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Insulin Resistance of Protein Anabolism Accompanies That of Glucose Metabolism in Lean, Glucose-Tolerant Offspring of Persons with Type 2 Diabetes

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Insulin Resistance of Protein Anabolism Accompanies That of Glucose Metabolism in Lean, Glucose-Tolerant Offspring of Persons with Type 2 Diabetes BMJ Open Diab Res Care: first published as 10.1136/bmjdrc-2016-000312 on 29 November 2016. Downloaded from Open Access Research Insulin resistance of protein anabolism accompanies that of glucose metabolism in lean, glucose-tolerant offspring of persons with type 2 diabetes Sergio A Burgos,1,2 Vikram Chandurkar,3 Michael A Tsoukas,1 Stéphanie Chevalier,1 José A Morais,1 Marie Lamarche,1 Errol B Marliss1 To cite: Burgos SA, ABSTRACT Significance of this study Chandurkar V, Tsoukas MA, Objective: To test whether protein anabolic resistance et al . Insulin resistance of is an early defect in type 2 diabetes (T2D). protein anabolism What is already known about this subject? accompanies that of glucose Research design and methods: Seven lean, ▪ The offspring of patients with type 2 diabetes are metabolism in lean, glucose- normoglycemic T2D offspring (T2D-O) and eight at a higher risk of developing the disease. tolerant offspring of persons matched participants without family history (controls; ▪ 2 Previous studies have identified several abnor- with type 2 diabetes. BMJ C) underwent a 3-hour hyperinsulinemic (40 mU/m / malities in glucose and lipid metabolism in this Open Diabetes Research and min), euglycemic (5.5 mmol/L) and isoaminoacidemic population, but the status of protein metabolism Care 2016;4:e000312. clamp. Whole-body glucose and protein kinetics were 3 13 is not known. doi:10.1136/bmjdrc-2016- measured with D-[3– H]glucose and L-[l- C]leucine, 000312 respectively. Plasma amino acids were measured by What are the new findings? liquid chromatography-tandem mass spectrometry. ▪ The main finding of the study is the presence of Results: Fasting glycemia and glucose kinetic altered protein metabolism in lean young off- ▸ Additional material is variables did not differ between groups. Clamp spring of patients with type 2 diabetes. ▪ available. To view please visit decreases in glucose rate of appearance were not The defect is characterized by the inability of the journal (http://dx.doi.org/ different, but rate of disappearance increased 29% less insulin to stimulate protein synthesis with no 10.1136/bmjdrc-2016- in T2D-O, to a significantly lower rate. Fasting leucine defect in inhibiting protein breakdown. 000312). was higher in T2D-O, but kinetics did not differ. Clamp increases in leucine oxidation and decreases in How might these results change the focus of Received 16 August 2016 endogenous rate of appearance (protein breakdown) research or clinical practice? Revised 28 October 2016 were equal, but in T2D-O, non-oxidative rate of ▪ This study adds to the body of work characteriz- Accepted 6 November 2016 disappearance (protein synthesis) did not increase and ing the early abnormalities in the pathogenesis net balance (synthesis—breakdown) did not become of type 2 diabetes and may have implications for long-term protein balance. Prior presentation: This work positive as in C. http://drc.bmj.com/ was previously published in Conclusions: Resistance of whole-body protein abstract form: Burgos, S.A., anabolism (synthesis and net balance) accompanies 2–4 Chandurkar V., Tsoukas, M. resistance of glucose uptake in T2D-O. Mechanisms predicts development of the disease. This A., Chevalier, S., Morais, J.A., responsible, possible roles in the increased risk of population is often studied to identify early 56 Lamarche, M., Marliss, E.B. developing diabetes, and its potential impact on long- defects in the pathogenesis of T2D. Insulin resistance of protein term protein balance require definition. Indeed, even if glucose tolerant, lean T2D-O anabolism occurs in lean, glucose tolerant offspring of are often insulin resistant and display meta- on October 2, 2021 by guest. Protected copyright. persons with type 2 diabetes bolic abnormalities in glucose metabolism, (T2D) #2023P, American such as impaired insulin-stimulated glucose Diabetes Association 75th transport/phosphorylation78and glycogen Scientific Sessions, Boston, INTRODUCTION synthesis9 as well as fatty acid metabolism, 5–9 June 2015. Insulin is a key hormone that regulates including impaired whole-body lipid oxida- whole-body glucose, lipid, and protein tion,10 11 muscle mitochondrial function,12 13 metabolism through coordinated effects on and intramyocellular lipid content.14 15 multiple target tissues. Resistance to its However, a defect in protein metabolism in action is thought to play a primary role in T2D-O is not well established as only one For numbered affiliations see the development of type 2 diabetes (T2D). prior study assessed protein breakdown in end of article. This is