Mechanisms of Insulin Resistance in Man

描述(申请人提供)：7000万人有糖尿病前期或糖尿病，糖尿病占医疗保健费用的七分之一。了解这些疾病的发病机制并开发更好的治疗方法是非常重要的。氚水和同位素方法被广泛用于测量人类的糖异生作用。这两种方法都假定转醛醇酶交换可以忽略不计。在之前的赠款期间进行的研究已经对这一假设提出了质疑。具体目的I将通过输注[1-13C]醋酸酯和确定[3-13C]UDP-葡萄糖/[4-13C]UDP-葡萄糖的比值是否小于1.0来确定人类是否存在转醛醇酶交换，以及空腹血糖受损(IFG)的个体是否会增加转醛醇酶交换。受试者还将接受2H2O和正常血糖钳夹试验，以便这些实验数据可以用于特定的目标II，以检验如下假说：a)糖耐量正常(IFG/NGT)且IFG患者存在肝脏胰岛素抵抗；b)IFG/IGT合并患者的肝脏胰岛素抵抗程度比IFG/NGT患者更严重；以及c)IFG患者的肝脏胰岛素抵抗是由于糖原分解和糖异生受到抑制所致。我们还在前一次赠款期间证实，内脏床将大量的皮质醇转化为皮质醇，并提供了几乎所有这种转化都发生在肝脏内的证据。提示11 2-HSD-1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。特定目标III将开发和使用一种新的三重示踪方法来确定肥胖或2型糖尿病是否通过让瘦的非糖尿病、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]皮质松([13C]皮质松)来降低肝脏皮质醇到皮质醇的转化率。[2H]皮质醇和[13C]皮质醇的出现率将使用静脉输注[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]皮质醇的肝脏提取液和肝脏将摄入的[13C]皮质醇转化为[13C]皮质醇，从而无需肝静脉插管即可测量肝脏11 2-HSD-1流量。由于人类对肝脏112-HSD-1活性的激素调节几乎一无所知，因此特定目标IV将采用随机研究设计来确定胰岛素是否减少、糖皮质激素是否增加肝脏皮质醇的产生。在随机研究设计中，受试者服用氢化可的松或安慰剂一周，然后接受高胰岛素正血糖钳或生理盐水输注，并结合特定目标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，以寻求确定肥胖和2型糖尿病患者肝脏胰岛素抵抗是否由胰岛素和/或由于循环皮质醇微妙升高而引起的过度刺激所致。与公共健康相关：在美国，近7000万人患有糖尿病前期或糖尿病。这些情况造成了巨大的人类痛苦，并给经济和卫生保健系统带来了巨大的代价。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，并有望最终治愈。这个应用程序将特别关注肝脏如何以及为什么会将过多的葡萄糖释放到血流中，从而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.