Patterns of postmeal insulin secretion in individuals with sulfonylurea-treated KCNJ11 neonatal diabetes show predominance of non-KATP-channel pathways

Pamela Bowman, Timothy J McDonald, Bridget A Knight, Sarah E Flanagan, Maria Leveridge, Steve R Spaull, Beverley M Shields, Suzanne Hammersley, Maggie H Shepherd, Robert C Andrews, Kashyap A Patel, Andrew T Hattersley, Pamela Bowman, Timothy J McDonald, Bridget A Knight, Sarah E Flanagan, Maria Leveridge, Steve R Spaull, Beverley M Shields, Suzanne Hammersley, Maggie H Shepherd, Robert C Andrews, Kashyap A Patel, Andrew T Hattersley

Abstract

Objective: Insulin secretion in sulfonylurea-treated KCNJ11 permanent neonatal diabetes mellitus (PNDM) is thought to be mediated predominantly through amplifying non-KATP-channel pathways such as incretins. Affected individuals report symptoms of postprandial hypoglycemia after eating protein/fat-rich foods. We aimed to assess the physiological response to carbohydrate and protein/fat in people with sulfonylurea-treated KCNJ11 PNDM.

Research design and methods: 5 adults with sulfonylurea-treated KCNJ11 PNDM and five age, sex and body mass index-matched controls without diabetes had a high-carbohydrate and high-protein/fat meal on two separate mornings. Insulin(i) and glucose(g) were measured at baseline then regularly over 4 hours after the meal. Total area under the curve (tAUC) for insulin and glucose was calculated over 4 hours and compared between meals in controls and KCNJ11 cases.

Results: In controls, glucose values after carbohydrate and protein/fat were similar (median glucose tAUC0-4h21.4 vs 19.7 mmol/L, p=0.08). In KCNJ11 cases glucose levels were higher after carbohydrate than after protein/fat (median glucose tAUC0-4h58.1 vs 31.3 mmol/L, p=0.04). These different glycemic responses reflected different patterns of insulin secretion: in controls, insulin secretion was greatly increased after carbohydrate versus protein/fat (median insulin tAUC0-4h727 vs 335 pmol/L, p=0.04), but in KCNJ11 cases insulin secretion was similar after carbohydrate and protein/fat (median insulin tAUC0-4h327 vs 378 pmol/L, p=0.50).

Conclusions: Individuals with sulfonylurea-treated KCNJ11 PNDM produce similar levels of insulin in response to both carbohydrate and protein/fat meals despite carbohydrate resulting in much higher glucose levels and protein/fat resulting in relatively low glucose levels. This suggests in an inability to modulate insulin secretion in response to glucose levels, consistent with a dependence on non-KATP pathways for insulin secretion.

Trial registration number: NCT02921906.

Keywords: SU (Sulfonylurea); insulin secretion; permanent Neonatal Diabetes; physiology.

Conflict of interest statement

Competing interests: None declared.

© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. Published by BMJ.

Figures

Figure 1
Figure 1
(A) Glucose total area under the curve (AUC) over 4 hours. Controls are shown in light gray (diamonds are individuals and lines are group medians). KCNJ11 cases are shown in dark gray (circles are individuals and lines are group medians). (B) Insulin total AUC over 4 hours. Controls are shown in light gray (diamonds are individuals and lines are group medians). KCNJ11 cases are shown in dark gray (circles are individuals and lines are group medians).
Figure 2
Figure 2
Incremental glucose (blue solid line), insulin (red solid line) and glucagon (black broken line) in controls without diabetes and sulfonylurea-treated KCNJ11 cases with carbohydrate (upper panel) and protein/fat (lower panel) meals. Values shown are medians.
Figure 3
Figure 3
Glucagon total area under the curve (AUC) over 4 hours. Controls are shown in light gray (diamonds are individuals and lines are group medians). KCNJ11 cases are shown in dark gray (circles are individuals and lines are group medians).

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