Insulin Resistance Of Protein Metabolism Research Articles

Muscle Loss in Chronic Liver Diseases: The Example of Nonalcoholic Liver Disease.

Recent publications highlight a frequent loss of muscle mass in chronic liver diseases, including nonalcoholic fatty liver disease (NAFLD), and its association with a poorer prognosis. In NAFLD, given the role of muscle in energy metabolism, muscle loss promotes disease progression. However, liver damage may be directly responsible of this muscle loss. Indeed, muscle homeostasis depends on the balance between peripheral availability and action of anabolic effectors and catabolic signals. Moreover, insulin resistance of protein metabolism only partially explains muscle loss during NAFLD. Interestingly, some data indicate specific alterations in the liver–muscle axis, particularly in situations such as excess fructose/sucrose consumption, associated with increased hepatic de novo lipogenesis (DNL) and endoplasmic reticulum stress. In this context, the liver will be responsible for a decrease in the peripheral availability of anabolic factors such as hormones and amino acids, and for the production of catabolic effectors such as various hepatokines, methylglyoxal, and uric acid. A better understanding of these liver–muscle interactions could open new therapeutic opportunities for the management of NAFLD patients.

Effect of 10% dietary protein intake on whole body protein kinetics in type 2 diabetic adults

Insulin resistance of protein metabolism occurs in obesity and type 2 diabetes (T2D). Hyperaminoacidemia during a simulated fed steady-state clamp compensates for this resistance. We tested whether decreasing protein intake affects the response to insulin with or without added amino acids, and if this response differs by sex. Protein intake was reduced from usual (15%) to 10% of an isoenergetic diet energy for 11 days, in T2D obese men (n = 8) and women (n = 10). Whole-body leucine kinetics (1-(13)C-leucine, surrogate for protein) were determined postabsorptive and during a hyperinsulinemic (∼600 pmol/L), hyperglycemic (8 mmol/L), isoaminoacidemic, followed by hyperaminoacidemic clamp and compared to those of T2D men on a 17% protein diet. Initial negative nitrogen balance approached equilibrium by day 10 but remained lower than with the 17% protein diet. During the hyperinsulinemic, isoaminoacidemic clamp, total leucine flux was less, with both lower endogenous rates of appearance (catabolism) and nonoxidative rates of disposal (synthesis), resulting in net balance at zero. With hyperaminoacidemia, net balance increased to 0.39 ± 0.09 μmol/kgLBM⋅min in men, significantly less than in men on 17% protein (0.98 ± 0.09, p < 0.01). There were no sex differences in clamp responses with 10% protein. After 11 days of 10% protein diet, there was a slight improvement in insulin sensitivity, but a blunted anabolic response to hyperaminoacidemia. Longer-term consequences of lesser anabolic efficiency at reduced protein intakes require study and may contribute to increased risk of sarcopenia in persons with T2D with aging.

Metabolic and Body Composition Responses to a Moderate Energy Restriction, Abundant Protein Diet in Type 2 Diabetic Adults

We reported insulin resistance of protein metabolism in hyperglycemic type 2 diabetic adults. Resulting inefficient protein utilization could be exacerbated by weight loss diets that keep protein as a fixed % of energy. We tested whether a moderately hypoenergetic, abundant-protein diet could prevent this, while preserving the glucoregulatory improvement. Diet provided 60% of energy requirements, 45% of energy as carbohydrate, 26% as protein (1.9 g/kgLBM/day) for 5 weeks in obese diabetic adults (n=5, 52 to 64 years). Insulin sensitivity of whole-body glucose (3-3H-glucose) and protein (13C-leucine) kinetics were quantified pre- and post-diet, postabsorptive and during hyperinsulinemic (∼500pM), isoglycemic (7.7±0.4 pre vs. 5.7±0.2 mM post), isoaminoacidemic clamps. Weight loss was 5.3±0.7 kg, as fat 4.0±0.3 kg (both p<0.004) and LBM 1.2±1.0 kg (NS), and RMR/LBM maintained. The following decreased post-diet (p<0.05): postabsorptive glycemia (7.7±0.4 to 5.7±0.2 mM), insulin (109±17 to 69±8 pM), HOMA-IR (6.2±1.0 to 2.9±0.4), A1C (7.6 to 6.6%) and antihypertensive and/or diabetes medications. Whereas glucose Ra and Rd (1.9±0.2 mg/kgBW/min) did not change, MCR (Rd/glycemia) increased. Notably, protein catabolism and oxidation decreased, resulting in less negative net balance (p<0.05). Clamp glucose Ra and Rd responses did not improve, but MCR increased from 2.3±0.2 to 3.5±0.4 mL/kg∙min (p=0.01); protein catabolism was suppressed but synthesis not stimulated, resulting in no net anabolism improvement. Weight lost was fat, lean mass preserved, fasting glycemia, insulin and protein balance improved. In response to hyperinsulinemia, only MCR improved, but protein metabolism did not worsen. Thus, abundant protein appears to preserve body proteins in the face of energy deficit and insulin resistance.

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.

