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Randomized Controlled Trial
. 2016 Jan;65(1):74-84.
doi: 10.2337/db15-0675. Epub 2015 Aug 31.

Mechanism by Which Caloric Restriction Improves Insulin Sensitivity in Sedentary Obese Adults

Matthew L Johnson  1 , Klaus Distelmaier  1 , Ian R Lanza  1 , Brian A Irving  1 , Matthew M Robinson  1 , Adam R Konopka  1 , Gerald I Shulman  2 , K Sreekumaran Nair  3
Affiliations
Randomized Controlled Trial

Mechanism by Which Caloric Restriction Improves Insulin Sensitivity in Sedentary Obese Adults

Matthew L Johnson et al. Diabetes. 2016 Jan.

Abstract

Caloric restriction (CR) improves insulin sensitivity and reduces the incidence of diabetes in obese individuals. The underlying mechanisms whereby CR improves insulin sensitivity are not clear. We evaluated the effect of 16 weeks of CR on whole-body insulin sensitivity by pancreatic clamp before and after CR in 11 obese participants (BMI = 35 kg/m(2)) compared with 9 matched control subjects (BMI = 34 kg/m(2)). Compared with the control subjects, CR increased the glucose infusion rate needed to maintain euglycemia during hyperinsulinemia, indicating enhancement of peripheral insulin sensitivity. This improvement in insulin sensitivity was not accompanied by changes in skeletal muscle mitochondrial oxidative capacity or oxidant emissions, nor were there changes in skeletal muscle ceramide, diacylglycerol, or amino acid metabolite levels. However, CR lowered insulin-stimulated thioredoxin-interacting protein (TXNIP) levels and enhanced nonoxidative glucose disposal. These results support a role for TXNIP in mediating the improvement in peripheral insulin sensitivity after CR.

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Figures

Figure 1
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
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
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
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.
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