A Novel Insulin Analog With Unique Properties

Abstract

The potentially enhanced mitogenic activity of insulin analogs represents a safety risk that requires detailed analysis of new analogs considered for therapeutic applications. We assessed the signaling properties and mitogenic potency of two novel rapid-acting insulin analogs, Lys Insulin therapy of diabetic patients aims to achieve tight blood glucose control to reduce the progression of long-term complications (1). However, the pharmacokinetic characteristics of currently available insulin preparations are unable to mimic the pattern of endogenous insulin secretion and make it impossible to achieve sustained normoglycemia (2). Great efforts have been made to develop novel insulin molecules with altered pharmacodynamic characteristics that might lead to improved glycemic control using recombinant DNA technology (rev. in 3-5). One limiting factor is the slow absorption of conventional unmodified insulin from subcutaneous tissues because of the slow dissociation rate of hexameric insulin complexes into monomers at the injection site (6,7). Modification of the B26ϪB30 region of the insulin molecule, particularly substitution of amino acids with charged residues at the association sites, allows the production of a range of insulin analogs with reduced selfassociation that exhibit no profound perturbations of insulin receptor recognition (4,8). This has been demonstrated for insulin analogs such as Lispro (Lys B28 ,Pro B29 ) insulin and insulin aspart (Asp B28 insulin), two rapidacting insulins that are in clinical use and improve postprandial glycemic control (3,5).A major concern related to the long-term use of insulin analogs stems from the observation that modification of the insulin molecule in the B10 and B26ϪB30 regions alters the affinity for the IGF-I receptor more than for the insulin receptor and may lead to enhanced mitogenic activity of these analogs (9). This potential safety risk was first recognized for the analog Asp B10 insulin, which was found to exhibit a tumor-promoting activity in SD rats (10) and to induce a profound mitogenic effect in many cell systems (11-13). The enhanced mitogenic signaling profile of an insulin analog may result from 1) an increased affinity toward the IGF-I receptor, resulting in augmented IGF-I receptor signaling (9); 2) the so-called time-dependent specificity that describes a distinct correlation between the mitogenic potential and the occupancy time at the insulin receptor for a given insulin analog (14); and 3) a combination of both IGF-I and insulin receptorϪ mediated processes. Most recent data suggest that the mitogenic properties correlate better with the IGF-I recep-

Insulin Glulisine

“…In rat cardiomyocytes, a prominent phosphorylation of IRS-2 has been described, with only marginal IRS-1 phosphorylation (7). Comparable results were obtained for human skeletal muscle cells incubated with an extensive amount of insulin glulisine (7). Moreover, an inhibition of cytokine and fatty acidϪinduced apoptosis was described in a rat insulinoma cell line through activation of IRS-2 and was favored as an antiapoptotic activity of insulin glulisine, thereby opening a new field for optimized insulin treatment (10).…”

“…Recent studies have revealed that insulin glulisine predominantly activates the IRS-2Ϫdependent pathway (7,10). Because enhanced IRS-2 signaling has been proposed to be involved in mitogenic signal transduction, the phosphorylation state of IRS-2 was determined in vivo in lysates of muscle and liver after insulin stimulation.…”

“…Recent in vitro data suggest that the novel insulin analog predominantly activates the IRS-2 signaling pathway, which raises a safety concern, as IRS-2 is known to be involved in cell proliferation and mitogenic signaling (7).…”

IGF-1 receptor signalling determines the mitogenic potency of insulin analogues in human smooth muscle cells and fibroblasts

“…Under these conditions the affinity of a certain insulin analogue towards IGF-1R becomes increasingly important. It has been shown that AspB10 and glargine have a six to eightfold and insulin lispro a 1.5-fold higher affinity for IGF-1R than normal insulin [21], while aspart [31] and glulisine [32,33] have a low affinity for IGF-1R, like normal insulin.…”

Effects of new insulin analogues HMR1964 (insulin glulisine) and HMR1423 on insulin receptors

“…A reasonable mechanism for the decreased mitogenic activity of HMR1964 was recently suggested by Rakatzi et al [18], who demonstrated in an in vitro model that HMR1964 shows lower IRS-1 phosphorylation than regular insulin.…”