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Longitudinal Regulatory Changes Standardized to Identify the Sequence of Key Mechanisms in the Progression from Normal to Overt Type 2 Diabetes Mellitus: Translation from Nonhuman Primates (NHP's) to Human Cohort Studies
Author(s) -
Hansen Barbara C,
Newcomb Jennifer D.,
Lin Paul,
Jen KaiLin Catherine
Publication year - 2019
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2019.33.1_supplement.759.2
Subject(s) - cohort , diabetes mellitus , logistic regression , medicine , longitudinal study , biology , type 2 diabetes , endocrinology , pathology
Chaos and logistic mapping to illuminate the “phases” in the progression from normal to overt Type 2 diabetes mellitus (T2DM) have been identified in detailed longitudinal studies of nonhuman primates (NHPs) and applied to longitudinal cohorts in humans (e.g. Hulman, Tabak, 2017, and others). We have studied prospectively a large NHP colony (N=324) maintained under constant environmental conditions and a constant “healthy” diet, and here identify the criteria at each phase essential to translating this DM progression to humans. These nonlinear patterns and their underlying mechanisms have been generally obscured in humans due to: a) insensitivity in defining initial conditions, b) failure to standardize amplitudes of measured features across time and individuals, c) failure to identify the “accordion phenomenon” in the normal‐to‐diabetes trajectory—with different initiation points and highly varied rates of progression, d) nonlinear progression trajectories negating logistic regressions, e) ignoring the “butterfly effect” of a change in one feature resulting in large effects later in the progression, and f) patterns obscured by “noise” and “imprecisions” introduced by (a) through (e). The results shown below lead to the conclusion that early (likely CNS) regulatory defects controlling the synthesis and secretion of insulin appear to be primary in the earliest phases initiating the progression to overt T2DM, long before any change in glycemia. Standardization of frequent longitudinal observations to synchronize both the rate of progression and the amplitudes of feature excursions proved to be essential to identifying the earliest events. Although mitigation of insulin resistance has been a long time target, prevention of hyperinsulinemia may represent an excellent untapped target for prevention of DM. Support or Funding Information Supported by NIA NO1AG31012 and NIA HHSN2532008002CStandardized trajectories of DM features in longitudinal study of NHPsThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .