Réjeanne Gougeon

Insulin Resistance of Protein Metabolism in Type 2 Diabetes

OBJECTIVE—We previously demonstrated that 1) obesity impairs and 2) sex influences insulin sensitivity of protein metabolism, while 3) poor glycemic control in type 2 diabetes accelerates protein turnover in daily fed-fasted states. We hypothesized that type 2 diabetes alters the insulin sensitivity of protein metabolism and that sex modulates it. RESEARCH DESIGN AND METHODS—Hyperinsulinemic (∼570 pmol/l), euglycemic (5.5 mmol/l), and isoaminoacidemic (kept at postabsorptive concentrations) clamps were performed in 17 hyperglycemic type 2 diabetic subjects and 23 subjects without diabetes matched for age and body composition, after 7 days on a inpatient, protein-controlled, isoenergetic diet. Glucose and leucine kinetics were determined using tracers. RESULTS—In type 2 diabetes, postabsorptive (baseline) glycemia was 8–9 mmol/l, glucose production (Ra) and disposal (Rd) were elevated, and once clamped, endogenous glucose Ra remained greater and Rd was less (P < 0.05) than in control subjects. Baseline leucine kinetics did not differ despite higher insulin levels. The latter was an independent predictor of leucine flux within each sex. With clamp, total flux increased less (P = 0.016) in type 2 diabetic men, although protein breakdown decreased equally (∼20%) in male groups but less in female groups. Whereas protein synthesis increased in male control subjects and in both female groups, it did not in male subjects with type 2 diabetes. In men, homeostasis model assessment of insulin resistance predicted 44%, and, in women, waist-to-hip ratio predicted 40% of the change in synthesis. CONCLUSIONS—During our clamp, men with type 2 diabetes have greater insulin resistance of protein metabolism than that conferred by excess adiposity itself, whereas women do not. These results may have implications for dietary protein requirements.

Elevations of plasma methylarginines in obesity and ageing are related to insulin sensitivity and rates of protein turnover

Aims/hypothesisIncreased circulating methylarginines (MA) have been linked to the metabolic syndrome to explain endothelial dysfunction and cardiovascular disease risk. Proteins that contain MA are regulatory and release them during catabolism. We hypothesised that increased protein turnover in insulin-resistant states contributes to an increase in circulating MA.Matwerials and methodsWe performed hyperinsulinaemic, euglycaemic, and isoaminoacidaemic experiments on 49 lean, obese and elderly subjects, with measurements of the kinetics of glucose and protein metabolism. Plasma MA, i.e. asymmetrical dimethylarginine (ADMA), symmetrical dimethylarginine (SDMA), and N -monomethyl-l-arginine (NMMA), lipids and body composition were measured.ResultsInsulin resistance of glucose and protein metabolism occurred in obese and elderly subjects. ADMA concentrations were 29 to 120% higher in obese and 34% higher in elderly than in lean subjects. SDMA were 34 and 20% higher in obese than in lean and than in elderly subjects, respectively. NMMA were 32% higher in obese than in lean subjects. ADMA differed by sex, being higher in men, namely by 1.75× in obese men and by 1.27× in elderly men. Postabsorptive ADMA (r=0.71), SDMA (r=0.46), and NMMA (r=0.31) correlated (all p<0.05) with rates of protein flux. All three MA correlated negatively with clamp glucose infusion rates and uptake (p<0.001). ADMA and SDMA correlated negatively with net protein synthesis and clamp amino acid infusion rates (p<0.05). All MA also correlated with adiposity indices and fasting insulin and triglycerides (p<0.05).Conclusions/interpretationObesity, sex and ageing affect MA. Elevations of the three MA in obese, and of ADMA in elderly men, are related to increased protein turnover and to lesser insulin sensitivity of protein metabolism. These interrelationships might amplify insulin resistance and endothelial dysfunction.

Whole-body protein anabolic response is resistant to the action of insulin in obese women

BACKGROUND Obesity is associated with insulin resistance of glucose and lipid metabolism. OBJECTIVE We sought to determine the effects of obesity on the insulin sensitivity of protein metabolism. DESIGN Whole-body [(13)C]leucine and [(3)H]glucose kinetics were measured in 9 lean and 10 obese women in the postabsorptive state and during a hyperinsulinemic, euglycemic, isoaminoacidemic clamp. RESULTS In the postabsorptive state, the leucine endogenous rate of appearance (catabolism), normalized for fat-free mass, was 11% greater and the nonoxidative rate of disappearance (synthesis) was 8% greater in the obese than in the lean women, but net balance was 29% more negative (P < 0.05). Clamp amino acid and glucose infusion rates were significantly lower in the obese women than in the lean women (0.65 +/- 0.02 compared with 0.85 +/- 0.04 and 5.7 +/- 0.3 compared with 9.1 +/- 0.5 mg x kg fat-free mass(-1) x min(-1), respectively; P < 0.0001 for both), and their rates correlated positively (r = 0.635, P = 0.005). During hyperinsulinemia, synthesis was stimulated less and net leucine balance was much lower in the obese women than in the lean women (-0.08 +/- 0.06 and 0.30 +/- 0.03 mumol x kg fat-free mass(-1) x min(-1), respectively; P < 0.0001). The percentage change in net leucine balance correlated negatively with all adiposity indexes. Plasma free fatty acids were less suppressed and the respiratory quotient was lower in the obese women than in the lean women. CONCLUSION Obese women show a blunted protein anabolic response to hyperinsulinemia that is consistent with resistance to the action of insulin on protein concurrent with that on glucose and lipid metabolism.

Effect of NIDDM on the Kinetics of Whole-Body Protein Metabolism

We postulated that dietary protein utilization and body protein metabolism are altered in hyperglycemic individuals with non-insulin-dependent diabetes mellitus (NIDDM). This was tested by estimating the kinetics of protein metabolism in obese NIDDM patients in the hyperglycemic state of isoenergetic feeding and in the normoglycemic state induced by the prolonged use of a very-low-energy diet (VLED) and comparing them with results in obese nondiabetic subjects studied previously. Seven obese subjects with NIDDM (one male, six females, body mass index = 35.8 ± 2.0 kg/m2) were given a 1.7 MJ (410 kcal) all protein (93 g/day) diet derived from hydrolyzed collagen and supplemented with tryptophan and methionine, which provides 16% of its amino acids as essential, a multivitamin and mineral supplement, and 16 mmol KCl for 42 days. During the seven-day isoenergetic diet and at weeks 4 and 6 of the VLED, amino nitrogen (N) flux rate was calculated from the urine [15N]urea enrichment by using the 60-h oral [15N]glycine method to obtain the integrated feeding-fasting metabolism. Rates of synthesis (S) and breakdown (B) were calculated from N flux. At day 7 of the isoenergetic diet, whole-body N flux, S, B, and resting metabolic rate (RMR) were 12–24% greater (P < 0.05) in the NIDDM subjects than observed in nondiabetic obese subjects. Mean plasma glucose decreased (P < 0.05) from the isoenergetic period (14.9 ± 2.4 mM) to 7.2 ± 1.2 mM at week 4 and 6.5 ± 1.1 mM at week 6 of the VLED. RMR declined progressively by 25% at week 5 of the VLED. Corresponding significant (P < 0.05) decreases from isoenergetic feeding to weeks 4 and 6 of the VLED occurred in whole-body N flux (from 51 ± 2 to 42 ± 1 g N/day), in S (from 38 ± 3 to 24 ± 1 g N/day), and in B (from 39 ± 3 to 26 ± 1 g N/day) resulting in net losses (S – B). S – B was significantly more negative (P < 0.05) in NIDDM than in the nondiabetic obese subjects at week 4 (−1.5 ± 0.5 vs. 0.9 ± 0.3 g N/day) but not at week 6 (−1.3 ± 0.4 vs. −0.9 ± 4 g N/day). During the VLED, N balance became less negative with time but never reached equilibrium in NIDDM. Thus, abnormal protein metabolism is present in NIDDM in the isoenergetic fed state with moderate hyperglycemia and persists during a VLED that restores glycemia to near normal.

Dietary Cod Protein Reduces Plasma C-Reactive Protein in Insulin-Resistant Men and Women

Chronic low-grade inflammation has been associated with insulin resistance and type 2 diabetes. Recently, we showed that cod protein (CP) improved insulin sensitivity in insulin-resistant subjects. In this study, we investigated the effects of dietary CP compared with those of other animal proteins on plasma concentrations of inflammatory markers, lipids, and lipoproteins in insulin-resistant subjects. Nineteen Caucasian men and women aged 40-65 y, overweight or obese (BMI > 25 kg/m(2)), and insulin resistant, rotated in a crossover design and consumed a CP diet and a similar diet containing lean beef, pork, veal, eggs, milk, and milk products (BPVEM) for 4 wk each. Diets differed only in protein source and thus provided equivalent amounts of dietary fibers, monounsaturated fat, PUFA [including (n-3) fatty acids], and SFA. Blood samples were collected before and after each experimental diet. Notably, the CP diet decreased high-sensitivity C-reactive protein (hsCRP; P = 0.021), whereas the BPVEM diet tended to increase it (P = 0.063), leading to a significant difference between diets (P = 0.041). Changes in plasma interleukin-6, tumor necrosis factor-alpha, and adiponectin concentrations did not differ between diets. Plasma total cholesterol (P = 0.0007), LDL cholesterol (P = 0.014), and apolipoprotein B (P = 0.005) were reduced only by the BPVEM diet. Thus, changes in total cholesterol differed between diets (P = 0.040), whereas changes in LDL cholesterol (P = 0.052) and apolipoprotein B (P = 0.075) tended to differ. Changes in all other lipids and lipoproteins did not differ between diets. Therefore, these results show that CP can lower hsCRP, a marker of inflammation associated with insulin resistance and type 2 diabetes.

Effects of Aerobic Training, Resistance Training, or Both on Percentage Body Fat and Cardiometabolic Risk Markers in Obese Adolescents: The Healthy Eating Aerobic and Resistance Training in Youth Randomized Clinical Trial

IMPORTANCE Little evidence exists on which exercise modality is optimal for obese adolescents. OBJECTIVE To determine the effects of aerobic training, resistance training, and combined training on percentage body fat in overweight and obese adolescents. DESIGN, SETTING, AND PARTICIPANTS Randomized, parallel-group clinical trial at community-based exercise facilities in Ottawa (Ontario) and Gatineau (Quebec), Canada, among previously inactive postpubertal adolescents aged 14 to 18 years (Tanner stage IV or V) with body mass index at or above the 95th percentile for age and sex or at or above the 85th percentile plus an additional diabetes mellitus or cardiovascular risk factor. INTERVENTIONS After a 4-week run-in period, 304 participants were randomized to the following 4 groups for 22 weeks: aerobic training (n = 75), resistance training (n = 78), combined aerobic and resistance training (n = 75), or nonexercising control (n = 76). All participants received dietary counseling, with a daily energy deficit of 250 kcal. MAIN OUTCOMES AND MEASURES The primary outcome was percentage body fat measured by magnetic resonance imaging at baseline and 6 months. We hypothesized that aerobic training and resistance training would each yield greater decreases than the control and that combined training would cause greater decreases than aerobic or resistance training alone. RESULTS Decreases in percentage body fat were -0.3 (95% CI, -0.9 to 0.3) in the control group, -1.1 (95% CI, -1.7 to -0.5) in the aerobic training group (P = .06 vs controls), and -1.6 (95% CI, -2.2 to -1.0) in the resistance training group (P = .002 vs controls). The -1.4 (95% CI, -2.0 to -0.8) decrease in the combined training group did not differ significantly from that in the aerobic or resistance training group. Waist circumference changes were -0.2 (95% CI, -1.7 to 1.2) cm in the control group, -3.0 (95% CI, -4.4 to -1.6) cm in the aerobic group (P = .006 vs controls), -2.2 (95% CI -3.7 to -0.8) cm in the resistance training group (P = .048 vs controls), and -4.1 (95% CI, -5.5 to -2.7) cm in the combined training group. In per-protocol analyses (≥ 70% adherence), the combined training group had greater changes in percentage body fat (-2.4, 95% CI, -3.2 to -1.6) vs the aerobic group (-1.2; 95% CI, -2.0 to -0.5; P = .04 vs the combined group) but not the resistance group (-1.6; 95% CI, -2.5 to -0.8). CONCLUSIONS AND RELEVANCE Aerobic, resistance, and combined training reduced total body fat and waist circumference in obese adolescents. In more adherent participants, combined training may cause greater decreases than aerobic or resistance training alone. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00195858.

Muscle protein anabolism in type 2 diabetes.

Purpose of reviewProtein anabolism is abnormal in human type 2 diabetes (T2DM). We review studies of anabolic stimuli that identify potential causes. If uncorrected, and combined with aging effects, they will compromise muscle function and mass. Knowing causes can guide studies of preventive and treatment measures. Recent findingsT2DM accelerates age-related decreases in muscle mass. This could be related to insulin resistance of whole-body protein anabolism demonstrated in hyperglycemic obese men. In contrast, their protein anabolic response to hyperaminoacidemia suggested that ample amino acid administration, especially branched chain amino acids might overcome such insulin resistance. One study of chronic leucine supplementation in elderly T2DM patients did not increase muscle mass. However, they lacked sarcopenia and had adequate dietary protein intake, so may be atypical. Exercise induced similar increases in muscle protein synthesis, mass and strength in healthy and T2DM patients suggesting that physical activity might also overcome insulin resistance of protein anabolism. SummaryMuscle protein anabolism in T2DM is resistant to the action of insulin but perhaps not to amino acid supply or exercise. Whether leucine supplementation improves muscle mass and function in persons with T2DM (especially elderly) with reduced protein intake or muscle mass needs to be determined.

