Glucose and protein metabolic responses to an energy- but not protein- restricted diet in type 2 diabetes.

AIMS: To test the effect of energy restriction with maintained protein intake on body composition and on insulin sensitivity of glucose and protein metabolism in adults with type 2 diabetes (T2D). MATERIALS AND METHODS: After 3 days of an isoenergetic diet with 1.2 g/kg/d protein, obese adults with T2D (three women, two men) followed a 5-week diet providing 60% of energy requirements with 45% carbohydrate, and with protein maintained at pre-intervention level. Isotopic tracers were used to quantify whole-body glucose (3-3 H-glucose) and protein (13 C-leucine) metabolism pre- (day 4) and post-intervention (day 39), in the postabsorptive state and during a hyperinsulinaemic, isoglycaemic, isoaminoacidaemic clamp. Body composition was measured using dual-energy x-ray absorptiometry. RESULTS: After energy restriction, 6% weight loss occurred via total body (11%) and visceral fat losses (25%), but lean mass was preserved. Fasting glucose level, serum insulin level, homeostatic model assessment of insulin resistance index and C-peptide level decreased significantly (29%, 38%, 54% and 38%, respectively) as did other cardiometabolic risk factors. Between clamp studies, postabsorptive protein turnover and oxidation rates decreased (12% and 32%), resulting in less negative net balance, consistent with protein conservation. The rates of glucose turnover decreased, and glucose metabolic clearance rate improved (24%). During the clamp, protein flux was lower (9%) and breakdown suppressed (12%), and net balance became less negative but not different. Although glucose turnover did not differ, metabolic clearance improved by 47%. CONCLUSIONS: In obese adults with T2D, an energy-restricted diet with maintained protein intake of ~1.2 g/kg/d improved the kinetics of protein metabolism (particularly in the postabsorptive state), and preserved lean body mass and increased glucose metabolic clearance rate.

Academic stress and personality interact to increase the neural response to high-calorie food cues.

Psychosocial stress is associated with an increased intake of palatable foods and weight gain in stress-reactive individuals. Personality traits have been shown to predict stress-reactivity. However, it is not known if personality traits influence brain activity in regions implicated in appetite control during psychosocial stress. The current study assessed whether Gray's Behavioural Inhibition System (BIS) scale, a measure of stress-reactivity, was related to the activity of brain regions implicated in appetite control during a stressful period. Twenty-two undergraduate students participated in a functional magnetic resonance imaging (fMRI) experiment once during a non-exam period and once during final exams in a counter-balanced order. In the scanner, they viewed food and scenery pictures. In the exam compared with the non-exam condition, BIS scores related to increased perceived stress and correlated with increased blood-oxygen-level dependent (BOLD) response to high-calorie food images in regions implicated in food reward and subjective value, such as the ventromedial prefrontal cortex, (vmPFC) and the amygdala. BIS scores negatively related to the functional connectivity between the vmPFC and the dorsolateral prefrontal cortex. The results demonstrate that the BIS trait influences stress reactivity. This is observed both as an increased activity in brain regions implicated in computing the value of food cues and decreased connectivity of these regions to prefrontal regions implicated in self-control. This suggests that the effects of real life stress on appetitive brain function and self-control is modulated by a personality trait. This may help to explain why stressful periods can lead to overeating in vulnerable individuals.

Exercise in ZDF rats does not attenuate weight gain, but prevents hyperglycemia concurrent with modulation of amino acid metabolism and AKT/mTOR activation in skeletal muscle.

