MECHANISMS OF ACTION OF EXUBERA TO NORMALIZE FASTING PLASMA GLUCOSE IN T2DM

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 目的：探讨短效胰岛素Exubera降低空腹血糖浓度的作用机制(S)。空腹血糖浓度主要由睡眠时间内内源性(主要是肝脏)葡萄糖生成率决定。 研究计划：临床试验已经证明，每天三次随餐服用Exubera可以使口服药物治疗不能充分控制的2型糖尿病患者的空腹血糖(FPG)浓度正常化或接近正常化(DeFronzo等人，糖尿病护理28：1922-1928,2005)。空腹血糖的主要决定因素是整个睡眠时间普遍存在的内源性(主要是肝脏)葡萄糖产生(EGP)的基本比率(DeFronzo等人，代谢38：387-395,1989)。由于Exubera是一种短效(4-6小时)胰岛素，每天三次给药(7-8 AM、12-1 PM、6-7 PM)会影响12M至次日上午7-8AM的EGP基础比率，这有点自相矛盾。这具有非常重要的临床意义，因为它意味着“短效”胰岛素制剂可以使空腹血糖正常化或导致空腹血糖浓度非正常化，从而不再需要“长效”胰岛素，即Lantus或NPH。这也意味着Exubera可以作为新诊断的或药物初治的2型糖尿病患者的单一疗法。 方法：我们认为空腹血糖正常化或接近正常化与三个因素有关：(1)全天血糖水平正常化，即8AM-12MN，导致糖毒性的改善(Rossetti&DeFronzo，糖尿病护理13：610-630,1990)。长期升高的血糖水平上调了肝脏葡萄糖-6-磷酸酶的活性，这是肝脏葡萄糖释放的限速酶(Massilon and；Rossetti J Biol Chem 273：228-234,1998)。在白天(8AM-12MN)对肝脏的这种糖毒效应的逆转可能足以在整个睡眠时间(12MN-8AM)下调葡萄糖-6-磷酸酶并使HGP/FPG正常化；(Ii)在控制不佳的2型糖尿病患者中，相当数量的葡萄糖被肌肉摄取(继发于高血糖的集体作用效应)，进入糖酵解周期，但不能被氧化，以乳酸的形式离开细胞(Del Prato，DeFronzo，et al JCI 91：484-494,1993)。在肝脏中，乳酸被吸收并转化为葡萄糖，即CORI循环(Cusi and；DeFronzo JCEM 81：4059-4067,1996)。Exubera通过使全天的血糖浓度正常化和刺激葡萄糖氧化，减少高血糖的集体作用效应，并将丙酮酸重定向到Krebs循环，导致肌肉释放的乳酸减少。这反过来减少了底物(乳酸)向肝脏的输送，从而抑制了肝脏的糖异生；(Iii)改进的胰岛素也可能抑制脂解。血浆甘油浓度的下降导致糖异生通量的减少，而血浆FFA浓度的下降预计会抑制糖异生的限速酶PEPCK。 临床意义：我们预计，每天三次服用Exubera将改善/消除葡萄糖毒性，导致肝糖-6-磷酸酶活性下调，并将基础肝糖生成抑制到正常或接近正常值。由于24小时血糖水平得到控制，较少的葡萄糖将进入肌肉并转化为乳酸，导致乳酸的可获得性降低，从而推动肝脏糖异生。CORI循环活性降低，再加上抑制脂肪分解(用2H5-甘油测量)和血浆FFA水平降低(继发于胰岛素注射)，将导致乳酸和甘油周转减少，乳酸和甘油到葡萄糖的转换减少(用14C-乳酸和2H5甘油测量)，以及糖异生(用D20测量)。 此外，我们预计，持续一天的高血糖的降低将消除对β细胞的糖毒效应，并导致胰岛素分泌的改善，如胰岛素分泌率的增加以及葡萄糖敏感性和基础胰岛素分泌张力的改善。我们还预计松田胰岛素敏感性指数将随着糖毒性的改善而改善。最后，我们期望看到餐后高脂血症的显著改善，以及心血管疾病的炎症/血栓前标志物(CRP、ICAM、VACM、PAI-1、抵抗素、白介素6)的改善。餐后高脂血症日益被认为是动脉粥样硬化性心血管疾病的主要危险因素。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. OBJECTIVE: To examine the mechanism(s) via which Exubera, a "short acting" insulin administered three times daily, reduces the fasting plasma glucose concentration which primarily is determind by the rate of endogenous (primarily hepatic) glucose production throughout the sleeping hours. RESEARCH PLAN: Clinical trials have demonstrated that Exubera, adminstered three times daily with meals, can cause normalization or near-normalization of the fasting plasma glucose (FPG) concentration in type 2 diabetic patients who are inadequately controlled on oral agent therapy (DeFronzo et al, Diabetes Care 28:1922-1928, 2005). The major determinant of the FPG is the basal rate of endogenous (primarily hepatic) glucose production (EGP) that prevails throughout the sleeping hours (DeFronzo et al, Metabolism 38:387-395, 1989). Because Exubera is a short acting (4-6 hours) insulin, it is somewhat paradoxical that three daily administrations (7-8 AM, 12-1 PM, 6-7 PM) can influence the basal rate of EGP that prevails from 12 M to 7-8 AM on the following day. This has very important clinical implications since it implies that a "short acting" insulin preparation can normalize or cause non-normalization of the FPG concentration, obviating the need for a "long acting" insulin, i.e. Lantus or NPH. It also implies that Exubera can be used as monotherapy in newly diagnosed or drug naive type 2 diabetic patients. METHODS: We believe that the normalization or near-normalization of FPG (and basal hepatic glucose production) is related to three factors: (i) normalizaton of plasma glucose levels throughout the day, i.e. 8 AM-12 MN, leading to amelioration of glucotoxicity (Rossetti amp; DeFronzo, Diabetes Care 13:610-630, 1990). Chronically elevated plasma glucose levels upregulate hepatic glucose-6-phosphatase activity, the rate limiting enzyme for hepatic glucose release (Massilon amp; Rossetti J Biol Chem 273:228-234, 1998). Reversal of this glucotoxic effect on the liver throughout the daytime hours (8 AM - 12 MN) may be sufficient to down regulate glucose-6-phosphatase throughout the sleeping hours (12 MN - 8 AM) and normalize HGP/FPG; (ii) In inadequately controlled type 2 diabetic individuals, a significant amount of the glucose that is taken up by muscle (secondary to the mass action effect of hyperglycemia), enters the glycolytic cycle but cannot be oxidized and leaves the cell as lactate (Del Prato, Defronzo, et al JCI 91:484-494, 1993). In the liver the lactate is taken up and converted to glucose, i.e., the Cori cycle (Cusi amp; DeFronzo JCEM 81:4059-4067, 1996). Exubera, by normalizing the plasma glucose concentration throughout the day and stimulating glucose oxidation, reduces the mass action effect of hyperglycemia and redirects pyruvate to the Krebs cycle, leading to diminished lactate release from muscle. This, in turn, decreases substrate (lactate) delivery to the liver, thereby inhibiting hepatic gluconeogenesis; (iii) It also is likely that improved insulinization inhibits lipolysis. The decrease in plasma glycerol concentration leads to a reduction in gluconeogenic flux, while the decline in plasma FFA concentration would be expected to inhibit PEPCK, the rate limiting enzyme for gluconeogenesis. CLINICAL RELEVANCE: We expect that administration of Exubera, three times daily, will ameliorate/remove glucose toxicity, leading to down regulation of heaptic glucose-6-phosphatase activity and supression of basal hepatic glucose production to normal or near normal values. Because 24-hour plasma glucose levels are controlled, less glucose will move into muscle and be converted to lactate, leading to reduced lactate availability to drive hepatic gluconeogenesis. Decreased Cori cycle activity, in combination with inhibition of lipolysis (measured with 2H5-glycerol) and reduced plasma FFA levels (secondary to insulin administration), will result in decreased lactate and glycerol turnover, reduced lactate and glycerol conversion to glucose (measured with 14C-lactate and 2H5 glycerol), and reduced gluconeogenesis (measured with D20). Further, we expect that decreased day-long hyperglycemia will remove the glucotoxic effect on the beta cell and lead to an improvement in insulin secretion as measured by an increase in insulin secretion rate and improvement in glucose sensitivity and basal insulin secretory tone. We also expect that the Matsuda index of insulin sensitivity will improve secondary to amelioration of glucotoxicity. Lastly, we expect to observe a marked improvement in postprandial hyperlipemia, which is becoming increasingly recognized as a major risk factor for atherosclerotic cardiovascular disease, and an improvement in inflammatory/prothrombotic markers (CRP, ICAM, VACM, PAI-1, resistin, interleukin 6) of cardiovascular disease.