Effect of Food Composition on Postprandial Insulin Secretion in Neonatal Diabetes (FoND)

Assessing the Effect of Food Composition on Postprandial Insulin Secretion in KCNJ11 Neonatal Diabetes (FoND Study)

Neonatal diabetes is diagnosed before 6 months of age and causes high blood glucose levels due to the pancreas not secreting insulin. Neonatal diabetes can be caused by a change in a DNA region called the KCNJ11 gene. KCNJ11 encodes a channel in the pancreas that acts as a switch to turn 'on' and 'off' insulin secretion. A change in KCNJ11 results in a faulty channel, which keeps insulin secretion 'switched off'. The diabetes can be treated with tablets called sulphonylureas that switch the pancreatic channel 'on', allowing it to secrete insulin in response to gut hormones called incretins. Previous research has shown that patients who switch from insulin to sulphonylureas have better blood glucose control, including fewer episodes of hypoglycaemia (glucose dropping too low), and also avoid the need for injections. It is thought that serious side effects from sulphonylureas are uncommon in KCNJ11 neonatal diabetes. Some patients report low glucose after meals and we think this may be because they make too much insulin if they eat a meal with protein but low amounts of carbohydrate. The investigators will test this by giving study participants different meals and measuring the amount of insulin, glucose and incretin hormone in the blood afterwards.

Anecdotal evidence from routine clinical care suggests that patients with sulphonylurea-treated KCNJ11 neonatal diabetes, when they eat, may experience mild hypoglycaemia if the food consumed lacks carbohydrate. It has been suggested that this may be due to regulation of insulin secretion via the incretin pathway as opposed to the classical ATP pathway. Therefore the investigators hypothesise that foods with a relatively high protein content compared to those with a relatively high carbohydrate content will result in excessive insulin secretion and relatively lower glucose values in KCNJ11 patients. This would be in contrast to healthy control subjects or subjects with SU-treated T2D where the insulin secretion will be moderated by the ambient glucose via the classical ATP pathway. The investigators will formally study this hypothesis by comparing the insulin, glucose and incretin hormone responses to a high protein meal with a high carbohydrate meal in people with KCNJ11 neonatal diabetes, people without diabetes and people with sulphonylurea-treated Type 2 Diabetes. To assess whether any effect seen is due to direct stimulation of the beta cell by the sulphonylurea itself, people with KCNJ11 neonatal diabetes will also undergo the same tests in the fasting state, having taken the sulphonylurea in the absence of any food.

People with neonatal diabetes due to mutations in the KCNJ11 gene who are treated with sulphonylureas and not on insulin.

Standard dose of paracetamol administered with each meal to allow measurement of rate of gastric emptying.

Inclusion Criteria: Age ≥8yrs. Willing and able to provide informed consent (adults i.e. participants aged >16 years). Willing and able to provide assent and parents willing to provide informed consent (children and young people <16 years). Exclusion Criteria: Age <8yrs. Unable/unwilling to provide informed consent (adults). Unable/unwilling to provide assent (children) or parents unwilling to provide informed consent. Known liver disease or chronic renal impairment (EGFR <60ml/min).

Bowman P, McDonald TJ, Knight BA, Flanagan SE, Leveridge M, Spaull SR, Shields BM, Hammersley S, Shepherd MH, Andrews RC, Patel KA, Hattersley AT. Patterns of postmeal insulin secretion in individuals with sulfonylurea-treated KCNJ11 neonatal diabetes show predominance of non-KATP-channel pathways. BMJ Open Diabetes Res Care. 2019 Dec 18;7(1):e000721. doi: 10.1136/bmjdrc-2019-000721. eCollection 2019.