Activating Mutations in Kir6.2 and Neonatal Diabetes

New Clinical Syndromes, New Scientific Insights, and New Therapy

Andrew T. Hattersley; Frances M. Ashcroft


Diabetes. 2005;54(9):2503-2513. 

In This Article

From Genetics to Therapy

For patients with neonatal diabetes resulting from Kir6.2 mutations, diagnosis of the genetic etiology of their disease has revolutionized therapy. KATP channels that are insensitive to ATP as a consequence of Kir6.2 mutations can still be closed by sulfonylureas and glinides that bind to the SUR subunit and close the channel directly.[7] Thus, sulfonylurea tablets can be considered as an alternative to insulin injections.

Patients with Kir6.2 mutations have all the clinical characteristics of being insulin dependent. They present with ketoacidosis and C-peptide levels similar to those found in type 1 diabetes. Even when stimulated by glucagon, serum C-peptide concentration is very low (typically <200 pmol/l). Consequently, they were previously treated with insulin therapy. However, initial physiological studies in three patients showed that although there was no response to intravenous glucose, insulin secretion was observed within minutes of receiving intravenous tolbutamide.[2] Furthermore, a 46-year-old patient has had life-long good glycemic control after being treated with sulfonylurea tablets from diagnosis.[2]

A number of patients with Kir6.2 mutations have been able to discontinue their insulin injections completely and obtain as good, or better, glycemic control using oral sulfonylureas.[2,37,38,40,43] Continuous glucose monitoring, and the insulin response to intravenous glucose, suggest that patients with Kir6.2 mutations taking sulfonylureas have glucose-responsive insulin secretion.[43] Importantly, these patients require high doses of sulfonylureas: e.g., 0.4-1.0 mg/kg glibenclamide compared with a maximum suggested dose of 0.33 mg/kg for a 60-kg adult with type 2 diabetes. Mutations that affect the open probability of the channel (i.e., that cause neurological symptoms) are less sensitive to inhibition by sulfonylureas in vitro.[59,61] Thus, even higher drug doses may be necessary in these patients. Long-term follow-up studies are now required to assess whether the response to sulfonylureas is maintained; to date, the longest a patient has remained off insulin is 1 year, although over one-third have been able to reduce their dose of sulfonylureas while maintaining good control.

The neurological symptoms found in DEND syndrome probably arise as a consequence of enhanced activity of KATP channels in tissues other than the β-cell, such as muscle and/or nerve. Although insulin therapy can control blood glucose levels, it cannot alleviate the extrapancreatic consequences of enhanced KATP channel activity. Theoretically, sulfonylureas should also close KATP channels in extrapancreatic tissues and thereby ameliorate the neurological symptoms. However, the extent to which neurological features respond to sulfonylureas is still uncertain; it will be influenced by many factors, such as the extent to which the drug crosses the blood-brain barrier, the severity of the mutation, the plasticity of the brain, and the SUR subtype the channel contains. With respect to the latter, the choice of sulfonylurea may be important. Most subjects to date have been tested with glibenclamide, which binds to both SUR1 and SUR2 and can therefore block all types of KATP channels.[7] It is important to remember that while an SUR1-selective sulfonylurea (gliclazide and tolbutamide) will close β-cell KATP channels, it will not bind to the SUR2 receptors of muscle and brain KATP channels.[7] Thus, nonspecific sulfonylureas may be the better choice when attempting to alleviate neurological symptoms.


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