Progressive hyperglycemia across the glucose tolerance continuum in older obese adults is related to skeletal muscle capillarization and nitric oxide bioavailability

Abstract

Context: Reduced tissue nutrient exposure may aid in the progression of glucose intolerance.

Objective: The aim of the study was to examine peripheral tissue glucose disposal in relation to muscle capillarization and plasma nitric oxide bioavailability.

Design: Participants were carefully matched for age, adiposity, and lipid status and stratified into normal (n = 20), impaired (n = 20), and type 2 diabetic (n = 20) glucose-tolerant groups.

Setting: The study was conducted in an outpatient setting at a Clinical Research Unit.

Participants: Older, obese men and women (n = 60; age, 65 ± 1 yr; body mass index, 32.7 ± 0.5 kg/m(2)) participated in the study.

Intervention: We performed a cross-sectional study.

Main outcome measures: Body composition, energy metabolism, aerobic fitness (maximum oxygen consumption), insulin sensitivity (glucose clamp), vastus lateralis muscle morphology, and plasma nitric oxide were assessed.

Results: Although subjects were identical with respect to age, body composition, energy expenditure, and lipid status, insulin-stimulated glucose disposal and maximum oxygen consumption showed progressive decline with increasing glucose intolerance. Muscle fiber type composition and mitochondrial density were not different between groups. However, capillary density markedly declined with advancing glucose intolerance (1.86 ± 0.31, 1.70 ± 0.28, 1.42 ± 0.24 capillary/fiber; P < 0.05), a trend that was mirrored by fasting plasma nitric oxide concentrations (26.3 ± 3.6, 19.8 ± 2.3, 15.2 ± 2.1 μmol/liter; P < 0.05). Furthermore, skeletal muscle capillary density correlated with insulin sensitivity (r = 0.65; P < 0.001).

Conclusions: Impaired muscle capillarization and reduced nutrient exposure to the metabolizing tissue may play a major role in the progression of insulin resistance across the glucose tolerance continuum, independent of age, adiposity, lipid status, and resting energy metabolism. These data also highlight plasma nitric oxide as a potential surrogate marker of these impairments and may be indicative of the progression toward type 2 diabetes.

Figures

Fig. 1.

Representative photomicrographs of skeletal muscle morphology. Vastus lateralis skeletal muscle biopsies were obtained, and histomounts were stained using an amylase-periodic acid Schiff histochemical stain (A), and an ATPase histochemical stain (B). I, Type I muscle fibers; II, type 2 muscle fibers. Blue staining indicates nuclei; purple staining indicates capillaries. The inset bar represents 50 μm.

Fig. 2.

Progressive reduction in plasma nitric oxide levels across the glucose tolerance continuum. Older, obese men and women were divided into three age-, BMI-, adiposity-, and lipid status-matched groups according to their state of glucose tolerance: normal glucose tolerance (Obese-NGT; n = 20), impaired glucose tolerance (Obese-IGT; n = 20), and T2DM (Obese-T2DM; n = 20). Plasma nitrite/nitrate concentrations, a marker of nitric oxide production (NOx), were measured in the basal (A) and insulin-stimulated (B) states. NOx levels were also progressively decreased with advancing glucose intolerance but unresponsive to hyperinsulinemia in each group. Significant differences between means were identified by one-way ANOVA (*, P < 0.05).

Fig. 3.

The relationship between insulin sensitivity and skeletal muscle capillary density. Skeletal muscle histochemical procedures were performed in 40 individuals (16 Obese-NGT, 15 Obese-IGT, and nine Obese-T2DM). Regression analyses revealed that insulin-stimulated glucose disposal (GDR, mg/kg · min) was significantly related to skeletal muscle capillary density (CD, mm−2; r = 0.65; P < 0.001).