PURPOSE: Protein metabolism is altered in obesity, accompanied by elevated plasma amino acids (AA). Previously, we showed that exercise delayed progression to type 2 diabetes in obese ZDF rats with maintenance of ß cell function and reduction in hyperglucocorticoidemia. We hypothesized that exercise would correct the abnormalities we found in circulating AA and other indices of skeletal muscle protein metabolism. METHODS: Male obese prediabetic ZDF rats (7-10/group) were exercised (swimming) 1 h/day, 5 days/week from ages 6-19 weeks, and compared with age-matched obese sedentary and lean ZDF rats. RESULTS: Food intake and weight gain were unaffected. Protein metabolism was altered in obese rats as evidenced by increased plasma concentrations of essential AA, and increased muscle phosphorylation (ph) of Akt(ser473) (187%), mTOR(ser2448) (140%), eIF4E-binding protein 1 (4E-BP1) (111%), and decreased formation of 4E-BP1*eIF4E complex (75%, 0.01 ≤ p ≤ 0.05 for all measures) in obese relative to lean rats. Exercise attenuated the increase in plasma essential AA concentrations and muscle Akt and mTOR phosphorylation. Exercise did not modify phosphorylation of S6K1, S6, and 4E-BP1, nor the formation of 4E-BP1*eIF4E complex, mRNA levels of ubiquitin or the ubiquitin ligase MAFbx. Positive correlations were observed between ph-Akt and fed circulating branched-chain AA (r = 0.56, p = 0.008), postprandial glucose (r = 0.42, p = 0.04) and glucose AUC during an IPGTT (r = 0.44, p = 0.03). CONCLUSION: Swimming exercise-induced attenuation of hyperglycemia in ZDF rats is independent of changes in body weight and could result in part from modulation of muscle AKT activation acting via alterations of systemic AA metabolism.

Adiponectin signaling in the liver.

High glucose production contributes to fed and fasted hyperglycemia in Type 1 Diabetes (T1D) and Type 2 Diabetes (T2D). The breakdown of the adiponectin signaling pathway in T1D and the reduction of circulating adiponectin in T2D contribute to this abnormal increase in glucose production. Sufficient amounts of insulin could compensate for the loss of adiponectin signaling in T1D and T2D and reduce hyperglycemia. However, the combination of low adiponectin signaling and high insulin resembles an insulin resistance state associated with cardiovascular disease, fatty liver disease and decreased life expectancy. The future development of "adiponectin sensitizers", medications that correct the deficiency in adiponectin signaling, could restore the metabolic balance in T1D and T2D and reduce the need for insulin. This article reviews the adiponectin signaling pathway in the liver through T-cadherin, AdipoR1, AdipoR2, AMPK, ceramidase activity, APPL1 and the recently discovered Suppressor Of Glucose from Autophagy (SOGA).

Acute hyperaminoacidemia does not suppress insulin-mediated glucose turnover in healthy young men.

Elevated circulating amino acids (AA) concentrations are purported to cause insulin resistance (IR) in humans. To quantify hyperaminoacidemia effects on insulin-mediated glucose turnover in healthy men, we performed 2-stage pancreatic clamps using octreotide with glucagon and growth hormone replacement. In the basal stage, insulin was infused to maintain euglycemia at postabsorptive levels. During the clamp stage, insulin was raised to postprandial levels, glycemia clamped at 5.5 mmol/L by glucose infusion, and branched-chain AA (BCAA) maintained at either postabsorptive (Hyper1; n = 8) or postprandial (Hyper2; n = 7) by AA infusion. Glucose turnover was measured by d-3-[3H]glucose dilution. Octreotide suppressed C-peptide; glucagon, growth hormone, and glycemia were maintained at postabsorptive levels throughout. Insulin did not differ at postabsorptive (72 ± 5 vs. 60 ± 5 pmol/L; Hyper1 vs. Hyper2) and increased to similar concentrations at basal (108 ± 11 vs. 106 ± 14) and clamp stages (551 ± 23 vs. 540 ± 25). Postabsorptive BCAA were maintained during Hyper1 and increased >2-fold (830 ± 26 µmol/L) during Hyper2. Endogenous glucose production was similarly suppressed (0.95 ± 0.16 vs. 1.37 ± 0.23 mg/kg lean body mass/min; Hyper1 vs. Hyper2) and basal glucose disposal (3.44 ± 0.12 vs. 3.67 ± 0.14) increased to similar levels (10.89 ± 0.56 vs. 11.11 ± 1.00) during the clamp. Thus, acute physiological elevation of AA for 3 h did not cause IR in healthy men. Novelty: A 2-step pancreatic clamp was used to quantify the effect of AA on insulin sensitivity in humans. Acute physiological elevation of circulating AA to postprandial levels does not cause IR in healthy men.