inferred in part from prospective T2D-O using the conventional hyperinsuline- studies demonstrating the presence of mic clamp.16 Whereas it showed attenuated Correspondence to insulin resistance decades before the onset suppression of protein breakdown in T2D-O, 12 Dr Errol B Marliss; of the disease. In offspring of patients with data on synthesis were not available. Protein [email protected] type 2 diabetes (T2D-O), insulin resistance metabolism is important for protein BMJ Open Diabetes Research and Care 2016;4:e000312. doi:10.1136/bmjdrc-2016-000312 1 BMJ Open Diab Res Care: first published as 10.1136/bmjdrc-2016-000312 on 29 November 2016. Downloaded from Metabolism homeostasis and energy expenditure, and its impair- Table 1 Participant characteristics ment in young individuals could have long-term conse- quences for protein and energy balance. Characteristic C T2D-O – – Several groups17 21 and we22 24 have modified the n (W/M) 4/4 4/3 hyperinsulinemic clamp to combine both the tracer- Age (years) 24.6±1.1 26.0±2.1 estimated kinetic responses of glucoregulation (with Height (cm) 170.3±3.1 171.2±3.8 Weight (kg) 59.9±3.1 68.6±5.0 stable- or tritium-labeled isotopes), with those of protein 2 13 BMI (kg/m ) 20.6±0.4 23.2±0.7* metabolism (with L-[1– C]leucine). This allows for the LBM (kg) 44.7±3.2 47.2±4.5 estimation of endogenous glucose rate of appearance AMMI (kg/m2) 6.9±0.4 7.4±0.5 (Ra) and disappearance (Rd, uptake), as well as whole- Trunk fat mass (kg) 5.7±0.8 8.9±1.4 body protein synthesis (S, non-oxidative leucine Rd), Estimated visceral adipose 148±47 322±198 breakdown (B, endogenous leucine Ra) and oxidation. tissue (g) In healthy persons, the standard clamp technique Body fat (%) 21.3±2.9 27.6±2.6 showed that hyperinsulinemia inhibits protein B but Waist circumference (cm) 70.6±2.0 76.3±3.3 does not stimulate S, thereby blunting the net synthesis Hip circumference (cm) 90.2±2.3 95.2±1.6 – (S–B) response.25 27 The latter is due to the decreased Waist/hip 0.78±0.02 0.80±0.03 availability of circulating amino acids (AA) as substrates, 2 Hours OGTT plasma 5.6±0.4 5.3±0.4 rather than a direct effect of insulin. This was proved glucose (mmol/L) directly in muscle in vivo.28 When aminoacidemia is OGTT net glucoseAUC (mg/dL/ 3573±967 2578±768 120 min) kept constant at postabsorptive levels by clamping with OGTT net insulinAUC (µU/mL/ 4594±969 5544±828 variable-rate infusion of a mixture of AA, inhibition of 120 min) whole-body B and stimulation of S occur, a more physio- Matsuda-ISI index 8.94±1.34 6.23±0.91 24 logical response. HOMA-IR index 1.1±0.2 1.4±0.2 Using this hyperinsulinemic, euglycemic, isoaminoaci- HbA1c (%) (mmol/mol) 5.1±0.1 5.5±0.2 (37 demic clamp, we have determined that in several insulin- (32±1) ±2)* resistant states, there is concurrent resistance of glucose Triglycerides (mmol/L) 0.64±0.07 0.56±0.07 and protein metabolism.22 Notably, this occurs in obesity Total cholesterol (mmol/L) 4.36±0.08 4.07±0.28 (with normal glucose tolerance)22 and T2D.23 But HDL cholesterol (mmol/L) 1.78±0.11 1.57±0.22 whether this is a primary feature of the insulin-resistance LDL cholesterol (mmol/L) 2.29±0.12 2.25±0.14 syndrome or due to excess adiposity and hyperglycemia Energy intake (kcal/day) 2081±153 1990±188 Protein intake (g/day) 86.8±6.6 80.0±8.5 has not been established. Hence, we used this technique REE (kcal/day) 1369±113 1511±108 to test the hypothesis that glucose-tolerant T2D-O with npRQ 0.82±0.01 0.80±0.01 no other known diabetes risk factors will show insulin Fat oxidation (mg/min) 46.4±5.3 60.6±5.9 resistance of whole-body protein anabolism concurrently Glucose oxidative Rd (mg/min) 64.5±7.8 60.5±8.6 with that of the well-documented glucose metabolism. Glucose non-oxidative Rd 75.4±9.0 81.2±10.3 (mg/min) Data are mean ± SEM. http://drc.bmj.com/ MATERIALS AND METHODS *p<0.05 vs C, by independent samples t-test. Participants AMMI, appendicular muscle mass index; npRQ, non-protein respiratory quotient; OGTT, oral glucose tolerance test; REE, Seven lean young offspring of at least one T2D parent, resting energy expenditure. and eight age- and body-composition-matched volun- teers without a family history of diabetes (controls, C) Study design were recruited through local advertisements. Screening on October 2, 2021 by guest. Protected copyright. exclusion criteria included smoking, unstable weight Participants were instructed to consume a weight- (>±3 kg) for the last 6 months, cancer in the previous maintaining diet and refrain from strenuous physical 5 years, unconventional diets, and medications known to activity for 3 days preceding the study. On the morning affect metabolism. Respondents who met the inclusion prior, they were admitted to the study unit of the Centre criteria were screened with medical history and physical for Innovative Medicine of the Royal Victoria Hospital/ examination, electrocardiogram, chest X-ray, 24-hour McGill University Health Centre.
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