Thomas P. J. Solomon

The Effects of Free-Living Interval-Walking Training on Glycemic Control, Body Composition, and Physical Fitness in Type 2 Diabetic Patients A randomized, controlled trial

OBJECTIVE To evaluate the feasibility of free-living walking training in type 2 diabetic patients and to investigate the effects of interval-walking training versus continuous-walking training upon physical fitness, body composition, and glycemic control. RESEARCH DESIGN AND METHODS Subjects with type 2 diabetes were randomized to a control (n = 8), continuous-walking (n = 12), or interval-walking group (n = 12). Training groups were prescribed five sessions per week (60 min/session) and were controlled with an accelerometer and a heart-rate monitor. Continuous walkers performed all training at moderate intensity, whereas interval walkers alternated 3-min repetitions at low and high intensity. Before and after the 4-month intervention, the following variables were measured: VO2max, body composition, and glycemic control (fasting glucose, HbA1c, oral glucose tolerance test, and continuous glucose monitoring [CGM]). RESULTS Training adherence was high (89 ± 4%), and training energy expenditure and mean intensity were comparable. VO2max increased 16.1 ± 3.7% in the interval-walking group (P < 0.05), whereas no changes were observed in the continuous-walking or control group. Body mass and adiposity (fat mass and visceral fat) decreased in the interval-walking group only (P < 0.05). Glycemic control (elevated mean CGM glucose levels and increased fasting insulin) worsened in the control group (P < 0.05), whereas mean (P = 0.05) and maximum (P < 0.05) CGM glucose levels decreased in the interval-walking group. The continuous walkers showed no changes in glycemic control. CONCLUSIONS Free-living walking training is feasible in type 2 diabetic patients. Continuous walking offsets the deterioration in glycemia seen in the control group, and interval walking is superior to energy expenditure–matched continuous walking for improving physical fitness, body composition, and glycemic control.

Progressive Hyperglycemia across the Glucose Tolerance Continuum in Older Obese Adults Is Related to Skeletal Muscle Capillarization and Nitric Oxide Bioavailability

CONTEXTnReduced tissue nutrient exposure may aid in the progression of glucose intolerance.nnnOBJECTIVEnThe aim of the study was to examine peripheral tissue glucose disposal in relation to muscle capillarization and plasma nitric oxide bioavailability.nnnDESIGNnParticipants 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.nnnSETTINGnThe study was conducted in an outpatient setting at a Clinical Research Unit.nnnPARTICIPANTSnOlder, obese men and women (n = 60; age, 65 ± 1 yr; body mass index, 32.7 ± 0.5 kg/m(2)) participated in the study.nnnINTERVENTIONnWe performed a cross-sectional study.nnnMAIN OUTCOME MEASURESnBody composition, energy metabolism, aerobic fitness (maximum oxygen consumption), insulin sensitivity (glucose clamp), vastus lateralis muscle morphology, and plasma nitric oxide were assessed.nnnRESULTSnAlthough 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).nnnCONCLUSIONSnImpaired 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.

Insulin sensitivity and metabolic flexibility following exercise training among different obese insulin-resistant phenotypes

Impaired fasting glucose (IFG) blunts the reversal of impaired glucose tolerance (IGT) after exercise training. Metabolic inflexibility has been implicated in the etiology of insulin resistance; however, the efficacy of exercise on peripheral and hepatic insulin sensitivity or substrate utilization in adults with IFG, IGT, or IFG + IGT is unknown. Twenty-four older (66.7 ± 0.8 yr) obese (34.2 ± 0.9 kg/m(2)) adults were categorized as IFG (n = 8), IGT (n = 8), or IFG + IGT (n = 8) according to a 75-g oral glucose tolerance test (OGTT). Subjects underwent 12-wk of exercise (60 min/day for 5 days/wk at ∼85% HRmax) and were instructed to maintain a eucaloric diet. A euglycemic hyperinsulinemic clamp (40 mU·m(2)·min(-1)) with [6,6-(2)H]glucose was used to determine peripheral and hepatic insulin sensitivity. Nonoxidative glucose disposal and metabolic flexibility [insulin-stimulated respiratory quotient (RQ) minus fasting RQ] were also assessed. Glucose incremental area under the curve (iAUCOGTT) was calculated from the OGTT. Exercise increased clamp-derived peripheral and hepatic insulin sensitivity more in adults with IFG or IGT alone than with IFG + IGT (P < 0.05). Exercise reduced glucose iAUCOGTT in IGT only (P < 0.05), and the decrease in glucose iAUCOGTT was inversely correlated with the increase in peripheral but not hepatic insulin sensitivity (P < 0.01). Increased clamp-derived peripheral insulin sensitivity was also correlated with enhanced metabolic flexibility, reduced fasting RQ, and higher nonoxidative glucose disposal (P < 0.05). Adults with IFG + IGT had smaller gains in clamp-derived peripheral insulin sensitivity and metabolic flexibility, which was related to blunted improvements in postprandial glucose. Additional work is required to assess the molecular mechanism(s) by which chronic hyperglycemia modifies insulin sensitivity following exercise training.