Maintaining adequate nutrition, not probiotic administration, prevents growth stunting and maintains skeletal muscle protein synthesis rates in a piglet model of colitis.

Malnutrition and cytokine-induced catabolism are pervasive in children with inflammatory bowel diseases (IBD), however, the benefits of aggressive nutrition support or of probiotics on nutrient and functional deficiencies and growth remain unclear. Piglets with dextran sulfate (DS)-induced colitis consuming a 50% macronutrient restricted diet (C-MR) were compared with those receiving probiotics (C-MRP) or adequate nutrition (C-WN) and with healthy well-nourished controls (REF). C-WN versus REF had reduced growth (-34% chest circumference and -22% snout-to-rump length gain) and a tendency toward lesser weight gain, but no differences in skeletal muscle protein fractional synthesis rates (FSR) or initiation of translation via the mTOR pathway were observed. Compared with C-WN, the C-MR and C-MRP piglets had lower weight gain, growth, and skeletal muscle FSR, and lower phosphorylated p70S6K1 with higher eIF4E*4E-BP1, indicative of reduced initiation of protein translation. Finally, plasma leucine concentrations were positively correlated with weight and phosphorylated p70S6K1, whereas negatively correlated with eIF4E*4E-BP1. In conclusion, reductions in weight gain, growth, protein turnover, skeletal muscle FSR, and initiation of protein translation with moderate macronutrient restriction in colitis are not ameliorated by probiotic supplementation. However, maintaining adequate nutrient intake during colitis preserves whole body protein metabolism, but growth remains compromised.

Neurocognitive and Hormonal Correlates of Voluntary Weight Loss in Humans.

Insufficient responses to hypocaloric diets have been attributed to hormonal adaptations that override self-control of food intake. We tested this hypothesis by measuring circulating energy-balance hormones and brain functional magnetic resonance imaging reactivity to food cues in 24 overweight/obese participants before, and 1 and 3 months after starting a calorie restriction diet. Increased activity and functional connectivity in prefrontal regions at month 1 correlated with weight loss at months 1 and 3. Weight loss was also correlated with increased plasma ghrelin and decreased leptin, and these changes were associated with food cue reactivity in reward-related brain regions. However, the reduction in leptin did not counteract weight loss; indeed, it was correlated with further weight loss at month 3. Activation in prefrontal regions associated with self-control could contribute to successful weight loss and maintenance. This work supports the role of higher-level cognitive brain function in body-weight regulation in humans.

Variations in practice patterns for adult cancer patients on home parenteral nutrition in Canada.

OBJECTIVES: Cancer has become a major indication for home parenteral nutrition (HPN). However, the use of HPN in adult cancer patients is highly variable between countries and may also differ within each country. The aim of the present study was to characterize regional variations in practice patterns for cancer patients on HPN using data from the Canadian HPN Registry. METHODS: This retrospective analysis included all cancer patients (n = 164) enrolled in the registry from 2005 to 2016. Patient demographic and clinical characteristics were described. Differences in baseline characteristics were evaluated by province and duration of HPN therapy. Survival was estimated with the Kaplan-Meier method and compared among different tumor types and provinces using the log-rank test. RESULTS: The most common tumors were gastrointestinal (54.2%) and gynecologic (31.8%). Most patients were from the provinces of Ontario (54.3%) and Alberta (41.5%). Patients who received HPN for ≥3 mo (64.6%) had a higher baseline Karnofsky Performance Status (80 versus 50) and albumin (35 versus 26 mmol/L) compared with those on HPN for <3 mo. There were no differences in survival based on tumor category. Patients in Ontario programs had a longer median survival (11.3 versus 7.1 mo) and higher proportion of secondary indications for HPN relative to patients in Alberta programs. CONCLUSIONS: Most cancer patients on HPN have gastrointestinal or gynecologic cancers. Those surviving for ≥3 mo have better baseline characteristics. Regional variability in the prevalence, selection, and survival of cancer patients receiving HPN suggests the need for consensus on the use of HPN in this population.

