Kv1.3 potassium channel blockade as an approach to insulin resistance
SummaryThe R&D activity surrounding novel oral treatments of diabetes is considerable and one particular target that has recently received attention is the Kv1.3 potassium channel. Blocking this channel has been thought to be of value in the treatment of multiple sclerosis and more recently for preventing weight gain. Now researchers from Yale have demonstrated that Kv1.3 channel blockers may also increase insulin sensitivity in genetically obese and diabetic mice
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 market for diabetes therapeutics is also rising with global sales reportedly topping $8.1 billion for the 12 months to September 2000, a 19% increase over the previous 12 months (for a full analysis of diabetes therapeutics and market opportunities click here).
Sales of insulin, to which many diabetics must resort as a treatment option with time, stand at around 30%. Further increases are inevitable and the market for diabetes medications could exceed $20 billion by 2006.
According to our recent feature “Insulin Use in Type 2 Diabetes - From Last Resort to Early Intervention”, only 13-28% of drug-treated type 2 diabetes patients receive insulin therapy. This is due in part to the lack of non-injectable insulin formulations and R&D activity surrounding the development of oral and inhaled insulin is thus immense.
Oral antidiabetic drugs are however the leading class of drugs used to treat the disease and account for almost 63% of sales. This drug class has traditionally focussed on metformin and sulphonylurea. Until 1995, the sulfonylurea class of drugs which act by increasing insulin secretion was the only choice in the other than insulin for treating type 2 diabetes. The explosion of drugs available for controlling blood glucose began when Glucophage (metformin) became available in 1995, quickly followed by the approval of the insulinotropic agent Repaglinide in 1997 and the thiazolidinedione insulin sensitizers such as Avandia and Actos, which were both launched in 1999. The search for novel insulin sensitizers continues and Yale researchers have been focusing their attentions on the potassium channel Kv1.3 in this respect.
Ion channels underlie many drug discovery projects spanning a broad range of indications (for a full overview of this area, Click here to access Ion Channels as Therapeutic Targets for Multiple Diseases). Despite already generating over $6 billion in sales per annum the market for ion channel modulators is under-exploited and is set to explode as improved screening tools as well as highly targeted libraries of candidate channel modulators become available (see for example our feature “Ion Channel Assays in the Drug Discovery Process” as well as the Potassium channel enterprise library recently highlighted by LeadDiscovery).
One channel that is receiving growing interest in the scientific community is the voltage-gated K+ channel, Kv1.3. This channel is one of two potassium channels expressed by human T lymphocytes that are involved in proliferation and cytokine secretion (the other is the calcium-activated K + channel IKCa1). Researchers at the have recently reported that myelin-reactive encephalitogenic rat T cells expressed unusually high numbers of Kv1.3 channels following antigenic stimulation. Furthermore adoptive transfer of these T cells induced multiple sclerosis-like inflammation in rats, an effect which was reduced by Kv1.3 blockade. The search for Kv1.3 blockers or molecules able to prevent channel expression could therefore provide novel anti-inflammatory molecules.
In addition to being involved in T cell function, examination of Kv1.3-deficient mice revealed a previously unrecognized role for Kv1.3 in body weight regulation. Indeed, Kv1.3(-/-) mice weigh significantly less than control littermates. Moreover, knockout mice are protected from diet-induced obesity and gain significantly less weight than littermate controls when placed on a high-fat diet. While food intake did not differ significantly between Kv1.3(-/-) and controls, basal metabolic rate, measured at rest by indirect calorimetry, was significantly higher in knockout animals. These data indicate that Kv1.3 channels may participate in the pathways that regulate body weight and that channel inhibition increases basal metabolic rate.
Now researchers from Yale have demonstrated that Kv1.3-/- mice or wild-type mice treated acutely with margatoxin to block Kv1.3 channels are more sensitive to insulin. In their recent PNAS paper Xu et al then went on to investigate the pathophysiological role of Kv1.3, demonstrating that margatoxin is also able to increase insulin sensitivity as indicated by an exaggerated hypoglycemic response to insulin, in genetically obese and diabetic mice (ob/ob and db/db mice). Mechanistically this was shown to be due to increased glucose uptake by both adipose tissue and skeletal muscle and at a molecular level results from a translocation of the GLUT4 glucose transporter to the plasma membrane. The authors suggest that Kv1.3 act to decrease TNF-alpha and IL-6 release by adipocytes which in turn leads to a decrease in the activity of mitogen-activated protein kinases such as JNK, and an increase in GLUT4 transcription and insulin receptor substrate (IRS)-1 activity.
This important study offers considerable proof of concept for the development of Kv1.3 channel inhibitors as a means of reversing insulin insensitivity, which constitutes a central feature of obesity and diabetes. A number of companies, notably Merck are developing Kv1.3 inhibitors as immunosuppressive agents and investigating the activity of these candidates in the context of metabolic disorders should considerably increase the therapeutic potential of such molecules.
Original research Xu et al, Proc Natl Acad Sci U S A. 2004 Mar 2;101(9):3112-7
Source: TherapeuticAdvances, June 2004