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

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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.