HYPERGLYCEMIA EFFECT PER SE ON HEPATIC GLUCOSE FLUXES IN NIDDM

内源性葡萄糖生成（GP）增强是糖尿病（DM）患者空腹高血糖的主要原因。血糖和胰岛素水平的升高通常会抑制GP的发生。事实上，在非糖尿病动物和人类中，当血浆葡萄糖浓度急剧升高时，GP被独立于激素信号抑制。然而，糖尿病患者在面对高血糖和高胰岛素血症时，GP均升高。拟议的实验计划将首先解决在固定激素条件下，与正常人相比，1型和2型糖尿病患者的肝葡萄糖通量对高血糖本身的反应。在正常血糖（血浆葡萄糖~ 90mg /dl）和高血糖（180mg /dl）的情况下，在生长抑素输注、基础替代胰岛素和其他激素（“胰腺钳夹”）期间，测量肝脏葡萄糖生成率和葡萄糖循环率。假设高血糖增强葡萄糖激酶在肝脏中的通量的能力受损有助于糖尿病患者的空腹高血糖。因此，我们将确定通过少量催化量的果糖激活葡萄糖激酶是否可以恢复糖尿病患者葡萄糖诱导的葡萄糖抑制。在高血糖期输注果糖进行类似的正常/高血糖研究。测量肝脏葡萄糖生成和葡萄糖循环的速率。肝脏在调节空腹血糖水平中的重要作用表明，确定糖尿病患者因高血糖而失去正常的肝脏调节，对于制定有针对性的干预措施是有价值的。具体来说，用少量果糖增强肝脏中的葡萄糖激酶通量可能是一种简单且理论上有吸引力的改善糖尿病血糖控制的方法。

Enhanced endogenous glucose production (GP) is a major cause of fasting hyperglycemia in Diabetes Mellitus (DM). GP is normally inhibited by increased plasma levels of glucose and insulin. In fact, in response to acute increases in the plasma glucose concentration, GP is inhibited independently of hormonal signals in nondiabetic animals and humans. However, GP is increased in DM in the face of both hyperglycemia and hyperinsulinemia. The proposed experimental plan will first address the response of hepatic glucose fluxes to hyperglycemia per se in individuals with type 1 and type 2 DM as compared with normal individuals, in the presence of fixed hormonal conditions. Rates of hepatic glucose production and glucose cycling will be measured during somatostatin infusion with basal replacement of insulin and other hormones ("pancreatic clamp") in the presence of normoglycemia (plasma glucose ~ 90 mg/dl) and hyperglycemia (180 mg/dl). It is hypothesized that an impairment in the ability of hyperglycemia to enhance flux through glucokinase in the liver contributes to fasting hyperglycemia in DM. Thus, we will determine whether activation of glucokinase by small, catalytic amounts of fructose might restore glucose-induced suppression of GP in DM. Similar normoglycemic/hyperglycemic studies will be performed with infusion of fructose during the hyperglycemic phase, with measurement of rates of hepatic glucose production and glucose cycling. The vital role of the liver in the regulation of fasting plasma glucose levels suggests that defining the loss of normal hepatic regulation by hyperglycemia in DM would be valuable in developing targeted interventions. Specifically, enhancing glucokinase flux in the liver with small amounts of fructose may offer a simple and theoretically attractive means of improving glycemic control in Diabetes Mellitus.