Development of a long-acting insulin analog using albumin fusion technology.
The primary therapeutic goal for the treatment of diabetes is maintenance of a long-term, near-normoglycemic condition and prevention of the onset or progression of the complications associated with the disease. Although several analogs of human insulin have been developed, the currently prescribed long-acting insulin analogs do not provide a stable basal glycemia for more than a few hours. Here, we report the development of Albulin, a long-acting insulin analog obtained by direct gene fusion of a single-chain human insulin to human serum albumin. Albulin showed an elimination t(1/2) of approximately 7 h in normoglycemic mice. In vitro pharmacodynamic profiles for Albulin characterized by receptor binding, inhibition of gluconeogenesis, induction of glucose uptake, and global regulation of gene expression in relevant cell types showed that Albulin produced similar activity profiles compared with that of recombinant human insulin. A single Albulin administration in vivo normalized blood glucose level in diabetic mice in a relatively peakless and sustained (24-h) fashion. A further reduction in glucose levels was achieved by administering a recombinant human insulin a few hours after Albulin injection in mice, indicating the potential for Albulin therapy in combination with available fast-acting insulin derivatives. In summary, Albulin displays characteristics of a potent long-acting insulin analog that can be evaluated for use as a novel insulin therapy for patients with insulin-dependent diabetes.
Duttaroy
Alokesh
A
Division of Diabetes, Endocrinology and Metabolic Diseases, NIDDK/NIH, 6707 Democracy Blvd., Rm. 606, MSC5460, Bethesda, MD 20892-5460, USA.
Kanakaraj
Palanisamy
P
Osborn
Blaire L
BL
Schneider
Helmut
H
Pickeral
Oxana K
OK
Chen
Cecil
C
Zhang
Guiyi
G
Kaithamana
Shashi
S
Singh
Mallika
M
Schulingkamp
Robert
R
Crossan
Dan
D
Bock
Jason
J
Kaufman
Thomas E
TE
Reavey
Peter
P
Carey-Barber
Melisa
M
Krishnan
Surekha R
SR
Garcia
Andy
A
Murphy
Kelly
K
Siskind
Jana K
JK
McLean
Malia A
MA
Cheng
Susan
S
Ruben
Steve
S
Birse
Charles E
CE
Blondel
Olivier
O
D016475:3T3 Cells; D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D003001:Cloning, Molecular; D004926:Escherichia coli; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D005813:Genes, Synthetic; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000235:genetics* / Q000493:pharmacokinetics* / Q000494:pharmacology; D049528:Insulin, Long-Acting; D061386:Insulin, Regular, Human; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016133:Polymerase Chain Reaction; D011972:Receptor, Insulin / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000493:pharmacokinetics* / Q000494:pharmacology; D012709:Serum Albumin / Q000235:genetics* / Q000493:pharmacokinetics* / Q000494:pharmacology; D000075462:Serum Albumin, Human
C499251:Albulin; D007328:Insulin; D049528:Insulin, Long-Acting; D061386:Insulin, Regular, Human; D011993:Recombinant Fusion Proteins; D012709:Serum Albumin; D011972:Receptor, Insulin; D005947:Glucose; D000075462:Serum Albumin, Human