Severe iatrogenic hypoglycaemia modulates the fibroblast growth factor protein response

Abstract

Introduction: There is evidence that fibroblast growth factor (FGF) levels may be implicated in hypoglycaemia, with FGF19 being a potential contributor to insulin-independent pathways driving postprandial hypoglycaemia following bariatric surgery and basic FGF (FGF2) being elevated following mild hypoglycaemia occurring after the glucose tolerance test. However, their response following severe iatrogenic hypoglycaemia is unknown and therefore this pilot exploratory study was undertaken.

Methods: A case-control study of aged-matched type 2 diabetes (T2D; n = 23) and control (n = 23) subjects who underwent a hyperinsulinaemic clamp, initially to euglycaemia in T2D (5 mmol/L; 90 mg/dl), and then to hypoglycaemia (<2 mmol/L; <36 mg/dl) with subsequent follow-up time course to 24 h. FGF and FGF receptor proteins were determined by Slow Off-rate Modified Aptamer (SOMA)-scan plasma protein measurement.

Results: At baseline, FGF12 (p = .006) was higher and FGF20 (p = .004) was lower in T2D versus controls. At hypoglycaemia, FGF7 was lower in T2D. Post-hypoglycaemic levels of FGF18, FGF19, FGF20 and FGF23 were lower while FGF12 and FGF16 were higher in T2D versus control at different time points. No differences between T2D and controls were seen for FGF1, FGF2, FGF4, FGF6, FGF8, FGF9, FGF10, FGF21 or any of the FGF receptors. At 24 h post-hypoglycaemia, FGF20 (p = .01) differed between controls and T2D, while the levels for the other proteins measured returned to baseline. None of the FGF proteins altered from baseline to euglycaemia when clamped in T2D subjects. FGF23 negatively correlated with fasting blood glucose, but no FGFs correlated with body mass index in T2D.

Conclusion: Severe transient hypoglycaemia modulated FGF7, 16, 19, 20 and 23 (known to be associated with diabetes), together with FGF18 and 12, not previously reported to be associated with diabetes but that may be important in the pathophysiology of hypoglycaemia; FGF20 remained low at 24 h. Taken together, these data suggest that recurrent hypoglycaemia may contribute to the development of complications through changes in FGF proteins.

Trial registration: ClinicalTrials.gov NCT03102801.

Keywords: fibroblast growth factors; hypoglycaemia; proteomics; type 2 diabetes.