Diabetogenesis and Albumin Molecular Modifications Newer Biological Insights and Clinical Implications

Abstract

To address the many unmet scientific needs in diabetes care (pathogenesis pathways, earliest diagnosis, efficient monitoring, safer and better therapies and importantly prevention approaches), our research focussed on: (a) diabetogenesis and biomarkers and (b) albumin molecular modifications. Establishment of the “Samatvam – Indian Institute of Science” prospective longitudinal cohort, supported by a well annotated biobank repository and a robust cloud based electronic medical record platform, provided the foundation for this translational scientific endeavour.

Initially, the "IISc - PathShodh" electrochemistry technology based multianalyte point of care device (POC: anuPath) for selected diabetes biomarkers (HbA1c, hemoglobin, serum albumin, urine albumin and urine creatinine) was validated by simultaneous comparison with “gold standard” conventional laboratory assays. Health worker-based community implementation of this “lab – on – palm”, confirmed its utility both for “in-clinic” diabetes care and “remote” health monitoring.

Insulin resistance and beta-cell dysfunction, both genetic and environment determined, are the core defects of type 2 diabetes. Together they result in cell, tissue, vascular and organ damage in diabetes, through multiple deranged biochemical pathways, including pathological protein modifications like glycation and oxidation. Our studies on diabetogenesis highlighted the increased prevalence of insulin resistance (HOMA IR) and beta-cell dysfunction (HOMA B%) (i.e., compensatory hyperinsulinemia) even in the earliest stage of normal glucose tolerance (NGT). This pathogenetic profile was associated with increasing adiposity (i.e., overweight and obesity). This “healthy” (NGT) stage was also already marked by multiple abnormalities related to chronic inflammation, atherogenesis and other aspects of dysmetabolism. Our data indicated for the first time, that insulin resistance is one of the independent determinants of the prognostically useful “glycation gap” (GG). Thus, insulin resistance might be a mechanism for the reported association of higher (positive) GG with various microvascular and macrovascular diabetes complications and even increased mortality.

Albumin, the most abundant and physiologically vital serum protein, accumulates a range of chemical modifications (glycation, oxidation and truncation) as a consequence of its interactions with a large number of reactive small molecules which are formed or increased under conditions of abnormal pathology. Our investigations on albumin glycation, oxidation and truncation (mass spectrometry), in all stages in the evolution and progression of type 2 diabetes ("normoglycemia", prediabetes – obesity and overt diabetes), as well as in type 1 diabetes and in diabetes chronic kidney disease, yielded many novel biological and clinical insights. The common and distinctive features and mechanisms of albumin glycation and hemoglobin glycation were highlighted. Knowledge on the pathologic and clinical relevance and associations of albumin oxidation were further advanced. The potential diagnostic and prognostic significance of albumin truncation (reduction or “deficiency”) in diabetes was identified. During the course of diabetes therapy (upto 280 days), many subjects exhibited albumin glycation and albumin cysteinylation discordance, illuminating that the current “glucose-centric” only approaches to diabetes care are inadequate and incomplete and albumin cysteinylation needs independent therapeutic intervention in diabetes care. HNA2 and HNA2/eGFR index, as defined, showed potential as additional biomarkers of declining renal function, beginning at the earliest stages (including stage 1 hyperfiltration).

The many novel biological and clinical insights generated by our studies have fostered: (a) future identification of novel biomarkers battery (“diabetome”, “diabetomics”, “albuminomics”) driven diverse “healthy”, prediabetes, obesity and type 2 diabetes phenotypes and (b) discovery of better diagnostic, therapeutic and even preventive approaches for diabetes and related disorders (towards “Precision Medicine”).