|
|
Insulin and Sulfonylureas in Diabetic Patients with Kir6.2 Mutations« Back to Volume 22, Issue 4, December 2006 - Table of Contents Neonatal diabetes mellitus is a rare disorder and about half of those diagnosed before 6 months of age develop permanent diabetes. The most frequently identified genetic cause is related to heterozygous activating mutations in the KCNJ11 gene encoding the Kir6.2, a subunit of the ATP-sensitive potassium (KATP) channel. The activity of this channel in the pancreatic beta cell regulates insulin secretion. These activating mutations cause 30% to 58% of the cases of diabetes mellitus diagnosed in infants. Diabetes results from a failure of this channel to close in response to increased intracellular ATP, leading to impaired insulin secretion. Sulfonylureas, a class of drugs used to treat type 2 diabetes mellitus, close this potassium channel by an ATP-independent route, causing insulin secretion. Thus, this drug represents an alternative therapy to insulin in these patients. The first cases treated with sulfonylureas were reported 2 years ago; this study by Pearson et al is the first to assess the sustained response to sulfonylureas in a large cohort of patients who were initially treated with insulin. A total of 49 consecutive patients who had been diagnosed at less than 6 months of age with Kir6.2 mutations were switched from insulin to sulfonylurea therapy. An adequate dose of sulfonylureas was defined as a dose of glyburide (also known as glibenclamide) of at least 0.8 mg/kg/day. The change was considered to be successful if the patient was able to stop insulin treatment completely. Additionally, insulin secretory responses were assessed in subgroups receiving intravenous or oral glucose, a mixed meal, or intravenous glucagon before and after treatment with glyburide. Switching was successfully accomplished in 44 patients regardless of the type of sulfonylurea used, suggesting a class effect. The oldest patient was 36 years of age and the youngest was 3 months of age. The mean glycated hemoglobin level improved in all subjects and fell from 8.1% during insulin therapy to 6.4% after a mean of 12 weeks of sulfonylurea treatment and cessation of insulin. The initial improvement was sustained in the 12 patients who were insulin-independent for more than one year. The longest duration of insulin independence was 2.0 years, with a glycated hemoglobin level of 5.7%. Switching to sulfonylureas was unsuccessful in only 5 patients (10%). Of these patients, 4 (80%) had severe neurological features, including severe developmental delay, epilepsy, and neonatal diabetes, known as DEND syndrome. These neurological features occurred in only 6 patients (14%) who were successfully treated with sulfonylureas. In 2 families, the mothers were unable to switch from insulin therapy, even though their affected children were able to do so. Only 5 patients had transitory diarrhea while on sulfonylureas. The treatment had no detrimental effect on growth. There were no patient reports of severe hypoglycemia. In physiological studies sulfonylurea treatment increased insulin secretion. This was more highly stimulated by oral glucose or a mixed meal than by intravenous glucose. Exogenous glucagon increased insulin secretion only in the presence of sulfonylureas. The successful switch from insulin to sulfonylureas was reflected in vitro in xenopus oocytes with the same KATP channel mutation. Tolbutamide blocked more than 75% of the KATP current. The relatively high doses of sulfonylureas used in the treatment of these patients appeared to be safe on the short term. There was no increase in mild-to-moderate hypoglycemia, and a near-to-normal glycated hemoglobin level was achieved. The improved insulin secretory response to oral glucose and to mixed meals was interpreted as an effect of the sulfonylureas on the K channel, allowing the membrane to become depolarized, thereby the beta cell was able to respond to endogenous incretins (glucagon-like peptides). Because of the reported important therapeutic implications, the authors recommended a molecular diagnosis in all patients with neonatal diabetes mellitus diagnosed before the age of 6 months. It is also stressed that a longer follow-up is required to fully appreciate this progress in therapy of a genetic form of diabetes. Regulation of insulin secretion. The Kir6.2–SUR1 complex and its regulation and genetic variability. Panel A shows the detailed subunit structure of the KATP channel. Panel B shows the regulation of insulin secretion by glucose or amino acids (glutamate is used in this example). The beta cell senses the concentration of glucose or amino acid, or both, and converts their metabolism to energy in the form of ATP. In turn, ATP is converted to changes in the electrical membrane that regulate voltage-gated calcium channels to permit the influx of calcium and thereby insulin secretion. Central to these processes is the KATP channel, which is composed of four small subunits, Kir6.2, that surround a central pore and four larger regulatory subunits constituting SUR1. In the normal resting state, the potassium channel is open, modulated by the ratio of ATP to ADP. Hence, the beta-cell membrane is hyperpolarized, and the voltage-gated calcium channel (L type) remains closed. With the ingestion of food, the glucose concentration rises and enters the beta cell by way of the non–insulin-dependent glucose transporter 2. Glucose is rapidly phosphorylated by glucokinase, yielding glucose-6-phosphate, and further metabolism yields energy-rich ATP. The now altered ratio of ATP to ADP closes the KATP channel, causing the accumulation of some intracellular potassium, membrane depolarization, opening of the voltage-regulated calcium channel, and triggering of insulin exocytosis. PIP2 denotes phosphatidylinositol-4, Reprinted with permission. Sperling MA. N Engl J Med. 2006;355:507 – 510. Copyright © MMS. 2006. All rights reserved. Editor’s CommentThis large collaborative study by the neonatal diabetes international collaborative group has confirmed and extended our knowledge of the treatment of the most frequently occurring genetic form of permanent neonatal diabetes resulting from activating Kir6.2 mutations of an ATP-sensitive potassium channel of the beta cell (Figure). This novel pharmacogenetic approach was based on a model of regulation of insulin secretion involving a KATP channel. Interestingly, inactivating mutations of the components of this channel have been identified as the cause of hyperinsulinemic hypoglycemia of infancy; an opposite condition, activating mutations causing diabetes mellitus by limiting insulin secretion. The authors not only carefully investigated the new treatment with sulfonylureas, but also established physiologic evidence that this treatment restored insulin secretion in relation to glucose metabolism by closure of mutant KATP channels; it also amplified the effect of incretins levels that are stimulated by nutrient ingestion. In an accompanying editorial, Sperling1 recommended that a test for this genetic mutation be included as part of routine newborn screening programs. In all cases, newborns with this disease should be tested for activating mutations affecting Kir6.2, an approach facilitated by the one exon structure of the gene. Furthermore extensive familial studies are needed and other phenotypes may be expected as a consequence of mutations with milder activity. Another cause of permanent neonatal diabetes was also reported by Babenko et al.2 A careful history is needed in all patients with the onset of diabetes in infancy. It is remarkable that some, but not all, adult patients were responsive to the treatment switch from insulin to sulfonylureas. More information is needed regarding the failures observed in about 10% of the patients with the same genetic mutations. Raphaël Rappaport, MD References - (linked to
|
Volume 24 Number 2
November 2008
www.GGHjournal.com
ISSN 1932-9032
)