Investigating the effect of low-dose sulfonylureas on glucagon secretion in diabetes mellitus

Background: Diabetes is a multi-hormonal disorder characterised by insufficient insulin secretion and aberrant glucagon secretion with fasting hyperglucagonaemia leading to increased rates of hepatic glucose production, which further exacerbates hyperglycaemia. Sulfonylureas used at low concentrations have been shown to partially restore appropriate glucose-regulated glucagon secretion in isolated islets from donors with type 2 diabetes (T2DM). The main objective of this thesis was to investigate whether low doses of the sulfonylurea glibenclamide could reduce fasting hyperglucagonaemia in patients with T2DM. In addition, the effect of age and sex on islet hormone secretion was examined in human islets, as was the impact of low-dose gliclazide (another sulfonylurea) on glucagon secretion in MODY patients.
Methods: I performed a pilot, dose-finding (0.3mg – 6mg/day) clinical trial (LEGEND-A) of a novel oral glibenclamide suspension in sixteen patients with T2DM (diet controlled or on metformin alone). Fasting plasma glucagon, glucose, insulin, C-peptide and glibenclamide were measured at each dose-change, and continuous glucose monitoring was used throughout. For the human islet hormone secretion study, a database analysis was performed which covered an 11-year period (2006-2017). Finally, a pilot clinical study (“Glucagon in MODY”) involving an oral glucose tolerance test before and after the omission of gliclazide for 72h was performed in three patients diagnosed with HNF1-α MODY (study ongoing).
Results: Glibenclamide at 0.3mg/day was able to reduce fasting glucagon levels by 30% in four T2DM patients who had hyperglucagonaemia, without causing insulin secretion and with no adverse effects. This effect was not observed at higher glibenclamide concentrations, nor in the twelve T2DM patient who had normal-range fasting glucagon levels. In addition, the islet hormone database analysis revealed the novel finding that islets from older donors (especially males) secreted twice as much insulin at euglycaemic conditions as those from younger donors, but only 40% as much glucagon when challenged with hypoglycaemic conditions. Finally, the preliminary results of the “Glucagon in MODY” study suggest that HNF1-α MODY patients may not display appropriate glucose-dependent glucagon suppression during an oral glucose tolerance test, and that this may be reinstated by using low doses of gliclazide.
Conclusions: Using low-dose sulfonylureas it may be possible to normalise aberrant glucagon secretion patterns in patients with diabetes, perhaps by subtly altering the activity of the alpha-cell ATP-sensitive potassium channel. This novel approach has the potential to be used both as a standalone therapy and as an adjunct to other medications, such as SGLT2 inhibitors, in which a reduction in glucagon could increase overall efficiency. I have also demonstrated that age and sex can impact the secretion of insulin and glucagon in ex vivo human islets, and this may in part provide a mechanistic explanation for the vulnerability of older people to sulfonylurea-induced hypoglycaemia episodes.

Keywords: Glucagon
Advisor: Rorsman, P
Karpe, F
Gough, S