Dietary Omega-3 Fatty Acids May Be Associated with Increased Neuropathic Pain in Nerve-Injured Rats

Certain dietary proteins and oils are capable of decreasing chronic neuropathic pain levels in rats after partial sciatic nerve ligation injury. We tested, for the first time, the role of dietary polyunsaturated fatty acids in suppressing pain in partial sciatic nerve ligation-injured rats. Six groups of male Wistar rats were fed an identical casein-based, fat-free diet for 1 wk preceding partial sciatic nerve ligation injury and for 1 wk thereafter. In addition, rats received, via gavage, 1 mL/day of pure canola, corn, hemp, soy, or sunflower oil, differing significantly in their &ohgr;-3 and &ohgr;-6 polyunsaturated fatty acid content, or 1 mL of plain water. Responses to tactile and noxious heat stimuli were recorded before and after surgery and a difference score was calculated for each group by subtracting the preoperative from the post-partial sciatic nerve ligation values. Heat hyperalgesia, but not tactile allodynia, was significantly different among the dietary groups (P = 0.005). Heat hyperalgesia of rats fed hemp oil, developing the most robust response, was significantly larger compared with rats fed corn oil, developing the least pain model (difference score: 24.3 ± 4.1 s versus 6.1 ± 3.1 s, respectively; P < 0.001). These oils contain similar levels of &ohgr;-6 polyunsaturated fatty acids (hemp, 60%; corn, 58%) but their &ohgr;-3 levels are 28-fold different (20% versus 0.7%, respectively). A significant correlation was found among dietary levels of &ohgr;-3, but not &ohgr;-6 or the &ohgr;-3/&ohgr;-6 ratio, of the six dietary groups and heat hyperalgesia (P = 0.006). We conclude that dietary oil might predict levels of neuropathic pain in rats and that this effect may be associated with dietary &ohgr;-3 levels.

Insulin resistance of protein metabolism in type 2 diabetes and impact on dietary needs: a review.

Evidence shows that the metabolism of protein is altered in type 2 diabetes mellitus and insulin resistance not only applies to glucose and lipid but protein metabolism as well. Population surveys report greater susceptibility to loss of lean tissue and muscle strength with aging in diabetes. Prevention of sarcopenia requires that protein receives more attention in dietary prescriptions. Protein intake of 1-1.2 g/kg of body weight (with weight at a body mass index of 25 kg/m(2))/day may be distributed equally among 3 meals a day, including breakfast, to optimize anabolism. Adopting a dietary pattern that provides a high plant-to-animal ratio and greater food volume favouring consumption of vegetables, legumes, fruits, complemented with fish, low fat dairy and meat (preferably cooked slowly in moisture), soy and nuts may assist with metabolic and weight control. Depending on the magnitude of energy restriction, usual protein intake should be maintained or increased, and the caloric deficit taken from fat and carbohydrate foods. Exercise before protein-rich meals improves skeletal muscle protein anabolism. Because high levels of amino acids lower glucose uptake in individuals without diabetes, the challenge remains to define the optimal protein intake and exercise regimen to protect from losses of muscle mass and strength while maintaining adequate glucose control in type 2 diabetes.

Effects of aerobic training, resistance training, or both on psychological health in adolescents with obesity: The HEARTY randomized controlled trial.

OBJECTIVE To determine the effects of aerobic training, resistance training, and combined training on mood, body image, and self-esteem in adolescents with obesity. METHOD After a 4-week prerandomization treatment, 304 postpubertal adolescents (91 males, 213 females) with obesity ages 14-18 years were randomized to 1 of 4 groups for 22 weeks: aerobic training (n = 75), resistance training (n = 78), combined aerobic and resistance training (n = 75), or nonexercising control (n = 76). All participants received dietary counseling, with a daily energy deficit of 250 kcal. Mood was measured using the Brunel Mood Scale. Body image was assessed using the Multiple Body Self-Relations Questionnaire, and physical self-perceptions and global self-esteem were measured using the Harter Physical Self-Perceptions Questionnaire. RESULTS Median adherence was 62%, 56%, and 64% in aerobic, resistance, and combined training, respectively. Resistance and combined training produced greater improvements than control on vigor, and resistance training reduced depressive symptoms. All groups improved on body image and physical self-perceptions, but combined showed greater increases than control on perceived physical conditioning, while only resistance training showed greater increases than controls on global self-esteem. Both combined and resistance training demonstrated greater increases in perceived strength than control. Psychological benefits were more related to better adherence and reductions in body fat than changes in strength or fitness. CONCLUSION Resistance training, alone or in combination with aerobic training, may provide psychological benefits in adolescents with overweight or obesity, and therefore could be an alternative to aerobic training for some individuals in the biological and psychological management of adolescent obesity.