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Differential contribution of alpha and beta cell dysfunction to impaired fasting glucose and impaired glucose tolerance

Abstract

Aims/hypothesis

People with isolated impaired fasting glucose (IFG) have normal beta cell function. We hypothesised that an increased glucose threshold for beta cell secretion explains IFG.

Methods

We used graded glucose infusion to examine the relationship of insulin secretion rate (ISR) and glucagon secretion rate (GSR) with rising glucose. We studied 39 non-diabetic individuals (53 ± 2 years, BMI 30 ± 1 kg/m2), categorised by fasting glucose and glucose tolerance status. After an overnight fast, a variable insulin infusion was used to maintain glucose at ~4.44 mmol/l (07:00 to 08:30 hours). At 09:00 hours, graded glucose infusion commenced at 1 mg kg−1 min−1 and doubled every 60 min until 13:00 hours. GSR and ISR were calculated by nonparametric deconvolution from concentrations of glucagon and C-peptide, respectively.

Results

The relationship of ISR with glucose was linear and the threshold for insulin secretion in isolated IFG did not differ from that in people with normal fasting glucose and normal glucose tolerance. GSR exhibited a single-exponential relationship with glucose that could be characterised by G50, the change in glucose necessary to suppress GSR by 50%. G50 was increased in IFG compared with normal fasting glucose regardless of the presence of impaired or normal glucose tolerance.

Conclusions/interpretation

These data show that, in non-diabetic humans, alpha cell dysfunction contributes to the pathogenesis of IFG independently of defects in insulin secretion. We also describe a new index that quantifies the suppression of glucagon secretion by glucose.

Graphical abstract

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Data availability

The de-identified datasets generated during the current study are available from the corresponding author on reasonable request.

Abbreviations

Φ:

Beta cell responsivity

Φd :

Dynamic beta cell responsivity

Φs :

Static beta cell responsivity

CRTU:

Clinical Research and Trials Unit

DI:

Disposition index

G50 :

Increment in glucose concentration necessary to suppress GSR by 50%

GGI:

Graded glucose infusion

GSR:

Glucagon secretion rate

IFG:

Impaired fasting glucose

IFG/IGT:

Impaired fasting glucose with impaired glucose tolerance

IGT:

Impaired glucose tolerance

IFG/NGT:

Impaired fasting glucose with normal glucose tolerance

ISR:

Insulin secretion rate

NFG:

Normal fasting glucose

NFG/IGT:

Normal fasting glucose with impaired glucose tolerance

S i :

Insulin sensitivity

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Acknowledgements

The authors wish to acknowledge the excellent editorial assistance of M. M. Davis, Endocrine Research Unit, Mayo Clinic, Rochester, MN, USA and the discussions that informed the study design with R. A. Rizza, Mayo Clinic College of Medicine, Rochester, MN, USA.

Authors’ relationships and activities

AV is the recipient of an investigator-initiated grant from Novo Nordisk and has consulted for vTv Therapeutics, Zeeland Pharmaceuticals, Crinetics and Rezolute. The other authors declare that there are no relationships or activities that might bias, or be perceived to bias, their work.

Contribution statement

JDK researched data and ran the studies, contributed to the discussion and reviewed/edited the manuscript; MCL undertook mathematical modelling of insulin and glucagon secretion, contributed to the discussion and reviewed/edited the manuscript; AME researched data and ran the studies, contributed to the discussion and reviewed/edited the manuscript; DSW assisted with data management and organisation as well as with the data analysis, contributed to the discussion and reviewed/edited the manuscript; KRB supervised the statistical analyses, contributed to the discussion and reviewed/edited the manuscript; CC and CDM supervised the mathematical modelling, contributed to the discussion and reviewed/edited the manuscript; AV designed the study, oversaw its conduct, researched data and wrote the first draft of the manuscript. AV is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. The order of first authors was determined by the time that each joined the project. All authors approved the final version of the manuscript.

Funding

The authors acknowledge the support of the Mayo Clinic General Clinical Research Center (DK TR000135). AV is supported by DK78646, DK116231 and DK126206. JDK received grant support from the Endocrine Fellows Foundation. CDM was supported by MIUR (Italian Ministry for Education) under the initiative ‘Departments of Excellence’ (Law 232/2016).

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Correspondence to Adrian Vella.

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Kohlenberg, J.D., Laurenti, M.C., Egan, A.M. et al. Differential contribution of alpha and beta cell dysfunction to impaired fasting glucose and impaired glucose tolerance. Diabetologia (2022). https://doi.org/10.1007/s00125-022-05794-3

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  • DOI: https://doi.org/10.1007/s00125-022-05794-3

Keywords

  • Alpha cell function
  • Beta cell function
  • Deconvolution
  • Glucagon suppression
  • Impaired fasting glucose
  • Impaired insulin action
  • Insulin secretion
  • Prediabetes