Mechanisms of Insulin Resistance in Man

描述（由申请人提供）：7000万人患有糖尿病前期或糖尿病，糖尿病占医疗保健费用的1/7。了解这些疾病的发病机制和开发更好的治疗方法是一个非常高的优先事项。氘代水和同位素异构体方法被广泛用于测量人类的生殖。这两种方法都假定转醛醇酶交换可忽略不计。在上一个赠款期间进行的研究对这一假设提出了质疑。具体目标I将通过输注[1- 13 C]醋酸盐并确定[3- 13 C] UDP-葡萄糖/ [4- 13 C] UDP-葡萄糖比值是否小于1.0（表明存在转醛醇酶交换），确定转醛醇酶交换是否在人体中发生以及在空腹血糖受损（IFG）个体中是否增加。还将给予个体2 H2O并进行正葡萄糖钳夹，因此这些实验的数据可用于特定目标II，以检验以下假设：a）IFG和正常葡萄糖耐量（IFG/NGT）人群具有肝脏胰岛素抵抗，B）IFG/IGT合并人群的肝脏胰岛素抵抗严重程度高于IFG/NGT，和c）IFG中的肝胰岛素抵抗是由糖原分解以及糖原生成的抑制受损引起的。我们还确定在前一个赠款期间，内脏床转化大量的可的松皮质醇，并提供证据表明，几乎所有的这种转换发生在肝脏。这表明，通过11 2-HSD 1型途径生成皮质醇可能是肝脏胰岛素作用的重要调节剂。Specific Aim III将开发并使用一种新的三重示踪剂方法，通过让瘦型非糖尿病、肥胖型非糖尿病和肥胖型糖尿病受试者摄入[9，12，12 - 2 H3]皮质醇（[2 H]皮质醇）和[4- 13 C]皮质醇（[13 C]皮质醇），确定肥胖或2型糖尿病是否降低了肝脏皮质醇转化为皮质醇的速率。[2 H]皮质醇和[13 C]皮质醇的出现率将使用静脉输注[1，2，6，7- 3 H]皮质醇（[3 H]皮质醇），以便同时测量摄取的[2 H]皮质醇的肝脏提取和摄取的[13 C]皮质醇向[13 C]皮质醇的肝脏转化，从而能够测量肝脏11 2-HSD-1。1流量，无需肝静脉插管。由于对人类肝脏112-HSD-1活性的激素调节几乎一无所知，因此具体目标IV将通过使用随机研究设计来确定胰岛素是否减少和糖皮质激素是否增加肝脏皮质醇的产生，在该随机研究设计中，受试者将摄入氢化可的松或安慰剂一周，随后进行高胰岛素-正葡萄糖钳夹或盐水输注，并结合具体目标III中概述的方法。如果是这样的话，这将与体外观察结果一致，并将为寻求确定胰岛素对肝脏112- HSD-1的抑制受损和/或由于循环皮质醇轻微升高引起的过度刺激是否有助于肥胖和2型糖尿病中的肝脏胰岛素抵抗的其他研究提供刺激。公共卫生相关性：美国近7000万人患有糖尿病前期或糖尿病。这些疾病给人类带来了巨大的痛苦，并给经济和卫生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，以便开发合理的方法来预防、治疗并希望最终治愈。特别是，这个应用程序将集中在如何和为什么肝脏释放太多的葡萄糖进入血液，导致血糖上升之前和之后吃。

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.