A Novel Insulin Analog With Unique Properties

• DOI: 10.2337/diabetes.52.9.2227
• Publication Date: 2007-03-06T19:04:22Z
• Authors: Irini Rakatzi; Stefanie Ramrath; Daniela Ledwig; Olaf Dransfeld; Thomas Bartels; Gerhard Seipke; Jürgen Eckel
• Keywords: Insulin receptor substrate; Internalization; IRS2

The potentially enhanced mitogenic activity of insulin analogs represents a safety risk that requires detailed analysis new considered for therapeutic applications. We assessed the signaling properties and potency two novel rapid-acting analogs, LysB3,GluB29 (HMR 1964) LysB3,IleB28 1153) using myoblasts cardiomyocytes. In myoblasts, both binding internalization were two- to threefold higher AspB10 HMR 1153 when compared with 1964 regular insulin. This finding correlated prominent Shc/IGF-I receptor interaction, tyrosine phosphorylation Shc, activation extracellular signal-regulated protein kinase (ERK)-1 -2, stimulation DNA synthesis by contrast, produced marginal Shc/ERK cascade was equipotent in stimulating myoblasts. Further, vivo growth-promoting this analog found be identical human minor substrate (IRS)-1 phosphorylation, but IRS-2, significantly stronger effect than Predominant IRS-2 also observed adult cardiomyocytes where increased 3-O-methylglucose transport Akt glycogen synthase kinase-3 same extent as concluded 1) may result from series initial interactions, including phosphorylation; 2) metabolic potential is insulin; 3) predominant open avenues optimized therapies.