Pancreatic β-cell function increases in a linear dose-response manner following exercise training in adults with prediabetes.

Although some studies suggest that a linear dose-response relationship exists between exercise and insulin sensitivity, the exercise dose required to enhance pancreatic β-cell function is unknown. Thirty-five older obese adults with prediabetes underwent a progressive 12-wk supervised exercise intervention (5 days/wk for 60 min at ~85% HRmax). Insulin and C-peptide responses to an OGTT were used to define the first- and second-phase disposition index (DI; β-cell function = glucose-stimulated insulin secretion × clamp-derived insulin sensitivity). Maximum oxygen consumption (Vo2max) and body composition (dual-energy X-ray absorptiometry and computed tomography) were also measured before and after the intervention. Exercise dose was computed using Vo2/heart-rate derived linear regression equations. Subjects expended 474.5 ± 8.8 kcal/session (2,372.5 ± 44.1 kcal/wk) during the intervention and lost ~8% body weight. Exercise increased first- and second-phase DI (P < 0.05), and these changes in DI were linearly related to exercise dose (DIfirst phase: r = 0.54, P < 0.001; DIsecond phase: r = 0.56, P = 0.0005). Enhanced DI was also associated with increased Vo2max (DIfirst phase: r = 0.36, P = 0.04; DIsecond phase: r = 0.41, P < 0.02) but not lower body fat (DIfirst phase: r = -0.21, P = 0.25; DIsecond phase: r = -0.30, P = 0.10) after training. Low baseline DI predicted an increase in DI after the intervention (DIfirst phase: r = -0.37; DIsecond phase: r = -0.41, each P < 0.04). Thus, exercise training plus weight loss increased pancreatic β-cell function in a linear dose-response manner in adults with prediabetes. Our data suggest that higher exercise doses (i.e., >2,000 kcal/wk) are necessary to enhance β-cell function in adults with poor insulin secretion capacity.

Mechanisms behind the superior effects of interval vs continuous training on glycaemic control in individuals with type 2 diabetes: a randomised controlled trial

AbstractAims/hypothesisBy use of a parallel and partly crossover randomised, controlled trial design we sought to elucidate the underlying mechanisms behind the advantageous effects of interval walking training (IWT) compared with continuous walking training (CWT) on glycaemic control in individuals with type 2 diabetes. We hypothesised that IWT, more than CWT, would improve insulin sensitivity including skeletal muscle insulin signalling, insulin secretion and disposition index (DI).MethodsBy simple randomisation (sequentially numbered, opaque sealed envelopes), eligible individuals (diagnosed with type 2 diabetes, no exogenous insulin treatment) were allocated to three groups: a control group (CON, nu2009=u20098), an IWT group (nu2009=u200912) and an energy expenditure-matched CWT group (nu2009=u200912). Training groups were prescribed free-living training, five sessions per week (60xa0min/session). A three-stage hyperglycaemic clamp, including glucose isotope tracers and skeletal muscle biopsies, was performed before and after a 4xa0month intervention in a hospitalised setting. No blinding was performed.ResultsThe improved glycaemic control, which was only seen in the IWT group, was consistent with IWT-induced increases in insulin sensitivity index (49.8u2009±u200914.6%; pu2009<u20090.001), peripheral glucose disposal (14.5u2009±u20094.9%; pu2009<u20090.05) and DI (66.2u2009±u200921.8%; pu2009<u20090.001), with no changes in the CWT or CON group. Moreover, only IWT improved insulin signalling in skeletal muscle via increased insulin-stimulated phosphorylation of AS160 (29.0u2009±u200910.8%; pu2009<u20090.05). No changes were seen in insulin secretion during hyperglycaemia alone, hyperglycaemia + glucagon-like peptide 1 infusion or arginine injection.Conclusions/interpretationIWT maintains insulin secretion and improves insulin sensitivity and DI, in contrast to energy expenditure-matched CWT. These results suggest that training with alternating intensity, and not just training volume and mean intensity, is a key determinant of changes in whole body glucose disposal in individuals with type 2 diabetes.n Trial registration: ClinicalTrials (NCT01234155).

