exercise-mediated beneficial changes in metabolic conditions and body composition with improved HISS-action.

Methods

We measured insulin- and HISS-sensitivity in 9, 14 and 21-week old rats with/without exercise. Metabolic markers were also determined in age-matched control and exercised rats.

Results

Exercise significantly improved HISS-dependent glucose uptake in all age groups. The direct action of insulin was minimally altered by age or exercise. Body composition and metabolic conditions were beneficially changed with exercise-induced improvements in the HISS response.

Conclusion

The therapeutic efficacy of voluntary exercise against insulin resistance in aging rats is achieved mainly through restoration of HISS-action.     

Understanding "insulin resistance": both glucose resistance and insulin resistance are required to model human diabetes

A mathematical model of normal glucose/insulin homoeostasis has been based on the known, experimentally determined responses of the liver and periphery to different glucose/insulin concentrations. Different defects of glucose resistance and insulin resistance have been applied to the model to investigate the degree to which these abnormalities could successfully predict the range of fasting glucose and insulin values found in normal, obese, and diabetic subjects. Modeling glucose resistance or insulin resistance at the liver or the periphery alone did not increase the plasma glucose to levels observed in diabetes, even when associated with marked deficiency of beta-cell function. A defect of either glucose resistance or insulin resistance affecting both periphery and liver allowed a wider range of basal glucose and insulin concentration values, but resulted in unphysiologically low hepatic glucose output: with modeling insulin resistance, hyperglycemia suppressed glucose output, whereas with glucose resistance, raised insulin levels suppressed hepatic glucose output. A wide range of glucose and insulin values, with appropriate basal hepatic glucose output, could only be modeled by insulin resistance at both the liver and periphery with additional glucose resistance at the liver. The modeling results are in accord with investigative studies that suggest secondary hepatic and peripheral glucose resistance in response to hyperglycemia. Modeling provides a systematic means of examining the likely effect of different putative defects in a complex physiological system.