Anticatabolic effects of avoiding preoperative fasting by intravenous hypocaloric nutrition: a randomized clinical trial.

OBJECTIVE: We tested the hypothesis that the avoidance of preoperative fasting by hypocaloric nutrition attenuates protein catabolism after surgery. SUMMARY BACKGROUND DATA: Prolonged fasting before major abdominal procedures has been demonstrated to accentuate the catabolic response to surgery. METHODS: Twenty-two patients undergoing colorectal cancer surgery were randomly assigned to receive glucose and amino acids intravenously starting either 20 hours before the operation or with surgical skin incision. Nutrition was administered until the second postoperative day, with glucose providing 50% and amino acids 20% of each patient's measured resting energy expenditure. Whole body leucine and glucose kinetics were assessed by L-[1-(13)C]leucine and [6,6-(2)H(2)]glucose before and after surgery. Fractional synthesis rates of muscle protein, albumin, and fibrinogen were determined using primed continuous infusions of L-[(2)H(5)]phenylalanine postoperatively, whereas the expression of mRNA of proteolytic genes in muscle (Mafbx/atrogin-1, ubiquitin, Murf 1) was determined by quantitative RT-PCR. Circulating concentrations of glucose, lactate, amino acids, insulin, glucagon, and cortisol were also measured. This study has been registered at ClinicalTrials.gov (Identifier: NCT00614133). RESULTS: Preoperative feeding inhibited endogenous protein breakdown (fasting group: 128 +/- 23 micromol . kg(-1) . h(-1); nutrition group: 96 +/- 22 micromol . kg(-1) . h(-1); P = 0.02) and blunted the increase in amino acid oxidation (fasting group: 27 +/- 5 micromol . kg(-1) . h(-1); nutrition group: 20 +/- 5 micromol . kg(-1) . h(-1); P = 0.03), resulting in positive whole-body protein balance after surgery (fasting group: -10 +/- 4 micromol . kg(-1) . h(-1); nutrition group: 1 +/- 3 micromol . kg(-1) . h(-1); P < 0.001). This anabolic response was associated with decreased muscle proteolytic gene expression and increased hepatic albumin synthesis. Total plasma protein, fibrinogen, and muscle protein synthesis were not affected. CONCLUSIONS: Hypocaloric nutrition decreases protein catabolism, with a contribution from the ubiquitin pathway in muscle, and stimulates albumin synthesis after colorectal surgery if initiated 1 day before the operation.

The greater contribution of gluconeogenesis to glucose production in obesity is related to increased whole-body protein catabolism.

Obesity is associated with an increase in the fractional contribution of gluconeogenesis (GNG) to glucose production. We tested if this was related to the altered protein metabolism in obesity. GNG(PEP) (via phosphoenol pyruvate [PEP]) was measured after a 17-h fast using the deuterated water method and 2H nuclear magnetic resonance spectroscopy of plasma glucose. Whole-body 13C-leucine and 3H-glucose kinetics were measured in the postabsorptive state and during a hyperinsulinemic-euglycemic-isoaminoacidemic clamp in 19 (10 men and 9 women) lean and 16 (7 men and 9 women) obese nondiabetic subjects. Endogenous glucose production was not different between groups. Postabsorptive %GNG(PEP) and GNG(PEP) flux were higher in obese subjects, and glycogenolysis contributed less to glucose production than in lean subjects. GNG(PEP) flux correlated with all indexes of adiposity and with postabsorptive leucine rate of appearance (Ra) (protein catabolism). GNG(PEP) was negatively related to the clamp glucose rate of disposal (Rd) and to the protein anabolic response to hyperinsulinemia. In conclusion, the increased contribution of GNG to glucose production in obesity is linked to increased postabsorptive protein catabolism and insulin resistance of both glucose and protein metabolism. Due to increased protein turnover rates, greater supply of gluconeogenic amino acids to the liver may trigger their preferential use over glycogen for glucose production.

Plasma Amino Acids vs Conventional Predictors of Insulin Resistance Measured by the Hyperinsulinemic Clamp.