Pancreatic β-cell Function Is a Stronger Predictor of Changes in Glycemic Control After an Aerobic Exercise Intervention Than Insulin Sensitivity

CONTEXTnUnderstanding intersubject variability in glycemic control following exercise training will help individualize treatment.nnnOBJECTIVEnOur aim was to determine whether this variability is related to training-induced changes in insulin sensitivity or pancreatic β-cell function.nnnDESIGN, SETTING, AND PARTICIPANTSnWe conducted an observational clinical study of 105 subjects with impaired glucose tolerance or type 2 diabetes.nnnINTERVENTIONS AND MAIN OUTCOME MEASURESnIndividual subject changes in fitness (VO2max), glycemia (glycosylated hemoglobin, fasting glucose, oral glucose tolerance test), insulin sensitivity (hyperinsulinemic-euglycemic clamp), oral glucose-stimulated insulin secretion (GSIS), and disposition index (DI) were measured following 12 to 16 weeks of aerobic exercise training. Regression analyses were used to identify relationships between variables.nnnRESULTSnAfter training, 86% of subjects increased VO2max and lost weight. Glycosylated hemoglobin, fasting glucose, and 2-hour oral glucose tolerance test were reduced in 69%, 62%, and 68% of subjects, respectively, while insulin sensitivity improved in 90% of the participants. Changes in glycemic control were congruent with changes in GSIS such that 66% of subjects had a reduction in first-phase GSIS, and 46% had reduced second-phase GSIS. Training increased first- and second-phase DI in 83% and 74% of subjects. Training-induced changes in glycemic control were related to changes in GSIS (P < .05), but not insulin sensitivity or DI, and training-induced improvements in glycemic control were largest in subjects with greater pretraining GSIS.nnnCONCLUSIONSnIntersubject variability in restoring glycemic control following exercise is explained primarily by changes in insulin secretion. Thus, baseline and training-induced changes in β-cell function may be a key determinant of training-induced improvements in glycemic control.

Glucagon Like Peptide-1-Induced Glucose Metabolism in Differentiated Human Muscle Satellite Cells Is Attenuated by Hyperglycemia

Background Glucagon like peptide-1 (GLP-1) stimulates insulin secretion from the pancreas but also has extra-pancreatic effects. GLP-1 may stimulate glucose uptake in cultured muscle cells but the mechanism is not clearly defined. Furthermore, while the pancreatic effects of GLP-1 are glucose-dependent, the glucose-dependency of its extra-pancreatic effects has not been examined. Methods Skeletal muscle satellite cells isolated from young (22.5±0.97 yr), lean (BMI 22.5±0.6 kg/m2), healthy males were differentiated in media containing either 22.5 mM (high) or 5 mM (normal) glucose for 7 days in the absence or presence of insulin and/or various GLP-1 concentrations. Myocellular effects of GLP-1, insulin and glucose were assessed by western-blot, glucose uptake and glycogen synthesis. Results We firstly show that the GLP-1 receptor protein is expressed in differentiated human muscle satellite cells (myocytes). Secondly, we show that in 5 mM glucose media, exposure of myocytes to GLP-1 results in a dose dependent increase in glucose uptake, GLUT4 amount and subsequently glycogen synthesis in a PI3K dependent manner, independent of the insulin signaling cascade. Importantly, we provide evidence that differentiation of human satellite cells in hyperglycemic (22.5 mM glucose) conditions increases GLUT1 expression, and renders the cells insulin resistant and interestingly GLP-1 resistant in terms of glucose uptake and glycogen synthesis. Hyperglycemic conditions did not affect the ability of insulin to phosphorylate downstream targets, PKB or GSK3. Interestingly we show that at 5 mM glucose, GLP-1 increases GLUT4 protein levels and that this effect is abolished by hyperglycemia. Conclusions GLP-1 increases glucose uptake and glycogen synthesis into fully-differentiated human satellite cells in a PI3-K dependent mechanism potentially through increased GLUT4 protein levels. The latter occurs independently of the insulin signaling pathway. Attenuation of both GLP-1 and insulin-induced glucose metabolism by hyperglycemia is likely to occur downstream of PI3K.

The Acute Effects of Interval- Vs Continuous-Walking Exercise on Glycemic Control in Subjects With Type 2 Diabetes: A Crossover, Controlled Study

