Mechanism by Which Caloric Restriction Improves Insulin Sensitivity in Sedentary Obese Adults
Article Figures & Tables
Figures
- Figure 1
Experimental design. Before and after 16 weeks of CR or CON, two outpatient visits and one inpatient visit were scheduled. One outpatient visit consisted of nuclear magnetic resonance (NMR) imaging, and the second outpatient visit was for measurements of REE, DEXA scan, and a VO2peak test on a bicycle ergometer. An inpatient visit at baseline and after 16 weeks of the intervention was conducted after 5 days of a weight-maintaining diet provided by the CRU metabolic kitchen. The inpatient visit consisted of a two-stage (low- and high-dose insulin) hyperinsulinemic-euglycemic pancreatic clamp over 6 h, followed by a skeletal muscle biopsy. Blood samples were obtained every 10 min to adjust the GIR to maintain euglycemia at ∼90 mg/dL. After the clamp and biopsy were completed, standardized meals were provided to keep participants’ weight stable. The following morning in the postabsorptive state, a second fasted skeletal muscle biopsy was performed. *Blood draw.
- Figure 2
Insulin sensitivity. The GIR required to maintain euglycemia in 10-min intervals during the 6-h insulin infusion in CR (A) and CON (B) and corresponding glucose concentrations. C and D: The AUC and glucose Rd during the last hour of the insulin clamp for CR and CON. E: EGP measured in the basal fasting state. F: EGP percentage suppression from overnight fasted to low-dose insulin. Means ± SEM are given, and a two-way (group, time) repeated-measures ANOVA was used to compare outcomes across groups. Precise P values are given for the ANOVA. When a significant interaction was found, a Sidak post hoc test was performed. ****P < 0.0001.
- Figure 3
Mitochondrial function. Mitochondrial oxygen consumption rates (JO2) were measured with carbohydrate-based mitochondrial substrates for CR (A) and CON (B) and then normalized for mitochondrial protein (C and D). E: In vivo oxidative capacity measured by magnetic resonance spectroscopy before and after the 16-week period. F: Mitochondrial coupling was assessed from the respiratory control ratio (RCR). G: mtH2O2 emissions were evaluated in isolated mitochondria under state 2 conditions. Means ± SEM are given, and a two-way (group, time) repeated-measures ANOVA was used to compare outcomes across groups.
- Figure 4
A: Skeletal muscle TXNIP expression was evaluated using quantitative PCR and normalized to β-2-microglobulin (B2M) in muscle biopsy samples after the insulin clamp. B: The ΔTXNIP mRNA was correlated using a Pearson correlation to the ΔAUC for the 6-h insulin clamp for all participants. C: Skeletal muscle protein content was evaluated using Western blot and normalized to vinculin. D: The ΔTXNIP protein was correlated using a Pearson correlation to the ΔAUC for the 6-h insulin clamp for all participants. ΔGINF, change in GIR. Means ± SEM are given, and a two-way (group, time) repeated-measures ANOVA was used to compare outcomes across groups. When a significant interaction was found, a Sidak post hoc test was performed. **P < 0.01.
