PATHOGENESIS OF DIABETES MELLITUS

在吸收后阶段，肝脏葡萄糖生成 成为新葡萄糖生产的主要来源， 糖尿病状态下高血糖的决定因素。 证据 表明在此期间肝葡萄糖生成（HGP） 可以由外围事件控制。 主要的假设是 测试的是，信号机制之间存在 外周和肝脏，这可能发挥重要作用后， 糖尿病的吸收性高血糖。 外围信号将 在两种情况下进行检查，其中HGP可以通过以下方式控制： 外周事件-在（1）睡眠期间，当HGP和外周 代谢事件是同步的，以及（2）随后 以不增加Rd的量给予胰岛素，或 门静脉胰岛素水平 外围信号将是 根据身体组成（男性，女性，年轻人， 老瘦肥胖，生长激素缺乏）。 具体 将通过替换任何 血浆浓度下降的代谢物 HGP（游离脂肪酸、甘油、乳酸盐、丙氨酸）减少。 这些信号对HGP定性方面的影响， HGP在糖原分解和糖原生成中的比例， 无效循环的比率也将被评估。 的 男性肥胖、人类基因组蛋白和碳水化合物之间的关系 将通过门静脉研究来探讨代谢， 信号/底物从网膜与外周脂肪释放， 网膜的代谢活性（脂解和再酯化） 与周围脂肪相比。 最后， 将在微孔中检查外周衍生代谢物- 用于检测碳通量的特定肝细胞培养系统 通过直接丙酮酸羧化酶或TCA转化为葡萄糖 在第一个分支点的途径中。 假定的信号传导机制将在非肥胖， 非糖尿病、肥胖和糖尿病受试者。 了实验 预期指示信号（与底物无关 供应）从外周包括网膜脂肪刺激 基因突变、无效循环和人类基因组计划，但 肥胖的高胰岛素血症抑制后两者。 仅在 当胰岛素分泌减少时的糖尿病状态是 观察到无效循环和HGP增加。

During the post-absorptive period hepatic glucose production becomes the major source of new glucose production and the major determinant of hyperglycemia in the diabetic state. Evidence suggests that during this period hepatic glucose production (HGP) may be controlled by peripheral events. The major hypothesis to be tested is that a signalling mechanism exists between the periphery and the liver which may play an important role in post- absorptive hyperglycemia of diabetes. Peripheral signalling will be examined in two situations in which HGP may be controlled by peripheral events--during (1) sleep when HGP and peripheral metabolic events are synchronized and (2) following administration of insulin in quantities not increasing Rd or portal vein insulin levels. Peripheral signalling will be evaluated in terms of body composition (males, females, young, old thin obese, growth hormone deficient). The specific signal(s) involved will be assessed by replacement of any metabolites whose plasma concentration has fallen in conjunction with reduced HGP (free fatty acids, glycerol, lactate, alanine). The effect of these signals on qualitative aspects of HGP such as the proportion of HGP from gluconeogenesis vs glycogenolysis and the rate of futile cycling will also be evaluated. The association between android obesity, HGP, and carbohydrate metabolism will be explored by portal vein studies assessing the signal/substrate release from omental vs peripheral fat and the metabolic activity (lipolysis and re-esterification) of omental compared to peripheral fat. Finally, the signalling nature of peripherally derived metabolites will be examined in a well- defined hepatocyte culture system designed to examine carbon flux into glucose via either the direct pyruvate carboxylase or TCA pathway at the first branch point in gluconeogenesis. The putative signalling mechanism will be examined in non-obese, non-diabetic, obese, and diabetic subjects. The experiments are expected to indicate that signals (independent of substrate provision) from the periphery including omental fat stimulate gluconeogenesis, futile cycling, and HGP, but that the hyperinsulinemia of obesity restrains the latter two. Only in the diabetic state when insulin secretion has decreased are the increase in futile cycling and HGP observed.