CONTEXTnGlycemic control improves with physical activity, but the optimal exercise mode is unknown.nnnOBJECTIVEnThe objective of the study was to determine whether interval-based exercise improves postprandial glucose tolerance and free-living glycemia more than oxygen consumption- and time duration-matched continuous exercise.nnnDESIGNnThis was a crossover, controlled study with trials performed in randomized order.nnnSETTINGnThe study was conducted in hospitalized and ambulatory care.nnnPATIENTSnPATIENTS diagnosed with type 2 diabetes mellitus (n=10, no withdrawals) participated in the study.nnnINTERVENTIONSnSubjects performed three 1-hour interventions: 1) interval walking (IW; repeated cycles of 3 min of slow and fast walking); 2) continuous walking (CW); and 3) control (CON). Oxygen consumption (VO2) was measured continuously to match mean VO2 between exercise sessions (∼75% VO2peak).nnnMAIN OUTCOME MEASURESnA mixed-meal tolerance test (MMTT; 450 kcal, 55% carbohydrate) with stable glucose isotopic tracers was provided after each intervention, and glucose kinetics were measured during the following 4 hours. Free-living glycemic control was assessed for approximately 32 hours after the MMTT using continuous glucose monitoring.nnnRESULTSnVO2 was well matched between the exercise interventions. IW decreased the mean and maximal incremental plasma glucose during the MMTT when compared with the CON (mean 1.2 ± 0.4 vs 2.0 ± 0.5 mmol/L, P < .001; maximal 3.7 ± 0.6 vs 4.6 ± 0.7 mmol/L, P = .005) and mean when compared with CW (1.7 ± 0.4 mmol/L, P = .02). No differences in the mean or maximal incremental plasma glucose values were seen between the CW and CON. The metabolic clearance rate of glucose during the MMTT was increased in the IW compared with CW (P = .049) and CON (P < .001). Continuous glucose monitoring mean glucose was reduced in IW compared with CW for the rest of the intervention day (8.2 ± 0.4 vs 9.3 ± 0.7 mmol/L, P = .03), whereas no differences were found between IW and CW the following day.nnnCONCLUSIONSnOne interval-based exercise session improves glycemic control in type 2 diabetes mellitus subjects when compared with an oxygen consumption- and time duration-matched continuous exercise session.

Menopause is associated with decreased whole body fat oxidation during exercise.

The purpose of this study was to examine if fat oxidation was affected by menopausal status and to investigate if this could be related to the oxidative capacity of skeletal muscle. Forty-one healthy women were enrolled in this cross-sectional study [premenopausal (n = 19), perimenopausal (n = 8), and postmenopausal (n = 14)]. Estimated insulin sensitivity was obtained from an oral glucose tolerance test. Body composition was measured by dual-energy X-ray absorptiometry and magnetic resonance imaging. Fat oxidation and energy expenditure were measured during an acute exercise bout of 45 min of ergometer biking at 50% of maximal oxygen consumption (Vo2 max). Muscle biopsies from the vastus lateralis of the quadriceps muscle were obtained before and immediately after the exercise bout. Postmenopausal women had 33% [confidence interval (CI) 95%: 12-55] lower whole body fat oxidation (P = 0.005) and 19% (CI 95%: 9-22) lower energy expenditure (P = 0.02) during exercise, as well as 4.28 kg lower lean body mass (LBM) than premenopausal women. Correction for LBM reduced differences in fat oxidation to 23% (P = 0.05), whereas differences in energy expenditure disappeared (P = 0.22). No differences between groups were found in mRNA [carnitine palmitoyltransferase I, β-hydroxyacyl-CoA dehydrogenase (β-HAD), peroxisome proliferator-activated receptor-α, citrate synthase (CS), pyruvate dehydrogenase kinase 4, peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α)], protein [phosphorylated AMP-activated protein kinase (AMPK), vascular endothelial growth factor, pyruvate dehydrogenase-1Eα, cytochrome oxidase I], or enzyme activities (β-HAD, CS) in resting skeletal muscle, except for an increased protein level of cytochrome c in the post- and perimenopausal women relative to premenopausal women. Postmenopausal women demonstrated a trend to a blunted exercise-induced increase in phosphorylation of AMPK compared with premenopausal women (P = 0.06). We conclude that reduced whole body fat oxidation after menopause is associated with reduced LBM.

Normal physical activity obliterates the deleterious effects of a high-caloric intake

A high-caloric intake combined with a sedentary lifestyle is an important player in the development of type 2 diabetes mellitus (T2DM). The present study was undertaken to examine if the level of physical activity has impact on the metabolic effects of a high-caloric (+2,000 kcal/day) intake. Therefore, healthy individuals on a high-caloric intake were randomized to either 10,000 or 1,500 steps/day for 14 days. Step number, total energy expenditure, dietary records, neuropsychological tests, maximal oxygen uptake (Vo2max), whole body dual-energy X-ray absorptiometry (DXA) and abdominal magnetic resonance imaging (MRI) scans, continuous glucose monitoring (CGM), and oral glucose tolerance tests (OGTT) with stable isotopes were performed before and after the intervention. Both study groups gained the same amount of body weight. However, the inactive group accumulated significantly more visceral fat compared with the active group. Following the 2-wk period, the inactive group also experienced a poorer glycemic control, increased endogenous glucose production, decreased hepatic insulin extraction, increased baseline plasma levels of total cholesterol and LDL, and a decreased cognitive function with regard to capacity of attention. In conclusion, we find evidence to support that habitual physical activity may prevent pathophysiological symptoms associated with diet-induced obesity.