Mechanisms of Insulin Resistance in Man

描述（由申请人提供）：7000万人患有前驱糖尿病或糖尿病，糖尿病占七分之一的医疗费用。了解这些疾病的发病机制和开发更好的治疗方法是非常重要的。氘水和同位素体方法被广泛用于测量人类的糖异生。两种方法都假定可忽略的转醛缩酶交换。在上一个赠款期间进行的研究对这一假设提出了质疑。我将通过输注[1-13C]醋酸盐，并测定[3-13C] udp -葡萄糖/ [4-13C] udp -葡萄糖比值是否小于1.0表明存在转醛缩酶交换，来确定人体内是否发生转醛缩酶交换，以及在空腹血糖受损（IFG）个体中是否增加。个体也将被给予2H2O和正糖钳，因此这些实验的数据可以用于Specific Aim II，以验证以下假设：a) IFG和正常葡萄糖耐量（IFG/NGT）的人有肝脏胰岛素抵抗，b) IFG/IGT联合患者的肝脏胰岛素抵抗的严重程度大于IFG/NGT，以及c) IFG中的肝脏胰岛素抵抗是由于糖原分解和糖异生抑制受损造成的。在之前的研究中，我们也证实了移植床将大量可的松转化为皮质醇，并提供证据表明几乎所有的这种转化都发生在肝脏内。这表明通过112 - hsd 1型途径产生的皮质醇可能是肝脏胰岛素作用的重要调节因子。Specific Aim III将开发并使用一种新的三重示踪方法，通过让瘦弱的非糖尿病、肥胖的非糖尿病和肥胖的糖尿病受试者摄入[9,12,12- 2h3]皮质醇（[2H]皮质醇）和[4-13C]可的松（[13C]可的松），来确定肥胖或2型糖尿病是否会降低肝脏可的松向皮质醇转化的速度。[2H]皮质醇和[13C]皮质醇的出现率将通过静脉注射[1,2,6,7-3H]皮质醇（[3H]皮质醇）来测量，以便同时测量摄入的[2H]皮质醇的肝脏提取和摄入的[13C]可的松到[13C]皮质醇的肝脏转化，从而可以在不需要肝静脉导管置入的情况下测量肝脏11 - hsd -1通量。由于关于人类肝脏112-HSD-1活性的激素调节几乎一无所知，特异性目的IV将通过使用随机研究设计来确定胰岛素是否会降低而糖皮质激素是否会增加肝脏皮质醇的产生，在该研究设计中，受试者将摄入氢化可的松或安慰剂一周，然后使用高胰岛素正糖钳或生理盐水注射，并结合特异性目的III中概述的方法。如果是这样，这将与体外观察结果一致，并将为进一步的研究提供刺激，以确定胰岛素对肝脏112- HSD-1的抑制受损和/或循环皮质醇的轻微升高引起的过度刺激是否有助于肥胖和2型糖尿病患者的肝脏胰岛素抵抗。公共卫生相关性：美国有近7000万人患有糖尿病前期或糖尿病。这些情况给人类带来了巨大的痛苦，给经济和医疗保健系统带来了巨大的成本。本申请中提出的研究的最终目标是了解这些疾病的原因，以便制定合理的预防、治疗和最终治愈方法。特别是，该应用程序将关注肝脏如何以及为什么向血液中释放过多的葡萄糖，导致进食前后血糖升高。

DESCRIPTION (provided by applicant): Seventy million people have pre-diabetes or diabetes and diabetes accounts for 1 in 7 health care dollars. Understanding the pathogenesis of and developing better therapies for these conditions is a very high priority. The deuterated water and isotopomer methods are extensively used to measure gluconeogenesis in humans. Both methods assume negligible transaldolase exchange. Studies performed during the previous grant period have called this assumption into question. Specific Aim I will determine whether transaldolase exchange occurs in humans and whether it is increased in individuals with impaired fasting glucose (IFG) by infusing [1-13C] acetate and determining whether the [3-13C] UDP-glucose/ [4-13C] UDP-glucose ratio is less than 1.0 indicating the presence of transaldolase exchange. Individuals also will be given 2H2O and euglycemic clamps performed so the data from those experiments can be used in Specific Aim II to test the hypotheses that a) people with IFG and normal glucose tolerance (IFG/NGT) have hepatic insulin resistance, b) the severity of hepatic insulin resistance is greater in people with combined IFG/IGT than IFG/NGT, and c) hepatic insulin resistance in IFG results from impaired suppression of glycogenolysis as well as gluconeogenesis. We also established during the previous grant period that the splanchnic bed converts large amounts of cortisone to cortisol and provided evidence that virtually all of this conversion occurs within the liver. This suggests that generation of cortisol via the 11 2-HSD type 1 pathway may be an important regulator of hepatic insulin action. Specific Aim III will develop and use a novel triple tracer approach to determine if obesity or type 2 diabetes decreases the rate of hepatic cortisone to cortisol conversion by having lean non-diabetic, obese non-diabetic and obese diabetic subjects ingest [9,12,12-2H3] cortisol ([2H] cortisol) and [4-13C] cortisone([13C] cortisone). Rates of appearance of [2H] cortisol and [13C] cortisol will be measured using intravenously infused [1,2,6,7-3H] cortisol ([3H] cortisol) in order to concurrently measure both hepatic extraction of the ingested [2H] cortisol and hepatic conversion of the ingested [13C] cortisone to [13C] cortisol thereby enabling measurement of hepatic 11 2-HSD-1 flux without the need for hepatic venous catheterization. Since virtually nothing is known regarding the hormonal regulation of hepatic 112-HSD-1 activity in humans, Specific aim IV will determine whether insulin decreases and glucocorticoids increase hepatic cortisol production by using a randomized study design in which subjects will either ingest hydrocortisone or placebo for one week followed by either a hyperinsulinemic euglycemic clamp or saline infusion combined with the methods outlined in Specific aim III. If so, this would be consistent with observations in vitro and would provide the stimulus for additional studies seeking to determine whether impaired suppression of hepatic 112- HSD-1 by insulin and/or excessive stimulation due to subtle elevations in circulating cortisol contribute to the hepatic insulin resistance in obesity and type 2 diabetes. PUBLIC HEALTH RELEVANCE: Almost 70 million people in the United States have either pre-diabetes or diabetes. These conditions cause a tremendous amount of human suffering and result in enormous costs to the economy as well as the heath care system. The ultimate goal of the studies proposed in this application is to understand the cause of these disorders in order to develop rational approaches for their prevention, treatment and hopefully ultimate cure. In particular, this application will focus on how and why the liver releases too much glucose into the blood stream causing blood sugars to rise both before and after eating.