Diabetes: Concepts of β-Cell Organ Dysfunction and Failure Would Lead to Earlier Diagnoses and Prevention

Abstract

As the world endures a viral pandemic superimposed on a diabetes pandemic, the latter incorporates most of the comorbidities associated with the former, thereby exacerbating risk of death in both. An essential approach to both pandemics is prevention and unrealized earlier treatment. Thus, in this Perspective relating to diabetes, we emphasize a paradigm of, first, reversible β-cell organ dysfunction and then irreversible β-cell organ failure, which directly indicate the potential for earlier prevention, also unrealized in current guidelines. Four pillars support this paradigm: epidemiology, pathophysiology, molecular pathology, and genetics. A substantial worldwide knowledge base defines each pillar and informs a more aggressive preventive approach to most forms of the disorder. This analysis seeks to clarify the temporal and therapeutic relationships between lost β-cell function and content, illuminating the potential for earlier diagnoses and, thus, prevention. We also propose that myriad pathways leading to most forms of diabetes converge at the endoplasmic reticulum, where stress can result in β-cell death and content loss. Finally, genetic and nongenetic origins common to major types of diabetes can inform earlier diagnosis and, potentially, prevention, with the aim of preserving β-cell mass.

High exposure variance enables candidate biomarker detection in a small EWAS of methylmercury-exposed Peruvian adults

“…Specifically, our data point to a potential mechanistic link between MeHg exposure and type 2 diabetes (T2D). T2D is characterized by persistently high blood glucose levels due to impaired insulin secretion from pancreatic β cells, insensitivity to insulin in peripheral tissues, and increased glucose production in the liver 107 . Several well-established genetic risk factors for T2D are variants in the transcription factor 7-like 2 (TCF7L2) gene 108-110 that drive expression of functional splice isoforms of this gene 109,111 .…”

Combined effect of pancreatic lipid content and gene variants (TCF7L2, WFS1 and 11BHSD1) on B-cell function in Middle Aged Women in a Post Hoc Analysis

“…This mechanism might be particularly relevant when the β-cells are prone to dysfunction due to the genetic susceptibility [ 50 ]. The effect of the 11ΒHSD1 gene variant on β-cells is less well characterized, however it is one of the “disallowed” genes in β-cells and the variant’s effect on the function and maintenance cannot be excluded [ 51 ].…”

Adult-onset type 1 diabetes: A changing perspective

“…Diagnostic levels also ignore the fact that any given HbA1c level is influenced by genetic, racial, and age-related variation [6], while glucose levels can be estimated in whole blood, plasma, or capillary glucose and by fasting or by an oral glucose load, itself a compromise between historically different glucose loads [3]. The increase in the prevalence of diabetes in adults has now reached a stage where more than half of adults in USA have dysglycaemia [6,7]. Indeed, in certain contexts it may be that dysglycaemia is the norm, certainly increasing adiposity in some populations has likely unveiled a widespread predisposition to inadequate allostasis and with that to dysglycaemia, even diabetes [7].…”

“…The increase in the prevalence of diabetes in adults has now reached a stage where more than half of adults in USA have dysglycaemia [6,7]. Indeed, in certain contexts it may be that dysglycaemia is the norm, certainly increasing adiposity in some populations has likely unveiled a widespread predisposition to inadequate allostasis and with that to dysglycaemia, even diabetes [7]. Currently, at diagnosis, the majority of adult diabetes cases are overweight (BMI ≥ 25) or obese (BMI ≥30) and the metabolic syndrome, a proxy for insulin insensitivity, is prevalent not only in T2D (~85%), but also in adult-onset T1D, including cases not initially requiring insulin therapy (~40% for each) [8,9].…”

“…But, childhood-adiposity may also have a causal relationship with T1D given that genetic studies support a link between the two; using inverse-variance weighted Mendelian randomization analysis with genetic variants as variables to test for causal associations, childhood adiposity genetic variants were positively associated with T1D risk [10]. As insulin secretion is compromised in obesity as well as both major types of diabetes, metabolic networks that maintain glucose homeostasis and glucose disposition will adapt to retain homeostasis [7]. Allostasis, the ability to adapt to sustain glucose homeostasis, if compromised then homeostasis is lost and dysglycemia ensues [7].…”