Incretin Drugs Help a Young Woman with Rare Genetic Diabetes Stop Insulin Injections and Drop HbA1c by Nearly 5% | Research

The takeaway

Adding sitagliptin and then semaglutide to a sulfonylurea allowed a 24-year-old with permanent neonatal diabetes to discontinue insulin entirely, reduce her HbA1c by 4.8%, and improve glucose variability without hypoglycemia.

4.8% HbA1c reduction with incretin therapy
Adding sitagliptin to existing treatment enabled complete insulin discontinuation in a patient with permanent neonatal diabetes who required 47 units of insulin daily

What the researchers found

Starting sitagliptin (DPP-4 inhibitor, 50 mg/day) enabled complete insulin discontinuation (from 47 U/day) and reduced HbA1c by 4.8% in a patient with permanent neonatal diabetes on high-dose glibenclamide (0.6 mg/kg/day). Doubling the sitagliptin dose and subsequently switching to semaglutide (GLP-1 receptor agonist, 0.25 then 0.5 mg/week) produced further HbA1c improvements with graded increases in endogenous insulin secretion.

Glibenclamide was safely downtitrated from 0.6 to 0.4 mg/kg/day without hypoglycemia. Continuous glucose monitoring showed improvements in both intra- and inter-day glucose variability, indicating more stable blood sugar control throughout the day.

Why it matters

Permanent neonatal diabetes is typically managed with insulin and sulfonylureas, but many patients struggle to achieve good glycemic control. This case demonstrates that incretin-based therapies — which work by enhancing the body's natural peptide hormone signaling — can dramatically improve outcomes even in a genetic form of diabetes where insulin secretion is inherently impaired. The 4.8% HbA1c reduction is clinically extraordinary and suggests that incretin pathways retain therapeutic potential even when β-cell function is genetically compromised.

How the study worked

This is a single case report of a 24-year-old woman with permanent neonatal diabetes mellitus. Treatment changes were made sequentially: addition of sitagliptin to existing insulin and glibenclamide, then sitagliptin dose escalation, then switch to semaglutide. Glycemic control was monitored through HbA1c, continuous glucose monitoring (for variability), and assessment of endogenous insulin secretion markers. Hypoglycemia episodes were tracked throughout.

What this study cannot tell us

This is a single case report (n=1), the weakest level of clinical evidence. The dramatic response may not be generalizable to other PNDM patients, as the specific genetic mutation was not detailed in the abstract and different mutations may respond differently. The mechanism behind the enhanced insulin secretion with incretin drugs in this genetic context is not fully explained. Follow-up duration was not specified, so long-term durability of the response is unknown.

How to read the evidence

This is a single case report — the lowest level of clinical evidence. While the treatment response is remarkable and well-documented with objective measures (HbA1c, CGM data), it represents one patient and cannot be generalized without further study.

When this study was published

Published in 2024, this is a very recent case report reflecting current treatment options including semaglutide for a rare diabetes subtype.

The bigger picture

This case challenges assumptions about which diabetes patients can benefit from incretin-based therapy. While GLP-1 receptor agonists and DPP-4 inhibitors are primarily prescribed for type 2 diabetes, this report shows benefit in a monogenic form of diabetes — permanent neonatal diabetes — where the genetic defect impairs β-cell function. It suggests the incretin pathway can augment whatever residual insulin secretory capacity exists, potentially broadening the clinical application of these peptide-based therapies to rare diabetes subtypes.

Questions still open

Which specific PNDM-causing mutations are most likely to respond to incretin-based therapy?
Could early initiation of incretin drugs in PNDM patients prevent the need for insulin from the start?
What is the mechanism by which sitagliptin and semaglutide enhance endogenous insulin secretion in a genetic disorder where β-cell function is inherently impaired?

Common questions

What is permanent neonatal diabetes and how is it different from type 1 or type 2 diabetes?

Permanent neonatal diabetes is a rare genetic condition diagnosed in infancy where specific gene mutations impair the pancreas's ability to produce insulin. Unlike type 1 diabetes (autoimmune destruction of β-cells) or type 2 diabetes (insulin resistance), PNDM has a defined genetic cause. Some patients respond to sulfonylurea pills, but many still need insulin. This case showed that adding incretin-based peptide drugs produced dramatic improvement beyond what insulin and sulfonylureas alone could achieve.

How did the incretin drugs help if the patient's genetic condition reduces insulin production?

Incretin drugs like sitagliptin and semaglutide work by enhancing the body's natural GLP-1 peptide signaling, which stimulates insulin release from whatever functioning β-cells remain. Even though PNDM genetically impairs β-cell function, some residual capacity apparently remained. The incretin drugs amplified this residual function enough to eliminate the need for insulin injections — a surprising finding that suggests these peptide pathways are more powerful β-cell stimulators than previously appreciated.

Read the original research

Long-Term Effects of Incretin-Based Drugs on Glycemic Control in Permanent Neonatal Diabetes.

JCEM case reports, 2(11), luae188

View on PubMed ↗Publisher’s paper ↗

Citation

Oshiro, Ayaka; Aotani, Ryoichiro; Sakamoto, Wakako; Kitazono, Takanari; Ohkuma, Toshiaki. (2024). Long-Term Effects of Incretin-Based Drugs on Glycemic Control in Permanent Neonatal Diabetes.. JCEM case reports, 2(11), luae188. https://doi.org/10.1210/jcemcr/luae188