The characteristics of the subjects are shown in . As expected, type 2 diabetic subjects had elevated fasting plasma glucose and FFA concentrations and impaired insulin sensitivity. Fasting RQ was similar in type 2 diabetic (0.83 ± 0.01) and nondiabetic participants (0.83 ± 0.01). However, under insulin-stimulated conditions, the ΔRQ was lower in type 2 diabetic versus nondiabetic individuals (0.06 ± 0.01 vs. 0.10 ± 0.01, P < 0.0001 adjusted for age, sex, race, and research center; ). Similarly, insulin-stimulated oxidative and nonoxidative glucose disposal rate were lower in type 2 diabetic versus nondiabetic subjects (P < 0.05 adjusted for FFM, FM, age, sex, race, and research center).
Characteristics of the subjects
FIG. 2 A: Respiratory quotient under fasting and insulin-stimulated conditions in obese with type 2 diabetes (•, n = 59) and obese without type 2 diabetes (○, n = 42); inset: metabolic flexibility in both groups. B: Glucose disposal rate in both (more ...)
Determinants of metabolic flexibility to glucose
In the whole group, metabolic flexibility to glucose was inversely correlated with fasting plasma glucose (r = −0.45, P < 0.0001) and insulin (r = −0.41, P < 0.0001) concentrations but positively with fasting plasma adiponectin concentration (r = 0.22, P = 0.04). During glucose/insulin infusion, metabolic flexibility to glucose was positively associated with glucose disposal rate (r = 0.65, P < 0.0001; ) but inversely to plasma FFA (r = −0.51, P < 0.0001; ) and glycerol (r = −0.29, P < 0.005).
FIG. 1 Correlation analysis in the whole study group between metabolic flexibility (steady-state RQ – fasting RQ) and glucose disposal rate (A) (type 2 diabetes: r = 0.52, P < 0.0001; obese without type 2 diabetes: r = 0.52, P = 0.0007) and steady-state (more ...)
By stepwise multiple regression analysis, glucose disposal rate (in milligrams per kilogram FFM per minute) was the main determinant of ΔRQ, explaining 46% of variance (slope = 0.04, P < 0.0001), whereas an additional 3% was explained by steady-state plasma FFA concentration (slope = −0.20, P = 0.03). Diabetes status, sex, and race were not significant.
Characteristics of metabolically flexible and inflexible to glucose
A total of 47 subjects were defined as metabolically flexible and 54 as inflexible. Similar proportions of type 2 diabetic individuals (62 vs. 56%, respectively, P = 0.53), women (55 vs. 59%, P = 0.69), and African-American subjects (21 vs. 19%, P = 0.86) were observed in each group. Anthropometric and metabolic characteristics were similar except for a higher BMI in the metabolically inflexible group (34.1 ± 0.4 vs. 32.3 ± 0.4 kg/m2, P = 0.01).
Metabolic flexibility to glucose in type 2 diabetes
The lower ΔRQ observed in type 2 diabetic versus nondiabetic individuals () was still significant after controlling for steady-state plasma FFA concentration (P = 0.0004); however, the difference was abolished after adjusting for glucose disposal rate (P = 0.19). Accordingly, the slopes and intercepts of the relationships between ΔRQ and glucose disposal rate were similar in both groups. Similar results were found after applying the same analysis to insulin-stimulated fat (P = 0.86) and glucose (P = 0.92) oxidation expressed in absolute rates or adjusted for FFM and FM. Nonoxidative glucose disposal rate between groups was also similar after controlling for glucose disposal rate (P = 0.87). Fasting energy expenditure was higher in type 2 diabetic versus nondiabetic participants after controlling for FFM, FM, age, race, sex, and research center (P = 0.003, ) but not after insulin stimulation (P = 0.10, ).
Effect of weight loss on metabolic flexibility to glucose
After 1-year of intensive lifestyle intervention in the type 2 diabetic participants, body weight (−9.5 ± 0.9 kg, P < 0.0001), body fat (−3.8 ± 0.4%, P < 0.0001), FM (−6.5 ± 0.7 kg, P < 0.0001), FFM (−3.0 ± 0.4 kg, P < 0.05), fasting plasma glucose (−17.3 ± 4.0 mg/dl, P < 0.0001), FFA (−0.13 ± 0.02 mmol/l, P < 0.0001), fasting insulin concentrations (−2.4 ± 0.8 IU/l, P = 0.004), and steady-state FFA concentration (−0.03 ± 0.01 mmol/l, P < 0.0001) were all reduced. Glucose disposal rate (P < 0.0001) and metabolic flexibility to glucose (P < 0.0001) were increased () mostly due to larger increases in steady-state RQ, since fasting RQ was unaltered. After controlling for glucose disposal rate, there was no difference in metabolic flexibility to glucose before and after weight loss (P = 0.17). Additional control for steady-state plasma FFA concentration did not modify this finding (P = 0.41).
FIG. 3 A: Respiratory quotient under fasting and insulin-stimulated conditions in obese type 2 diabetic subjects before (•, n = 59) and after (○, n = 59) 1-year weight loss intervention; inset: metabolic flexibility before and after intervention. (more ...)