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.
- obesity metabolism
- ethnic comparisons
- cardiovascular disease risk
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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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