Tables
- Table 1
Characteristics of the subjects
Characteristic CR Control P Baseline (N = 11) Post (N = 11) Baseline (N = 9) Post (N = 9) Group Time Interaction Age, year 55.3 ± 1.8 52.7 ± 1.6 — — — Height, cm 169.6 ± 2.4 177.8 ± 3.9 Weight, kg 101.8 ± 4.9 91.3 ± 4.6**** 109 ± 7.4 110.3 ± 7.7 0.1401 <0.001 <0.001 Weight % change −10.1 ± 1.2 +0.8 ± 0.6 — — — BMI, kg/m2 35.2 ± 1.3 31.8 ± 1.1**** 34.4 ± 1.4 34.6 ± 1.5 0.6103 <0.001 <0.001 Glucose, mg/dL 106.6 ± 2.5 102.3 ± 2.2 105.0 ± 3.3 105.3 ± 4.1 0.8716 0.1161 0.0767 Insulin, μIU/mL 12.7 ± 1.8 6.7 ± 0.9**** 11.3 ± 2.5 11.2 ± 2.3 0.5616 <0.002 <0.002 FFA, mmol/L 0.38 ± 0.04 0.45 ± 0.05 0.38 ± 0.06 0.39 ± 0.03 0.5620 0.1876 0.3880 β-Hydroxybutyrate, mmol/L 0.23 ± 0.01 0.28 ± 0.01*** 0.24 ± 0.01 0.25 ± 0.01 0.3826 0.0012 0.0387 Body fat, % 45.9 ± 1.6 42.4 ± 1.5**** 43.9 ± 2.0 44.3 ± 1.8 0.9918 <0.001 <0.001 Lean mass, kg 52.5 ± 3.2 50.3 ± 2.9** 59.5 ± 5.3 59.1 ± 5.0 0.1854 0.0034 0.0347 Fat mass, kg 39.6 ± 4.6 36.8 ± 2.2**** 45.9 ± 3.2 46.2 ± 3.2 0.1246 <0.001 <0.001 Visceral fat, cm2 14.6 ± 2.2 11.4 ± 1.3* 12.1 ± 1.6 13.9 ± 1.9 0.9891 0.4132 0.0081 Subcutaneous fat, cm2 45.1 ± 2.6 36.9 ± 2.6**** 43.2 ± 3.9 44.2 ± 4.1 0.5722 0.0078 0.0015 REE, kcal/day 1,668 ± 93 1,615 ± 92 1,865 ± 128 1,867 ± 109 0.1356 0.4925 0.4745 VO2peak, L/min 1.9 ± 0.1 2.2 ± 0.2 — — — Measurements were made before randomization (baseline) and again after 16 weeks of CR or CON in the fasting state. Means ± SEM are given, and a two-way (group, time) repeated-measures ANOVA was used to compare outcomes across groups. Precise P values are given for the ANOVA. When a significant interaction was found, a Sidak post hoc test was performed.
*P < 0.05;
**P < 0.01;
***P < 0.001;
****P < 0.0001.
- Table 2
Metabolic flexibility
Caloric restriction Control P Baseline Post Baseline Post Group Time Interaction RER Basal 0.864 ± 0.006 0.827 ± 0.015* 0.833 ± 0.005 0.850 ± 0.012 0.7513 0.2756 0.0095 Clamp 0.917 ± 0.013 0.933 ± 0.022 0.918 ± 0.02 0.921 ± 0.022 0.6537 0.7104 0.9356 Δ 0.053 ± 0.016 0.106 ± 0.025* 0.084 ± 0.019 0.071 ± 0.028 0.9597 0.1194 0.0147 CHO oxidation (μmol ⋅ kgFFM−1 ⋅ min−1) Basal 16.8 ± 1.3 13.9 ± 2.2 13.3 ± 0.8 15.1 ± 1.3 0.5165 0.7066 0.0704 Clamp 21.9 ± 1.5 22.3 ± 2.8 22.1 ± 2.5 22.2 ± 2.6 0.9849 0.8653 0.9051 Nonoxidative glucose disposal (μmol ⋅ kgFFM−1 ⋅ min−1) Basal 0.1 ± 1.4 0.9 ± 2.2 4.9 ± 4.4 2.5 ± 2.5 0.2949 0.7894 0.5297 Clamp 15.3 ± 6.3 31.5 ± 4.9** 28.2 ± 5.9 28.9 ± 6.0 0.5141 0.0097 0.0157 Lipid oxidation (μmol ⋅ kgFFM−1 ⋅ min−1) Basal 1.2 ± 0.1 1.5 ± 0.1* 1.5 ± 0.1 1.4 ± 0.1 0.4743 0.3587 0.0083 Clamp 0.8 ± 0.2 0.7 ± 0.2 0.7 ± 0.1 0.7 ± 0.2 0.7956 0.4845 0.6494 Measurements were made before randomization (baseline) and again after 16 weeks of CR or CON. Means ± SEM are given, and a two-way (group, time) repeated-measures ANOVA was used to compare outcomes across groups. Precise P values are given for the ANOVA. When a significant interaction was found, a Sidak post hoc test was performed.
CHO, carbohydrate.
*P < 0.05;
**P < 0.01.
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