CONTEXT: Specific plasma amino acid (AA) profiles including elevated postabsorptive branched-chain amino acids (BCAAs) have been associated with insulin resistance (IR), mostly estimated by homeostatic model assessment. This study assessed the associations of postabsorptive AAs with IR directly measured by insulin-mediated glucose disposal and determined the quantitative value of AAs and conventional IR predictors. DESIGN: Fifty-one healthy, 31 overweight or obese (Ow/Ob), and 52 men and women with type 2 diabetes (T2D) were studied retrospectively. The main outcome measures were the glucose disposal (M/I) index (using 3-[3H]-glucose) during a hyperinsulinemic-euglycemic clamp and whole-body protein turnover (using 1-[13C]-leucine). RESULTS: Compared with healthy participants, M/I was lower in Ow/Ob participants and lowest in those with T2D. BCAAs, glutamate, and lysine were higher in the Ow/Ob and T2D groups than in healthy participants; glycine and threonine were lower. Most AAs were higher in men. Principal component analysis identified component 1 (C1: BCAAs, methionine) and C3 (glycine, threonine, serine). Glutamate, C1, ornithine, lysine, methionine, and tyrosine correlated negatively with M/I; C3 and glycine correlated positively. Waist circumference and sex strongly influenced AA-IR relationships; only glutamate correlated after these factors were controlled for. From regression analysis, waist circumference, fasting glucose, insulin, and free fatty acids (FFAs) negatively predicted 64% of the M/I variance; glutamate added 2% more. In nondiabetic participants, IR was predicted by waist circumference, insulin, and FFAs, without contribution from AAs. CONCLUSION: Several postabsorptive AAs correlated with IR but added limited predictive value to conventional markers because levels were determined largely by abdominal adiposity. Data suggest a sex-specific regulation of AA metabolism by excess adiposity, particularly the BCAAs, warranting investigation.

Insulin resistance of protein anabolism accompanies that of glucose metabolism in lean, glucose-tolerant offspring of persons with type 2 diabetes.

OBJECTIVE: To test whether protein anabolic resistance is an early defect in type 2 diabetes (T2D). RESEARCH DESIGN AND METHODS: Seven lean, normoglycemic T2D offspring (T2D-O) and eight matched participants without family history (controls; C) underwent a 3-hour hyperinsulinemic (40 mU/m2/min), euglycemic (5.5 mmol/L) and isoaminoacidemic clamp. Whole-body glucose and protein kinetics were measured with d-[3-3H]glucose and l-[l-13C]leucine, respectively. Plasma amino acids were measured by liquid chromatography-tandem mass spectrometry. RESULTS: Fasting glycemia and glucose kinetic variables did not differ between groups. Clamp decreases in glucose rate of appearance were not different, but rate of disappearance increased 29% less in T2D-O, to a significantly lower rate. Fasting leucine was higher in T2D-O, but kinetics did not differ. Clamp increases in leucine oxidation and decreases in endogenous rate of appearance (protein breakdown) were equal, but in T2D-O, non-oxidative rate of disappearance (protein synthesis) did not increase and net balance (synthesis-breakdown) did not become positive as in C. CONCLUSIONS: Resistance of whole-body protein anabolism (synthesis and net balance) accompanies resistance of glucose uptake in T2D-O. Mechanisms responsible, possible roles in the increased risk of developing diabetes, and its potential impact on long-term protein balance require definition.

Intense exercise has unique effects on both insulin release and its roles in glucoregulation: implications for diabetes.

