Inhaled Insulin Is Associated with Prolonged Enhancement of Glucose Disposal in Muscle and Liver in the Canine

被引:3
作者
Edgerton, Dale S. [1 ]
Cherrington, Alan D. [1 ]
Neal, Doss W. [1 ]
Scott, Melanie [1 ]
Lautz, Margaret [1 ]
Brown, Nancy [1 ]
Petro, Jeff [1 ]
Hobbs, Charles H. [2 ]
Leach, Chet [2 ]
Del Parigi, Angelo [3 ]
Strack, Thomas R. [3 ]
机构
[1] Vanderbilt Univ, Med Ctr, Nashville, TN 37232 USA
[2] Lovelace Resp Res Inst, Albuquerque, NM USA
[3] Pfizer Inc, New York, NY USA
关键词
CONVERTING ENZYME-INHIBITORS; INDUCED DIABETIC-RATS; SUBCUTANEOUS INSULIN; COMPARATIVE TRIAL; EXUBERA; INHALATION; THERAPY; EFFICACY; SYSTEM; SAFETY;
D O I
10.1124/jpet.108.146985
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Diabetic patients treated with inhaled insulin exhibit reduced fasting plasma glucose levels. In dogs, insulin action in muscle is enhanced for as long as 3 h after insulin inhalation. This study was designed to determine whether this effect lasts for a prolonged duration such that it could explain the effect observed in diabetic patients. Human insulin was administered via inhalation (Exubera; n = 9) or infusion (Humulin R; n = 9) in dogs using an infusion algorithm that yielded matched plasma insulin kinetics between the two groups. Somatostatin was infused to prevent insulin secretion, and glucagon was infused to replace basal plasma levels of the hormone. Glucose was infused into the portal vein at 4 mg/kg/min and into a peripheral vein to maintain the arterial plasma glucose level at 160 mg/dl. Arterial and hepatic sinusoidal insulin and glucose levels were virtually identical in the two groups. Notwithstanding, glucose utilization was greater when insulin was administered by inhalation. At its peak, the peripheral glucose infusion rate was 4 mg/kg/min greater in the inhalation group, and a 50% difference between groups persisted over 8 h. Inhalation of insulin caused a greater increase in nonhepatic glucose uptake in the first 3 h after inhalation; thereafter, net hepatic glucose uptake was greater. Inhalation of insulin was associated with greater than expected (based on insulin levels) glucose disposal. This may explain the reduced fasting glucose concentrations observed in humans after administration of certain inhaled insulin formulations compared with subcutaneous insulin.
引用
收藏
页码:970 / 975
页数:6
相关论文
共 32 条
[1]   IMPORTANCE OF THE ROUTE OF INTRAVENOUS GLUCOSE DELIVERY TO HEPATIC GLUCOSE BALANCE IN THE CONSCIOUS DOG [J].
ADKINS, BA ;
MYERS, SR ;
HENDRICK, GK ;
STEVENSON, RW ;
WILLIAMS, PE ;
CHERRINGTON, AD .
JOURNAL OF CLINICAL INVESTIGATION, 1987, 79 (02) :557-565
[2]   The effect of smoking cessation and subsequent resumption on absorption of inhaled insulin [J].
Becker, RHA ;
Frick, AD ;
Sha, S ;
Fountaine, RJ .
DIABETES CARE, 2006, 29 (02) :277-282
[3]  
Brain J, 2008, AM J RESP CRIT CARE, V177, pA616
[4]   Assessment of insulin levels and comparison to subcutaneous injection [J].
Cherrington, AD ;
Neal, DW ;
Edgerton, DS ;
Glass, D ;
Bowen, L ;
Hobbs, CH ;
Leach, C ;
Rosskamp, R ;
Strack, TR .
DIABETES, 2004, 53 (04) :877-881
[5]   The kallikrein-kinin system, angiotensin converting enzyme inhibitors and insulin sensitivity [J].
Damas, J ;
Garbacki, N ;
Lefèbvre, PJ .
DIABETES-METABOLISM RESEARCH AND REVIEWS, 2004, 20 (04) :288-297
[6]   Hyperinsulinemia compensates for infection-induced impairment in net hepatic glucose uptake during TPN [J].
Donmoyer, CM ;
Chen, SS ;
Hande, SA ;
Lacy, DB ;
Ejiofor, J ;
McGuinness, OP .
AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM, 2000, 279 (02) :E235-E243
[7]   Inhalation of human insulin (Exubera) augments the efficiency of muscle glucose uptake in vivo [J].
Edgerton, Dale S. ;
Cherrington, Alan D. ;
Williams, Phillip ;
Neal, Doss W. ;
Scott, Melanie ;
Bowen, Larry ;
Wilson, Warren ;
Hobbs, Charles H. ;
Leach, Chet ;
Kuo, Mei-chang ;
Strack, Thomas R. .
DIABETES, 2006, 55 (12) :3604-3610
[8]   Inhalation of human insulin is associated with improved insulin action compared with subcutaneous injection and endogenous secretion in dogs [J].
Edgerton, Dale S. ;
Stettler, Kathryn M. ;
Neal, Doss W. ;
Scott, Melanie ;
Bowen, Larry ;
Wilson, Warren ;
Hobbs, Charles H. ;
Leach, Chet ;
Strack, Thomas R. ;
Cherrington, Alan D. .
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, 2006, 319 (03) :1258-1264
[9]   Inhalation of insulin (Exubera) is associated with augmented disposal of portally infused glucose in dogs [J].
Edgerton, DS ;
Neal, DW ;
Scott, M ;
Bowen, L ;
Wilson, W ;
Hobbs, CH ;
Leach, C ;
Sivakumaran, S ;
Strack, TR ;
Cherrington, AD .
DIABETES, 2005, 54 (04) :1164-1170
[10]   Small increases in insulin inhibit hepatic glucose production solely caused by an effect on glycogen metabolism [J].
Edgerton, DS ;
Cardin, S ;
Emshwiller, M ;
Neal, D ;
Chandramouli, V ;
Schumann, WC ;
Landau, BR ;
Rossetti, L ;
Cherrington, AD .
DIABETES, 2001, 50 (08) :1872-1882