New Data Shows Lantus® Activation of Insulin Receptor Comparable to Human Insulin

Paris (ots/PRNewswire) -

- Human and in vivo Studies Indicate Lantus(R) Metabolites do not
ConferCarcinogenic Potential via IGF-1 Receptor Activation

Sanofi announced at the 71st American Diabetes Association
Scientific Sessions 2011 the results of four studies[1,2,3,4]
indicating that the effect of Lantus(R) (insulin glargine)
metabolites on the IGF-1 receptor is distinctly different from
AspB10, the only insulin analog shown to have a carcinogenic effect.

Insulin receptor signalling pattern of AspB10 distinctly different
from glargine

The goal of the first study[1] by Tennagels et al was to
investigate the metabolic and mitogenic signalling of [AspB10]
insulin (AspB10 or also called X10) and insulin glargine in vitro and
in vivo. AspB10 is the only insulin analog shown so far to have a
tumorogenic effect (breast cancer in rats).The study showed that
following subcutaneous injection of 1.0 or 12.5 U/kg in rats, neither
human insulin nor insulin glargine nor AspB10 induced IGF-1 receptor
activation in responsive tissues, whereas IGF-1 injection produced a
robust activation.

In the study, AspB10 induced an increased and prolonged activation
of insulin receptor (IR) signalling molecules in several tissues. The
IR signalling pattern found for AspB10 is distinctly different from
that of human insulin and insulin glargine, confirming earlier in
vitro findings.

In vitro, AspB10 displays a higher affinity toward both IR and
IGF-1 receptors, a prolonged occupancy time at the IR and a higher
proliferation rate in mammalian cell lines. This is the basis for the
contention that insulin analogs with increased IGF-1 receptor
affinity in vitro also have increased growth promoting activity in
vivo. The study shows, however, that the IGF-1 receptor is not
involved in the mode of action of AspB10, the only insulin analog
shown to have a carcinogenic effect.

Furthermore, the study underlines the distinct differences between
insulin receptor signalling patterns of AspB10 is distinctly
different from human insulin and insulin glargine, suggesting that
insulin glargine does not confer carcinogenic potential through IGF-1
receptor activation.

The goal of the second study[2] by Tennagels et al was to further
elucidate the characteristics of insulin glargine signalling in rats.
It investigated the time action profile of insulin glargine in
different rat tissues with respect to pharmacological and signalling
parameters and compared it to human insulin, insulin detemir and
AspB10.

Male Wistar rats were injected subcutaneously with 1 U/kg of
either human insulin or each of the insulin analogs, and the effects
on blood glucose and activation status of IR, IGF-1 receptor and
additional pathways in tissue samples derived from muscle, fat,
liver, heart and kidney investigated over time. The time course of IR
signalling by human insulin and insulin glargine clearly correlated
with the time course of their pharmacodynamic effects, whereas the
time course of IR signalling by insulin glargine was found to be
distinctively different from that of AspB10.

Insulin glargine treatment resulted in activation levels of IR
that were comparable to human insulin although delayed in some
tissues. In contrast, AspB10 treatment resulted in at least two- to
threefold higher activation and significantly longer duration in most
tissues ex vivo, confirming the in vitro observations of increased
affinity and occupancy time of the IR.

Importantly, neither human insulin nor insulin glargine nor AspB10
treatment resulted in any detectable IGF-1 receptor activation in
muscle and heart tissue, whereas injection of IGF-1 increased
activation of this receptor.

Glargine metabolized to products with lower affinity for IGF-1 vs
human insulin

The goal of the third study[3], involving 12 patients with type 1
diabetes, was to investigate the plasma exposure to insulin glargine
and its metabolites. The study showed following subcutaneous
injection, insulin glargine was almost completely transformed into
two metabolites (M1 and M2), with M1 accounting almost totally for
the pharmacodynamic effect of injected glargine.

Insulin glargine and M2 were only detectable in approximately
one-third of patients and at a few time points only. When detectable,
insulin glargine and M2 exposure did not increase with increasing
dose, and concentrations were far below endogenous interprandial
plasma insulin concentrations of people without diabetes.

After injection of a therapeutic dose, glargine is minimally
detectable in blood

Finally, the goal of the fourth study[4] was to examine the
metabolism of insulin glargine in patients with type 2 diabetes. This
study confirmed that, after injection of a therapeutic dose in
patients with type 2 diabetes, insulin glargine is minimally
detectable in blood. Its metabolite M1 accounts for most (

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