Novo Nordisk publish data demonstrating proof of concept for potassium channel openers as treatments of diabetes
Summary
DailyUpdates 13th April: 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".DailyUpdates 13th April: 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
Recommended further reading:
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 treatment of elderly patients with isolated systolic hypertension with eprosartan mesylate...and much more.