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Insulin-sensitive and insulin-resistant obese and non-obese phenotypes: role in prediction of incident pre-diabetes in a longitudinal biracial cohort

Abstract

Objective We measured insulin sensitivity with euglycemic clamp (Si-clamp) in initially normoglycemic African Americans (AA) and European Americans (EA), to probe the existence of subphenotypes of obesity and leanness, and their impact on incident dysglycemia during longitudinal follow-up.

Research design and methods 320 healthy subjects (176 AA, 144 EA; mean age 44.2±10.6 years) underwent baseline assessments, including Si-clamp and homeostasis model of insulin resistance (HOMA-IR) and were stratified into: insulin-resistant obese (IRO) (body mass index (BMI) >30 kg/m2, Si-clamp <0.1, HOMA-IR >2.5); insulin-sensitive obesity (ISO) (BMI >30 kg/m2, Si-clamp >0.1, HOMA-IR <2.5); insulin-resistant non-obese (IRN) (BMI <28 kg/m2, Si-clamp <0.1, HOMA-IR >2.5); insulin-sensitive non-obese (ISN) (BMI <28 kg/m2, Si-clamp >0.1, HOMA-IR <2.5). Outcome measures were cardiometabolic risks and incident pre-diabetes/type 2 diabetes (T2D) during 5.5 years.

Results Compared with IRO, subjects with ISO had lower abdominal fat, triglycerides and high-sensitivity C reactive protein and higher adiponectin (p=0.015 to <0.0001). IRN subjects had higher cardiometabolic risk markers than ISN (p=0.03 to <0.0001). During 5.5-year follow-up, incident pre-diabetes/T2D was lower in ISO (31.3% vs 48.7%) among obese subjects and higher in IRN (47.1% vs. 26.0%) among non-obese subjects (p=0.0024). Kaplan-Meier analysis showed significantly different pre-diabetes/T2D survival probabilities across insulin sensitivity/adiposity phenotypes (p=0.0001).

Conclusions Insulin sensitivity predicts ~40% decrease in the relative risk of incident pre-diabetes/T2D among obese persons, whereas insulin resistance predicts ~80% increased risk among non-obese persons. This is the first documentation of healthy and unhealthy phenotypes of obesity and leanness in a prospective biracial cohort, using rigorous measurement of insulin sensitivity.

  • pre-diabetes
  • obesity metabolism
  • ethnic comparisons
  • cardiovascular disease risk

This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/

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Footnotes

  • Contributors SD-J: principal investigator, designed study, wrote manuscript. IO: collected data, reviewed and revised manuscript. NU: collected data, reviewed and revised manuscript. CP: collected data, reviewed and revised manuscript. JW: performed statistical analysis, reviewed and revised manuscript. SD-J, as the guarantor, takes full responsibility for the work including the study design, access to data, and the decision to submit and publish the manuscript.

  • Funding The POP-ABC study was supported by grants R01 DK067269 and R01 DK067269-04S1 from the National Institutes of Health and grant 7-07-MN-13 from the American Diabetes Association. The funding sources had no role in the design and execution of the POP-ABC study, or analysis and publication of the data obtained from the study.

  • Competing interests None declared.

  • Ethics approval The University of Tennessee Institutional Review Board.

  • Provenance and peer review Not commissioned; internally peer reviewed.

  • Data sharing statement No additional data are available.

  • Collaborators POP-ABC Research Group: Current: Samuel Dagogo-Jack, MD (Principal Investigator), Ann Ammons, BS, Amy Brewer, MS, RD, Fatoumatta Ceesay, BS, Ibiye Owei, MBBS, MPH, Casey Provo, MS, LDN, Nkiru Umekwe, MBBS, Jim Wan, PhD. Past members: Emmanuel Chapp-Jumbo, MBBS (2009–2011), Chimaroke Edeoga, MBBS, MPH (2007–2013), Ruben Cuervo, MD (2006–2007), Sotonte Ebenibo, MBBS, MPH (2011–2014), Nonso Egbuonu, MBBS (2007–2010), Nicoleta Ionica, MD (2007–2008), Dorota Malinowski, MD (2007–2008). Consultant: Steven Haffner, MD; Data and Safety Officer: Murray Heimberg, MD, PhD.

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