Acute sulfonylurea therapy at disease onset can cause permanent remission of KATP-induced diabetes.

Abstract

OBJECTIVE:

Neonatal diabetes mellitus (NDM) can be caused by gain-of-function ATP-sensitive K(+) (K(ATP)) channel mutations. This realization has led to sulfonylurea therapy replacing insulin injections in many patients. In a murine model of K(ATP)-dependent NDM, hyperglycemia and consequent loss of β-cells are both avoided by chronic sulfonylurea treatment. Interestingly, K(ATP) mutations may underlie remitting-relapsing, transient, or permanent forms of the disease in different patients, but the reason for the different outcomes is unknown.

RESEARCH DESIGN AND METHODS:

To gain further insight into disease progression and outcome, we examined the effects of very early intervention by injecting NDM mice with high-dose glibenclamide for only 6 days, at the beginning of disease onset, then after the subsequent progression with measurements of blood glucose, islet function, and insulin sensitivity.

RESULTS:

Although ∼70% of mice developed severe diabetes after treatment cessation, ∼30% were essentially cured, maintaining near-normal blood glucose until killed. Another group of NDM mice was initiated on oral glibenclamide (in the drinking water), and the dose was titrated daily, to maintain blood glucose <200 mg/dL. In this case, ∼30% were also essentially cured; they were weaned from the drug after ∼4 weeks and again subsequently maintained near-normal blood glucose. These cured mice maintain normal insulin content and were more sensitive to insulin than control mice, a compensatory mechanism that together with basal insulin secretion may be sufficient to maintain near-normal glucose levels.

CONCLUSIONS:

At least in a subset of animals, early sulfonylurea treatment leads to permanent remission of NDM. These cured animals exhibit insulin-hypersensitivity. Although untreated NDM mice rapidly lose insulin content and progress to permanently extremely elevated blood glucose levels, early tight control of blood glucose may permit this insulin-hypersensitivity, in combination with maintained basal insulin secretion, to provide long-term remission.

• Authors: Maria Sara Remedi, Sophia E Agapova, Arpita K Vyas, Paul W Hruz, Colin G Nichols
• Journal: Diabetes (Diabetes) Vol. 60 Issue 10 Pg. 2515-22 (Oct 2011) ISSN: 1939-327X [Electronic] United States
• PMID: 21813803 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Blood Glucose
• Hypoglycemic Agents
• KATP Channels
• Sulfonylurea Compounds
• Glucose
• Glyburide

Topics

• Animals
• Blood Glucose
• Diabetes Mellitus (drug therapy, genetics, metabolism)
• Glucose (metabolism)
• Glyburide (administration & dosage, therapeutic use)
• Humans
• Hypoglycemic Agents (administration & dosage, therapeutic use)
• Insulin Resistance
• Islets of Langerhans (metabolism)
• KATP Channels (genetics, metabolism)
• Mice
• Mice, Transgenic
• Mutation
• Sulfonylurea Compounds (administration & dosage, therapeutic use)