A moderate acute increase in physical activity enhances nutritive flow and the muscle protein anabolic response to mixed nutrient intake in older adults

Nutrient stimulation of muscle protein anabolism is blunted with aging and may contribute to the development and progression of sarcopenia in older adults. This is likely due to insulin resistance of protein metabolism and/or endothelial dysfunction with a reduction in nutritive flow, both of which can be improved by aerobic exercise. Our objective was to determine whether increasing physical activity can enhance the muscle protein anabolic effect of essential amino acid (EAA) + sucrose intake in older subjects by improving nutritive flow and/or insulin signaling. Using a randomized crossover design, we measured in older subjects [n = 6, 70 ± 3 y of age, BMI (in kg/m2) of 25 ± 1] the acute effects of increasing physical activity with aerobic exercise, as compared with normal sedentary lifestyle, on the response of blood flow, microvascular perfusion, insulin signaling, and muscle protein kinetics to EAA+sucrose intake. No differences between treatment groups were found in the basal state. The change from the basal state in blood flow, muscle perfusion, phenylalanine delivery, net balance, and muscle protein synthesis during the consumption of EAA+sucrose was significantly higher after the exercise than after the control treatment (P < 0.05). Insulin signaling increased during EAA+sucrose ingestion in both groups (P < 0.05). Our data indicate that a prior bout of aerobic exercise increases the anabolic effect of nutrient intake in older adults. This effect appears to be mediated by an exercise-induced improvement in nutrient-stimulated vasodilation and nutrient delivery to muscle rather than to improved insulin signaling. This trial was registered at clinicaltrials.gov as NCT00690534.

Postprandial hyperaminoacidaemia overcomes insulin resistance of protein anabolism in men with type 2 diabetes

Although protein is usually ignored when considering insulin resistance, we have shown resistance of protein concurrent with glucose metabolism in men with type 2 diabetes during a hyperinsulinaemic clamp at euglycaemia and fasting aminoacidaemia. We hypothesised that this resistance is even worse during conditions that simulate the postprandial state, when anabolism should be maximal. Eight overweight and obese men with type 2 diabetes underwent a hyperinsulinaemic-hyperglycaemic (8mmol/l) clamp, first with plasma amino acids at postabsorptive (Hyper-2) then at postprandial concentrations (Hyper-3). Whole-body protein kinetics were assessed using L-: [1-(13)C]leucine. Hyper-2 results were compared with those of diabetic men whose plasma glucose was lowered to 5.5mmol/l and fasting aminoacidaemia maintained during the hyperinsulinaemic clamp (Hyper-1). In Hyper-2 vs Hyper-1 clamps, leucine flux (2.99 ± 0.16 vs 2.62 ± 0.06μmol kg [fat-free mass (FFM)](-1) min(-1)), rates of synthesis (2.31 ± 0.15 vs 1.98 ± 0.06) and breakdown (2.38 ± 0.16 vs 2.00 ± 0.07) were higher (p < 0.05), but leucine oxidation and net balance did not differ. In Hyper-3 vs Hyper-2 clamps, leucine flux and synthesis and oxidation rates increased markedly as did net balance (0.84 ± 0.09 vs -0.07 ± 0.04μmol [kg FFM](-1) min(-1), p < 0.0001). In type 2 diabetic men, insulin resistance of protein metabolism is of the same magnitude at 8 vs 5.5mmol/l, but turnover rates are higher with hyperglycaemia. Contrary to our hypothesis, sustained postprandial-level hyperaminoacidaemia stimulated positive net protein balance comparable with that previously found in lean non-diabetic men. This was sufficient to overcome the insulin resistance of protein anabolism.

Innovation in the Treatment of Uremia: Proceedings from the Cleveland Clinic Workshop: Inflammation and Insulin Resistance as Novel Mechanisms of Wasting in Chronic Dialysis Patients

Over the last decade, there have been no proven therapies to lower the mortality and morbidity risk for chronic dialysis patients. One of the most important determinants of this poor clinical outcome is protein energy wasting (PEW), a unique and highly prevalent nutritional and metabolic abnormality primarily characterized by increased protein breakdown in the skeletal muscle compartment. Although the etiology and mechanisms leading to increased protein breakdown in chronic dialysis patients are complex and mostly ill-defined, two well-recognized and presumably interrelated metabolic abnormalities, insulin resistance and chronic inflammation, are likely to play a critical role in the pathogenesis of this condition. Multiple studies demonstrate the anabolic effects of insulin that extend beyond simple carbohydrate metabolism. Insulin is a mediator of accelerated protein breakdown in the catabolic condition such as advanced kidney disease. Chronic inflammation, a condition known to cause muscle catabolism in experimental conditions, has a strong association with advanced kidney disease in epidemiologic studies. Chronic inflammation is also known to induce insulin resistance, primarily by the induction of proinflammatory cytokines. The protein catabolic effects of inflammation and insulin resistance involve common cellular pathways. Thus, it is reasonable to speculate that chronic inflammation of advanced kidney disease mediates its protein catabolic effects by inducing insulin resistance of protein metabolism at both the physiologic and cellular levels. Modulating inflammatory response or insulin signaling by pharmacologic interventions could allow us to clarify the mechanisms contributing to the development of PEW in the setting of these particular metabolic derangements.

Insulin Resistance of Protein Metabolism in Type 2 Diabetes

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. Hyperinsulinemic ( approximately 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. In type 2 diabetes, postabsorptive (baseline) glycemia was 8-9 mmol/l, glucose production (R(a)) and disposal (R(d)) were elevated, and once clamped, endogenous glucose R(a) remained greater and R(d) 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 ( approximately 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. 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.