Conference Coverage

The dextrose-sulfonylurea challenge: a screen for monogenetic diabetes?


Key clinical point: Some patients with type 1 diabetes mellitus might need just a daily dose of a sulfonylurea instead of multiple insulin injections; a test to find them is being developed.

Major finding: Nearly one-third of patients with long-standing, insulin-dependent type 1 diabetes secreted their own insulin when given the beta-cell stimulator glipizide.

Study details: An observational study of 42 people with type 1 diabetes mellitus.

Disclosures: The investigators had no disclosures to report, and there was no industry funding.

Source: Nichols CG et al. ADA 2018, Abstract 310-LB.



ORLANDO – When investigators at Washington University, St. Louis, gave 42 patients with type 1 diabetes mellitus a dose of the sulfonylurea glipizide (Glucotrol), a curious thing happened.

C-peptide levels rose in 13 patients (31%), which means they secreted their own insulin.

The finding was unexpected; people with type 1 diabetes mellitus (T1DM) aren’t supposed to be able to produce endogenous insulin because they don’t have beta cells. They shouldn’t have had any response to glipizide, a beta-cell stimulator.

It wasn’t that the 13 subjects were in the honeymoon phase of T1DM, meaning that they still had a few beta cells left. Like the other patients, their glucose levels rose when they were given dextrose, but their C-peptide levels did not. Also, all patients, including the 13 who secreted insulin, had been diagnosed with T1DM for a mean of 6 years and were insulin dependent. They ranged in age up to 33 years, and their hemoglobin A1c was about 8.6%.

In short, the 13 patients didn’t have classic type 1 diabetes. They had something wrong with their beta cells, explained Colin G. Nichols, PhD, a professor of cell biology and physiology at Washington University.

They likely had monogenetic diabetes, a genetic mutation that caused potassium channels in their beta cells to be permanently hyperpolarized. Blocking the channels with a sulfonylurea allowed the cells to depolarize and secrete insulin.

Monogenetic diabetes is a known but underrecognized entity. If it’s not picked up in infancy, most patients are misdiagnosed with classic T1DM and inappropriately treated with insulin. If they finally try a sulfonylurea, “they don’t need insulin injections anymore. This has been a very magical story for this group of patients,” Dr. Nichols said at the annual scientific sessions of the American Diabetes Association.

All they need is a sulfonylurea pill once a day.

Monogenetic patients are missed because there are no easy, widely-available screening tests for the condition. Genetic testing works, but it’s expensive and often not done. Dr. Nichols and his team hope their dextrose-sulfonylurea challenge will solve the problem.

They are currently working to recruit more subjects and perform confirmatory genetic testing. They want to know how much insulin secretion is possible for their glipizide responders and how long their responses last. If funding comes through, they hope to do a screening and treatment trial in patients with T1DM.

The promise is that the dextrose-sulfonylurea challenge will shorten the time to a correct diagnosis and proper treatment, and save people from decades of insulin shots. It might also pick up nongenetic, metabolic causes of beta-cell potassium channel dysfunction that would respond to sulfonylureas. The challenge could even be used to prescreen for genetic testing, to increase its yield and shift the cost-benefit ratio more into the black.

As for the specifics of the study, the 42 patients were given an intravenous dextrose bolus of 0.5 g/kg, followed 20 minutes later by a single dose of glipizide, 0.3 mg/kg. Blood glucose and C-peptide were measured at baseline and at regular intervals during the 4-hour challenge. The challenge was safe; there were no serious side effects.

Among the 13 responders – meaning flat insulin secretion with dextrose but insulin secretion with glipizide – the peak change in C-peptide was around 0.41 ng/mL ± 0.45 an hour or so after the glipizide dose, and was maintained for about an hour from a baseline of about 0.6 ng/mL.

To make sure that the responders didn’t have just a delayed insulin response to dextrose, they were given another dextrose challenge 6 months later, without the glipizide. Again, their C-peptide levels were flat.

The investigators had no disclosures to report, and there was no industry funding.

SOURCE: Nichols CG et al. ADA 2018, Abstract 310-LB.

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