Longitudinal Changes in Insulin Resistance in Normal Weight, Overweight and Obese Individuals

Alice Tang, Adelle C F Coster, Katherine T Tonks, Leonie K Heilbronn, Nicholas Pocock, Louise Purtell, Matthew Govendir, Jackson Blythe, Jialiang Zhang, Aimin Xu, Donald J Chisholm, Nathan A Johnson, Jerry R Greenfield, Dorit Samocha-Bonet, Alice Tang, Adelle C F Coster, Katherine T Tonks, Leonie K Heilbronn, Nicholas Pocock, Louise Purtell, Matthew Govendir, Jackson Blythe, Jialiang Zhang, Aimin Xu, Donald J Chisholm, Nathan A Johnson, Jerry R Greenfield, Dorit Samocha-Bonet

Abstract

Background: Large cohort longitudinal studies have almost unanimously concluded that metabolic health in obesity is a transient phenomenon, diminishing in older age. We aimed to assess the fate of insulin sensitivity per se over time in overweight and obese individuals.

Methods: Individuals studied using the hyperinsulinaemic-euglycaemic clamp at the Garvan Institute of Medical Research from 2008 to 2010 (n = 99) were retrospectively grouped into Lean (body mass index (BMI) < 25 kg/m2) or overweight/obese (BMI ≥ 25 kg/m2), with the latter further divided into insulin-sensitive (ObSen) or insulin-resistant (ObRes), based on median clamp M-value (M/I, separate cut-offs for men and women). Fifty-seven individuals participated in a follow-up study after 5.4 ± 0.1 years. Hyperinsulinaemic-euglycaemic clamp, dual-energy X-ray absorptiometry and circulating cardiovascular markers were measured again at follow-up, using the same protocols used at baseline. Liver fat was measured using computed tomography at baseline and proton magnetic resonance spectroscopy at follow-up with established cut-offs applied for defining fatty liver.

Results: In the whole cohort, M/I did not change over time (p = 0.40); it remained significantly higher at follow-up in ObSen compared with ObRes (p = 0.02), and was not different between ObSen and Lean (p = 0.41). While BMI did not change over time (p = 0.24), android and visceral fat increased significantly in this cohort (ptime ≤ 0.0013), driven by ObRes (p = 0.0087 and p = 0.0001, respectively). Similarly, systolic blood pressure increased significantly over time (ptime = 0.0003) driven by ObRes (p = 0.0039). The best correlate of follow-up M/I was baseline M/I (Spearman's r = 0.76, p = 1.1 × 10-7).

Conclusions: The similarity in insulin sensitivity between the ObSen and the Lean groups at baseline persisted over time. Insulin resistance in overweight and obese individuals predisposed to further metabolic deterioration over time.

Keywords: fat-free mass; hyperinsulinaemic-euglycaemic clamp; insulin resistance; liver fat; obesity.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Study Flow (Consort Diagram). * Medical conditions precluding from follow-up screening included bowel cancer, mitral valve repair and cardiac arrhythmia, chronic lymphocytic lymphoma, breast cancer on letrozole, non-Hodgkin’s lymphoma, sleeve gastrectomy and trying to conceive. ** Medical conditions precluding from detailed phenotyping included tetralogy of fallot, venous thrombotic disease, venous access difficulty (axillary lymph node clearance), iron deficiency anemia of uncertain cause, significant coronary artery disease (requiring stenting, coronary artery bypass grafting and aspirin therapy), immunosuppressant therapy for psoriatic arthritis, renal failure and significant hypertension (189/109 mmHg), severe untreated autoimmune urticaria, excessive alcohol consumption (>20 g/day for a female participant) with paroxysmal atrial fibrillation.
Figure 2
Figure 2
Insulin resistance at baseline and follow-up in Lean and overweight/obese insulin-resistant (ObRes) and insulin-sensitive (ObSen) individuals. Insulin resistance (median clamp M-value (M/I), A and C) and fasting serum insulin (B and D) measured at baseline and follow-up, respectively, in Lean and overweight/obese individuals. Data are individual data points with median and interquartile range (IQR). Welsh’s ANOVA was calculated and the Games–Howell posthoc test was used to determine significant differences. The p for the Welsh’s ANOVA is indicated at the top of the plots, with the significance between groups indicated.
Figure 3
Figure 3
Change in anthropometry, metabolic health and glucose regulation markers from baseline to follow-up in Lean and overweight/obese insulin-resistant and insulin-sensitive individuals. Annual change in body mass index (BMI) (A), waist circumference (B), body fat (C), fat-free mass (D), android fat (E), visceral fat (F), systolic (G) and diastolic (H) blood pressure, fasting blood glucose (I), M/I (J), fasting insulin (K) and glucose infusion rate (GIR)/I (L) in Lean and overweight/obese individuals. Change (IQR) in variables as a function of time, for each of the baseline groups: Lean, ObRes and ObSen. The change was determined as Follow-up Value−Baseline ValueTime between measurements. Differences between the groups were assessed using a Welsh’s ANOVA (accounting for unequal variances in the change data) with the Games–Howell posthoc test. The pgroup value is indicated at the top of each plot for each variable. Changes over time for the cohort were assessed using a one-sample t-test for difference from zero with ptime also indicated at the top of each plot. The p values for the differences from zero for each individual group are shown at the bottom of each plot. A correction for multiple comparisons (Bonferroni) was applied with significance set at p ≤ 0.0167. Data are individual values of change (IQR). Abbreviations: WC, waist circumference; FFM, fat-free mass; SBP, systolic blood pressure; DBP, diastolic blood pressure; FBG, fasting blood glucose.
Figure 3
Figure 3
Change in anthropometry, metabolic health and glucose regulation markers from baseline to follow-up in Lean and overweight/obese insulin-resistant and insulin-sensitive individuals. Annual change in body mass index (BMI) (A), waist circumference (B), body fat (C), fat-free mass (D), android fat (E), visceral fat (F), systolic (G) and diastolic (H) blood pressure, fasting blood glucose (I), M/I (J), fasting insulin (K) and glucose infusion rate (GIR)/I (L) in Lean and overweight/obese individuals. Change (IQR) in variables as a function of time, for each of the baseline groups: Lean, ObRes and ObSen. The change was determined as Follow-up Value−Baseline ValueTime between measurements. Differences between the groups were assessed using a Welsh’s ANOVA (accounting for unequal variances in the change data) with the Games–Howell posthoc test. The pgroup value is indicated at the top of each plot for each variable. Changes over time for the cohort were assessed using a one-sample t-test for difference from zero with ptime also indicated at the top of each plot. The p values for the differences from zero for each individual group are shown at the bottom of each plot. A correction for multiple comparisons (Bonferroni) was applied with significance set at p ≤ 0.0167. Data are individual values of change (IQR). Abbreviations: WC, waist circumference; FFM, fat-free mass; SBP, systolic blood pressure; DBP, diastolic blood pressure; FBG, fasting blood glucose.
Figure 4
Figure 4
Associations between baseline and follow-up metabolic health, anthropometry and body composition. Pairwise Spearman coefficients were calculated and the p values determined. If 0 ≤ p < 0.05, then the R value of the correlation is shown in color, with upper triangle indicating 0 ≤ p < 0.05, and lower triangle indicating 0 ≤ p < 0.01 for the correlation. The correlation coefficient is indicated using the color scale.

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Source: PubMed

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