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.

GAD‐65 antibodies in a case of HNF1A‐Maturity‐Onset Diabetes of the Young: Double diabetes?

“…It is very difficult to prove if, or to what extent, the autoimmunity in this patient—albeit fairly strong—has contributed to his diabetes and impaired insulin secretion. Nonetheless, in a study of 77 individuals with long‐duration HNF1A‐MODY the lowest C‐peptide level was 0.36 nmol/L, 13 thus higher than in the present patient. This lends support to the notion that the autoimmunity contributed to the patient's impaired insulin secretion.…”

Oral delivery of the intracellular domain of the insulinoma-associated protein 2 (IA-2ic) by bacterium-like particles (BLPs) prevents type 1 diabetes mellitus in NOD mice

“…Compared to the BLPs group and IA-2ic-3LysM group, the BLPs-IA-2ic group performed significantly higher C-peptide levels during the late observation period (30–40 weeks). The traditional opinion that pancreatic β cells disappear completely and no endogenous insulin production in longstanding diabetes has been drastically changed based on the detection of persistent C-peptide secretion in individuals with long-term T1DM (Flatt et al., 2021 ; Perkins et al., 2021 ). Therefore, the protective effect toward islet cells provided by oral administration of BLPs-IA-2ic might be useful for preserving or restoring pancreatic islet reserve before or at disease onset.…”

Type 1 diabetes mellitus: much progress, many opportunities

“…Long-term outcomes in individuals with T1D have greatly improved with reduced frequency of retinopathy, nephropathy, and neuropathy and improved cardiovascular outcomes; it is becoming increasingly common for individuals to live for more than 50 years with T1D (115). This is partly due to improvements in glycemic control as demonstrated in the Diabetes Control and Complications Trial (DCCT) (116) and partly because of improvements in lipid and blood pressure management or treatments that reduce or delay nephropathy or retinopathy.…”

“…Still, some individuals develop debilitating or life-threatening complications such as end-stage renal disease or neuropathy (122)(123)(124)(125). Although intense glycemic control clearly reduces microvascular complications, other factors, such as genetic susceptibility, residual insulin secretion, activity of selected glycolytic enzymes, advanced glycation end-product production, and degree of activation of the renin-angiotensinaldosterone system, may explain the difference in the rates of complications across the T1D population (115,125). A recent estimate predicts a lifespan in individuals with T1D and near-normal glycemic control similar to the general population, a remarkable change from past outcomes (126,127).…”