Discoveries from the study of longstanding type 1 diabetes

Abstract

Award programmes that acknowledge the remarkable accomplishments of long-term survivors with type 1 diabetes have naturally evolved into research programmes to determine the factors associated with survivorship and resistance to chronic complications. In this review, we present an overview of the methodological sources of selection bias inherent in survivorship research (selection of those with early-onset diabetes, incidence–prevalence bias and bias from losses to follow-up in cohort studies) and the breadth and depth of literature focusing on this special study population. We focus on the learnings from the study of longstanding type 1 diabetes on discoveries about the natural history of insulin production loss and microvascular complications, and mechanisms associated with them that may in future offer therapeutic targets. We detail descriptive findings about the prevalence of preserved insulin production and resistance to complications, and the putative mechanisms associated with such resistance. To date, findings imply that the following mechanisms exist: strategies to maintain or recover beta cells and their function; activation of specific glycolytic enzymes such as pyruvate kinase M2; modification of AGE production and processing; novel mechanisms for modification of renin–angiotensin–aldosterone system activation, in particular those that may normalise afferent rather than efferent renal arteriolar resistance; and activation and modification of processes such as retinol binding and DNA damage checkpoint proteins. Among the many clinical and public health insights, research into this special study population has identified putative mechanisms that may in future serve as therapeutic targets, knowledge that likely could not have been gained without studying long-term survivors.

Graphical abstract

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Fig. 1
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Abbreviations

ANG-II:

Angiotensin-II

AT1:

Angiotensin 1

DKD:

Diabetic kidney disease

PKM2:

Pyruvate kinase M2

RAAS:

Renin–angiotensin–aldosterone system

RBP3:

Retinol binding protein 3

RVR:

Renal vascular resistance

SGLT:

Sodium–glucose cotransporter

SOLID:

Study Of Longevity In Diabetes

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Acknowledgements

We wish to thank the many inspiring participants who have taken part in studies that focus on longstanding type 1 diabetes survivorship. For the Canadian Study of Longevity in Type 1 Diabetes project, we thank our key study co-investigators: G. Boulet (L’Université de Laval); J. Lovshin, M. H. Brent, N. Paul and V. Bril (all at the University Health Network); and H. A. Keenan (Joslin Diabetes Center). We thank E. M. Halpern, D. Eldelekli (Lunenfeld-Tanenbaum Research Institute) and G. Boulet (L’Université de Laval) for their valuable recruitment work, including translation for our French-speaking participants.

Authors’ relationships and activities

BAP has received speaker honoraria from Abbott, Medtronic, Insulet and Novo-Nordisk, research support to his research institute from Boehringer Ingelheim and the Bank of Montreal (BMO), and has served as a consultant to Boehringer Ingelheim, Abbott and Novo-Nordisk. LEL receives support from a CIHR Canada Graduate Scholarship Doctoral Award. DZIC is supported by a Department of Medicine, University of Toronto Merit Award and receives support from the CIHR, Diabetes Canada and the Heart and Stroke Richard Lewar Centre of Excellence. All other authors declare that there are no relationships or activities that might bias, or be perceived to bias, their work.

Funding

We acknowledge the support from Diabetes Canada and JDRF Canada (grant no. 17-2013-312) and its Canadian Clinical Trial Network, BMO (the Bank of Montreal), and Boehringer Ingelheim, as well as Randy and Jenny Frisch and The Harvey and Annice Frisch Family Fund, the contributions of David and Jill Wright, and the Menkes Family Fund. BAP is grateful for funding from the Sam and Judy Pencer Family Chair in Diabetes Clinical Research.

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Correspondence to Bruce A. Perkins.

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Perkins, B.A., Lovblom, L.E., Lanctôt, S.O. et al. Discoveries from the study of longstanding type 1 diabetes. Diabetologia (2021). https://doi.org/10.1007/s00125-021-05403-9

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Keywords

  • Beta cell
  • Cardiovascular disease
  • Cognitive function
  • Diabetes
  • Long duration
  • Longevity
  • Nephropathy
  • Neuropathy
  • Retinopathy
  • Review
  • Type 1 diabetes