In intense exercise (>80% VO(2max)), unlike at lesser intensities, glucose is the exclusive muscle fuel. It must be mobilized from muscle and liver glycogen in both the fed and fasted states. Therefore, regulation of glucose production (GP) and glucose utilization (GU) have to be different from exercise at <60% VO(2max), in which it is established that the portal glucagon-to-insulin ratio causes the less than or equal to twofold increase in GP. GU is subject to complex regulation by insulin, plasma glucose, alternate substrates, other humoral factors, and muscle factors. At lower intensities, plasma glucose is constant during postabsorptive exercise and declines during postprandial exercise (and often in persons with diabetes). During such exercise, insulin secretion is inhibited by beta-cell alpha-adrenergic receptor activation. In contrast, in intense exercise, GP rises seven- to eightfold and GU rises three- to fourfold; therefore, glycemia increases and plasma insulin decreases minimally, if at all. Indeed, even an increase in insulin during alpha-blockade or during a pancreatic clamp does not prevent this response, nor does pre-exercise hyperinsulinemia due to a prior meal or glucose infusion. At exhaustion, GU initially decreases more than GP, which leads to greater hyperglycemia, requiring a substantial rise in insulin for 40--60 min to restore pre-exercise levels. Absence of this response in type 1 diabetes leads to sustained hyperglycemia, and mimicking it by intravenous infusion restores the normal response. Compelling evidence supports the conclusion that the marked catecholamine responses to intense exercise are responsible for both the GP increment (that occurs even during glucose infusion and postprandially) and the restrained increase of GU. These responses are normal in persons with type 1 diabetes, who often report exercise-induced hyperglycemia, and in whom the clinical challenge is to reproduce the recovery period hyperinsulinemia. Intense exercise in type 2 diabetes requires additional study.

Combined infusion of epinephrine and norepinephrine during moderate exercise reproduces the glucoregulatory response of intense exercise.

Intense exercise (IE) (>80% O(2max)) causes a seven- to eightfold increase in glucose production (R(a)) and a fourfold increase in glucose uptake (R(d)), resulting in hyperglycemia, whereas moderate exercise (ME) causes both to double. If norepinephrine (NE) plus epinephrine (Epi) infusion during ME produces the plasma levels and R(a) of IE, this would prove them capable of mediating these responses. Male subjects underwent 40 min of 53% O(2max) exercise, eight each with saline (control [CON]), or with combined NE + Epi (combined catecholamine infusion [CCI]) infusion from min 26-40. In CON and CCI, NE levels reached 7.3 +/- 0.7 and 33.1 +/- 2.9 nmol/l, Epi 0.94 +/- 0.08 and 7.06 +/- 0.44 nmol/l, and R(a) 3.8 +/- 0.4 and 12.9 +/- 0.8 mg. kg(-1). min(-1) (P < 0.001), respectively, at 40 min. R(d) increased to 3.5 +/- 0.4 vs. 11.2 +/- 0.8 mg. kg(-1). min(-1) and glycemia 5.2 +/- 0.2 mmol/l in CON vs. 6.5 +/- 0.2 mmol/l in CCI (P < 0.001). The glucagon-to-insulin ratio did not differ. Comparing CCI data to those from 14-min IE (n = 16), peak NE (33.6 +/- 5.1 nmol/l), Epi (5.32 +/- 0.93 nmol/l), and R(a) (13.0 +/- 1.0 mg. kg(-1). min(-1)) were comparable. The induced increments in NE, Epi, and R(a), all of the same magnitude as in IE, strongly support that circulating catecholamines can be the prime regulators of R(a) in IE.

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.

The influence of sex on the protein anabolic response to insulin.

We hypothesize that sex influences whole-body protein anabolism in the postabsorptive state and in response to hyperinsulinemia. Kinetics of 3-(3)H-glucose and (13)C-leucine were studied in 16 men and 15 women after energy- and protein-controlled diets, before and during a hyperinsulinemic, euglycemic, isoaminoacidemic clamp. In the postabsorptive state, women had 20% higher rates of leucine Ra (protein breakdown) and nonoxidative Rd (synthesis) adjusted for fat-free mass than men but net leucine balance was as negative. In response to hyperinsulinemia, leucine oxidation rates increased only in women and the change in net leucine balance was less than in men. Net leucine balance during the clamp correlated with rates of glucose disposal. Thus, women showed greater protein turnover rates when adjusted for fat free mass in the postabsorptive state, and lesser insulin sensitivity of protein anabolism and net protein accretion. A relationship exists between the protein anabolic response to insulin and the insulin sensitivity of glucose metabolism.

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

BACKGROUND & AIMS: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Protein and glucose metabolic responses to hyperinsulinemia, hyperglycemia, and hyperaminoacidemia in obese men.

