Quantification of Basal Insulin Peglispro and Human Insulin in Adipose Tissue Interstitial Fluid by Open-Flow Microperfusion.
Restoration of the physiologic hepatic-to-peripheral insulin gradient may be achieved by either portal vein administration or altering insulin structure to increase hepatic specificity or restrict peripheral access. Basal insulin peglispro (BIL) is a novel, PEGylated basal insulin with a flat pharmacokinetic and glucodynamic profile and altered hepatic-to-peripheral action gradient. We hypothesized reduced BIL exposure in peripheral tissues explains the latter, and in this study assessed the adipose tissue interstitial fluid (ISF) concentrations of BIL compared with human insulin (HI).



A euglycemic glucose clamp was performed in patients with type 1 diabetes during continuous intravenous (IV) infusion of BIL or HI, while the adipose ISF insulin concentrations were determined using open-flow microperfusion (OFM). The ratio of adipose ISF-to-serum concentrations and the absolute steady-state adipose ISF concentrations were assessed using a dynamic no-net-flux technique with subsequent regression analysis.



Steady-state BIL concentrations in adipose tissue ISF were achieved by ∼16 h after IV infusion. Median time to reach steady-state glucose infusion rate across doses ranged between 8 and 22 h. The average serum concentrations (coefficient of variation %) of BIL and HI were 11,200 pmol/L (23%) and 425 pmol/L (15%), respectively. The ISF-to-serum concentration ratios were 10.2% for BIL and 22.9% for HI.



This study indicates feasibility of OFM to measure BIL in ISF. The observed low ISF-to-serum concentration ratio of BIL is consistent with its previously demonstrated reduced peripheral action.
1 HEALTH-Institute for Biomedicine and Health Sciences , Joanneum Research Forschungsgesellschaft mbH, Graz, Austria .
Katrin
K
Tiffner
1 HEALTH-Institute for Biomedicine and Health Sciences , Joanneum Research Forschungsgesellschaft mbH, Graz, Austria .|2 Division of Endocrinology and Diabetology, Department of Internal Medicine, Medical University of Graz , Graz, Austria .
Beate
B
Boulgaropoulos
1 HEALTH-Institute for Biomedicine and Health Sciences , Joanneum Research Forschungsgesellschaft mbH, Graz, Austria .
Christian
C
Höfferer
1 HEALTH-Institute for Biomedicine and Health Sciences , Joanneum Research Forschungsgesellschaft mbH, Graz, Austria .
Thomas
T
Birngruber
3 Eli Lilly and Company , Indianapolis, Indiana.
Niels
N
Porksen
3 Eli Lilly and Company , Indianapolis, Indiana.
Helle
H
Linnebjerg
3 Eli Lilly and Company , Indianapolis, Indiana.
Parag
P
Garhyan
4 Lilly-NUS Centre for Clinical Pharmacology , Singapore, Singapore .
Eric Chen Quin
ECQ
Lam
3 Eli Lilly and Company , Indianapolis, Indiana.
Mary Pat
MP
Knadler
1 HEALTH-Institute for Biomedicine and Health Sciences , Joanneum Research Forschungsgesellschaft mbH, Graz, Austria .|2 Division of Endocrinology and Diabetology, Department of Internal Medicine, Medical University of Graz , Graz, Austria .
Thomas R
TR
Pieber
1 HEALTH-Institute for Biomedicine and Health Sciences , Joanneum Research Forschungsgesellschaft mbH, Graz, Austria .|2 Division of Endocrinology and Diabetology, Department of Internal Medicine, Medical University of Graz , Graz, Austria .
Frank
F
Sinner
D000328:Adult; D015992:Body Mass Index; D018592:Cross-Over Studies; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000150:complications / Q000188:drug therapy / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D045604:Extracellular Fluid / Q000378:metabolism*; D005240:Feasibility Studies; D005260:Female; D015309:Glucose Clamp Technique; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics* / Q000627:therapeutic use; D007262:Infusions, Intravenous; D007332:Insulin Infusion Systems; D061268:Insulin Lispro / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics / Q000627:therapeutic use; D061386:Insulin, Regular, Human / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics* / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D018670:Monitoring, Ambulatory; D050177:Overweight / Q000150:complications; D010477:Perfusion; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics* / Q000627:therapeutic use; D050507:Subcutaneous Fat, Abdominal / Q000378:metabolism*; D014018:Tissue Distribution
D007004:Hypoglycemic Agents; D061268:Insulin Lispro; D061386:Insulin, Regular, Human; C000621851:basal insulin peglispro; D011092:Polyethylene Glycols
Dynamic no-net-flux technique; Euglycemic glucose clamp; Insulin analogues; Open-flow microperfusion; Peripheral tissue concentration