HYPERGLYCEMIA EFFECT PER SE ON HEPATIC GLUCOSE FLUXES IN NIDDM

内源性葡萄糖生成（GP）增加是糖尿病（DM）空腹高血糖的主要原因。 GP通常被升高的血糖和胰岛素血浆水平抑制。 事实上，在非糖尿病动物和人类中，对血浆葡萄糖浓度的急性增加的反应是GP被独立于激素信号抑制。 然而，糖尿病患者在高血糖和高胰岛素血症时GP增加。 拟议的实验计划将首先解决在固定激素条件下，与正常个体相比，1型和2型DM个体的肝葡萄糖通量对高血糖本身的反应。 在血糖正常（血糖约90 mg/dl）和高血糖（180 mg/dl）的情况下，在输注生长抑素并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。 据推测，高血糖症增强通过肝脏中葡萄糖激酶的通量的能力受损有助于DM中的空腹高血糖症。 因此，我们将确定是否激活葡萄糖激酶的小，催化量的果糖可能恢复葡萄糖诱导的抑制GP在DM。 将在高血糖阶段输注果糖进行类似的血糖正常/高血糖研究，并测量肝脏葡萄糖生成率和葡萄糖循环。 肝脏在调节空腹血糖水平中的重要作用表明，定义糖尿病患者高血糖导致的正常肝脏调节功能丧失对制定有针对性的干预措施是有价值的。具体地说，用少量果糖增强肝脏中的葡萄糖激酶通量可能提供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.