OBJECTIVE: In insulin-resistant states, resistance of protein anabolism occurs concurrently with that of glucose, but can be compensated for by abundant amino acid (AA) provision. This effect and its mechanism were sought in obesity. METHODS: Pancreatic clamps were performed in 8 lean and 11 obese men, following 5-h postabsorptive, 3-h infusions of octreotide, basal glucagon, and growth hormone, with clamped postprandial-level insulin, glucose, and AA. Whole-body [1-(13) C]-leucine and [3-(3) H]-glucose kinetics, skeletal muscle protein ((2) H5 -phenylalanine) fractional synthesis rates, and insulin signaling were determined. RESULTS: Clamp Δ insulin and Δ branched-chain AA did not differ; fasting glucagon and growth hormone were maintained. Glucose uptake was 20% less in obese concurrent with less Akt(Ser473) , but also less IRS-1(Ser636/639) phosphorylation. Stimulation of whole-body, myofibrillar, and sarcoplasmic protein synthesis was similar. Whole-body protein catabolism suppression tended to be less (P=0.06), resulting in lesser net balance (1.09 ± 0.07 vs. 1.31 ± 0.08 µmol [kg FFM(-1) ] min(-1) , P=0.048). Increments in muscle S6K1(Thr389) phosphorylation were less in the obese, but 4E-BP1(Ser65) did not differ. CONCLUSIONS: Hyperaminoacidemia with hyperinsulinemia stimulated protein synthesis (possibly via nutrient signaling) normally in obesity, but suppression of proteolysis may be compromised. Whether long-term high protein intakes could compensate for the insulin resistance of protein anabolism remains to be determined.

Adiponectin-SOGA Dissociation in Type 1 Diabetes.

CONTEXT: Circulating adiponectin is elevated in human type 1 diabetes (T1D) and nonobese diabetic (NOD) mice without the expected indications of adiponectin action, consistent with tissue resistance. OBJECTIVE: Adiponectin stimulates hepatocyte production of the suppressor of glucose from autophagy (SOGA), a protein that inhibits glucose production. We postulated that due to tissue resistance, the elevation of adiponectin in T1D should fail to increase the levels of a surrogate marker for liver SOGA, the circulating C-terminal SOGA fragment. MAIN OUTCOME MEASURES: Liver and plasma SOGA were measured in NOD mice (n = 12) by Western blot. Serum adiponectin and SOGA were measured in T1D and control (Ctrl) participants undergoing a three-stage insulin clamp for the Coronary Artery Calcification in T1D study (n = 20). Glucose turnover was measured using 6,6[(2)H2]glucose (n = 12). RESULTS: In diabetic NOD mice, the 13%-29% decrease of liver SOGA (P = .003) and the 30%-37% reduction of circulating SOGA (P < .001) were correlated (r = 0.826; P = .001). In T1D serum, adiponectin was 50%-60% higher than Ctrl, SOGA was 30%-50% lower and insulin was 3-fold higher (P < .05). At the low insulin infusion rate (4 mU/m(2)·min), the resulting glucose appearance correlated negatively with adiponectin in T1D (r = -0.985, P = .002) and SOGA in Ctrl and T1D (r = -0.837, P = .001). Glucose disappearance correlated with adiponectin in Ctrl (r = -0.757, P = .049) and SOGA in Ctrl and T1D (r = -0.709, P = .010). At 40 mU/m(2)·min, the lowered glucose appearance was similar in Ctrl and T1D. Glucose disappearance increased only in Ctrl (P = .005), requiring greater glucose infusion to maintain euglycemia (8.58 ± 1.29 vs 3.09 ± 0.87 mg/kg·min; P = .009). CONCLUSIONS: The correlation between liver and plasma SOGA in NOD mice supports the use of the latter as surrogate marker for liver concentration. Reduced SOGA in diabetic NOD mice suggests resistance to adiponectin. The dissociation between adiponectin and SOGA in T1D raises the possibility that restoring adiponectin signaling and SOGA might improve the metabolic response to insulin therapy.