PATHOGENESIS OF DIABETES MELLITUS

在吸收后阶段肝脏葡萄糖的产生 成为新的葡萄糖生产的主要来源和主要 糖尿病状态下高血糖的决定因素。证据 提示在此期间，肝脏葡萄糖的产生(HGP) 可以由外围事件控制。主要的假设是 需要测试的是，在 外周和肝脏可能在后遗症中起重要作用 糖尿病的吸收性高血糖。外围设备信令将 在两种可能控制HGP的情况下进行检查 外周事件--在(1)睡眠期间，当HGP和外周 代谢事件是同步的，并且(2) 胰岛素用量不增加RD或 门静脉胰岛素水平。外围设备信令将 根据身体成分(男性、女性、年轻人、 老瘦肥胖，生长激素缺乏)。具体的 涉及的信号(S)将通过替换任何 血浆浓度同时下降的代谢物 减少HGP(游离脂肪酸、甘油、乳酸、丙氨酸)。 这些信号对HGP定性方面的影响，例如 糖异生与糖原分解的HGP比例及 无效骑行的比率也将被评估。这个 Android肥胖、HGP和碳水化合物之间的关系 新陈代谢将通过门静脉研究来探索 来自大网膜和外周脂肪的信号/底物释放和 大网膜的代谢活性(脂解和再酯化) 与外周脂肪相比。最后，信号的性质 外周衍生的代谢物将在井中进行检测- 用于检测碳通量的明确的肝细胞培养系统 通过直接丙酮酸羧基酶或三氯乙酸转化为葡萄糖 糖异生第一分支点的途径。 假定的信号机制将在非肥胖者中进行检查， 非糖尿病、肥胖和糖尿病受试者。这些实验是 预期指示信号(与底物无关 供应)来自外周，包括大网膜脂肪刺激 糖异生、徒劳的循环和HGP，但 肥胖症的高胰岛素血症抑制后两者。仅限于在 当胰岛素分泌减少时的糖尿病状态是 观察到无效骑行和HGP的增加。

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.