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| Novo
Nordisk publish data demonstrating proof of concept for potassium channel
openers as treatments of diabetes
DailyUpdates 13th April 2004: According to WHO, there are some 130 million diagnosed diabetics in the world, a figure that is predicted to increase to 300 million by 2025. Approximately 10-15% of these patients suffer type 1 diabetes. Novo Nordisk have shown that their Kir6.2/SUR1 channel opener, NN414 is able to preserve beta-cell function and reduction of insulitis presumable through the induction of "beta-cell rest". According to WHO, there are some 130 million diagnosed diabetics in the world, a figure that is predicted to increase to 300 million by 2025. The majority of patients suffer from type 2 diabetes however type 1 diabetes (also known as insulin-dependent diabetes (IDDM) or juvenile-onset diabetes) is common affecting 10-15% of all diabetes sufferers. The pancreatic defect in type 2 diabetes is characterized by a loss of the first phase of insulin secretion in response to a secretory stimulus. This leads to an inappropriately low suppression of hepatic glucose production and, therefore, to an enhanced level of systemic glycemia. This consequentially causes further demand on the beta-cell, producing hyperinsulinemia in the longer term. Hyperinsulinemic patients develop a gradually worsening peripheral insulin resistance which increases the workload of the pancreatic beta-cell. This further exacerbates hyperinsulinemia in a vicious circle of events that culminates, eventually, in beta-cell exhaustion and onset of frank diabetes. Oral antidiabetic drugs have traditionally focussed on metformin and sulphonylurea. The therapeutic action of the sulfonylureas results primarily from their ability to inhibit ATP-sensitive potassium channels in the beta cell plasma membrane and thereby stimulate insulin release to compensate for the failing beta-cell. The channel is an octameric complex of 2 structurally unrelated types of subunits, Kir6.2 and the sulfonylurea receptor SUR, which belongs to a family of ATP-binding cassette transporter proteins. SUR acts as a receptor for many drugs and endows Kir6.2 with sensitivity, both to sulfonylureas and to K+ channel openers. Two types of SUR have been cloned, with different pharmacologic sensitivities. The beta-cell channel is composed of Kir6.2 and SUR1, whereas cardiac channels comprise Kir6.2 and SUR2A.
Although increasing insulin secretion represents
the mainstay of diabetes therapeutics, overnight inhibition of insulin
secretion (induction of beta-cell rest) may also be of benefit as this can
lead to the quantitative normalization of pulsatile insulin secretion upon
subsequent stimulation. NN414 is a molecule developed by Novo
Nordisk which selectively opens Kir6.2/SUR1 channels in
pancreatic beta-cells and has been shown to be therapeutically active in
models of insulin resistance.
In their article published in the April edition of the journal Diabetes, Novo Nordisk researchers now report that NN414 improves beta-cell survival and reduced insulitis in a Type 1 diabetic rat model. Skak et al investigated whether NN414 can be used to improve beta-cell survival in rats rendered diabetic by modulation of their immune system. Rats were treated three times daily on days 1-19 with NN414, diazoxide, or vehicle. On day 21, an intravenous glucose tolerance test was conducted to assess beta-cell function. Postmortem histological analysis of rats' pancreata assessed the degree of insulitis and beta-cell volume.
Among NN414-treated rats, 46% were found to
have a beta-cell mass similar to that of nondiabetic controls and significant
glucose-stimulated C-peptide values, whereas only 11% of vehicle-treated rats
possessed a normal beta-cell mass and function. Furthermore, responsive
NN414-treated rats were almost free of insulitis. This study demonstrated
that treatment with NN414 can lead to preservation of beta-cell function
and reduction of insulitis in a rat diabetes model.
NN414 was, until recently in phase II stages of
development however in November 2003, Novo Nordisk decided to suspend the
exploratory clinical trials in people with Type 1 and Type 2 diabetes.
The suspension followed signs of an unwanted elevation of liver enzymes in the
blood, indicating an adverse effect on the liver during treatment with NN414.
It is currently unclear whether this adverse effect was class specific however
if derivatives of NN414 can be developed that are devoid of this effect, the
present study demonstrates the potential of such molecules in type 1 as well
as type II diabetes.
Source DailyUpdates 13th April; for a full abstract of the original papers see Diabetes. 2004 Apr;53(4):1089-95
In this edition of DailyUpdates, LeadDiscovery
also highlights the suppression of liver metastasis and invasive growth
of colon cancer in mice by hepatic gene expression of NK4, an HGF-antagonist/angiogenesis
inhibitor...NF1 a repressor of tissue plasminogen activator expression... the
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eprosartan mesylate...and much more.
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