Reversibility of brain glucose kinetics in type 2 diabetes mellitus

Elizabeth Sanchez-Rangel,Graeme F Mason,Janice Jin Hwang,Mary Savoye,Lihong Jiang,Douglas L Rothman,Felona Gunawan,Anastasia Coppoli,Feng Dai

doi:10.1007/s00125-022-05664-y

Abstract

Aims/hypothesisWe have previously shown that individuals with uncontrolled type 2 diabetes have a blunted rise in brain glucose levels measured by 1H magnetic resonance spectroscopy. Here, we investigate whether reductions in HbA1c normalise intracerebral glucose levels.MethodsEight individuals (two men, six women) with poorly controlled type 2 diabetes and mean ± SD age 44.8 ± 8.3 years, BMI 31.4 ± 6.1 kg/m2 and HbA1c 84.1 ± 16.2 mmol/mol (9.8 ± 1.4%) underwent 1H MRS scanning at 4 Tesla during a hyperglycaemic clamp (~12.21 mmol/l) to measure changes in cerebral glucose at baseline and after a 12 week intervention that improved glycaemic control through the use of continuous glucose monitoring, diabetes regimen intensification and frequent visits to an endocrinologist and nutritionist.ResultsFollowing the intervention, mean ± SD HbA1c decreased by 24.3 ± 15.3 mmol/mol (2.1 ± 1.5%) (p=0.006), with minimal weight changes (p=0.242). Using a linear mixed-effects regression model to compare glucose time courses during the clamp pre and post intervention, the pre-intervention brain glucose level during the hyperglycaemic clamp was significantly lower than the post-intervention brain glucose (p<0.001) despite plasma glucose levels during the hyperglycaemic clamp being similar (p=0.266). Furthermore, the increases in brain glucose were correlated with the magnitude of improvement in HbA1c (r = 0.71, p=0.048).Conclusion/interpretationThese findings highlight the potential reversibility of cerebral glucose transport capacity and metabolism that can occur in individuals with type 2 diabetes following improvement of glycaemic control.Trial registrationClinicalTrials.gov NCT03469492.Graphical abstract

Highlights

The prevalence of type 2 diabetes mellitus in the USA and worldwide continues to rise and despite many available treatment options many diabetic individuals fail to achieve glycaemic targets leading to increased morbidity and mortality [1, 2]
Our group showed that compared with lean participants without diabetes, brain glucose increments in response to a standardised increase in plasma glucose levels were lower in participants with poorly controlled type 2 diabetes [12], suggesting that chronic hyperglycaemia is associated with blunted brain glucose transport and/or metabolism
Using mixed-effects regression models, which take into account the repeated measures of brain and plasma glucose over the hyperglycaemic clamp, the pre-intervention brain glucose level during the hyperglycaemic clamp was significantly lower than the post-intervention brain glucose (p

Summary

Introduction

The prevalence of type 2 diabetes mellitus in the USA and worldwide continues to rise and despite many available treatment options many diabetic individuals fail to achieve glycaemic targets leading to increased morbidity and mortality [1, 2]. Our group showed that compared with lean participants without diabetes, brain glucose increments in response to a standardised increase in plasma glucose levels were lower in participants with poorly controlled type 2 diabetes [12], suggesting that chronic hyperglycaemia is associated with blunted brain glucose transport and/or metabolism. Whether these changes in cerebral glucose transport/ metabolism seen in individuals with poorly controlled diabetes can be reversed is unknown. This proof of concept study was undertaken to determine whether improvement of glycaemic control in individuals with poorly controlled type 2 diabetes would restore glucose brain transport kinetics

Methods

Results

Conclusion