Renal amino acid, fat and glucose metabolism in type 1 diabetic and non-diabetic humans: effects of acute insulin withdrawal

Møller, Niels; Jensen, Michael D.; Rizza, Robert A.; Andrews, James C.; Nair, K. Sreekumaran

doi:10.1007/s00125-006-0287-3

Cited by 24 publications

(12 citation statements)

References 30 publications

(77 reference statements)

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“…By then, complete mixing can be expected. Even in single organ balance studies, many groups chose to use plasma sampling in combination with whole blood flows rather than plasma flows (33)(34)(35)(36). The latter would reduce all kinetic rates by Ϯ40% (hematocrit) and yield improbably low kinetic rates.…”

Section: Discussionmentioning

confidence: 99%

Amino Acid Metabolism in the Human Fetus at Term: Leucine, Valine, and Methionine Kinetics

et al. 2011

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Human fetal metabolism is largely unexplored. Understanding how a healthy fetus achieves its fast growth rates could eventually play a pivotal role in improving future nutritional strategies for premature infants. To quantify specific fetal amino acid kinetics, eight healthy pregnant women received before elective cesarean section at term, continuous stable isotope infusions of the essential amino acids [1-13 C, 15 N]leucine, [U-13 C 5 ]valine, and [1-13 C]methionine. Umbilical blood was collected after birth and analyzed for enrichments and concentrations using mass spectrometry techniques. Fetuses showed considerable leucine, valine, and methionine uptake and high turnover rates. ␣-Ketoisocaproate, but not ␣-ketoisovalerate (the leucine and valine ketoacids, respectively), was transported at net rate from the fetus to the placenta. Especially, leucine and valine data suggested high oxidation rates, up to half of net uptake. This was supported by relatively low ␣-ketoisocaproate reamination rates to leucine. Our data suggest high protein breakdown and synthesis rates, comparable with, or even slightly higher than in premature infants. The relatively large uptakes of total leucine and valine carbon also suggest high fetal oxidation rates of these essential branched chain amino acids. (Pediatr Res 70: 566-571, 2011) H istorical wise, the fact that the design of current nutrition for premature neonates is merely step-by-step alterations of the original composition of breast milk (1) is not surprising. Years ago, gestational viability was closer to term than it is currently, and the analysis of normal neonatal nutrition was easier than the study of fetal nutrition. But with increased survival of less mature infants, metabolic demands of these young individuals probably deviate much more from those who receive breast milk or regular formula after term birth. Besides, we know from several decades of animal fetal research that intrauterine nutrient supply delivers more amino acids and less fat than is supplied during breast feeding (2). Today, however, the exact composition of human fetal nutrient supply still remains unknown.With the availability of harmless tracer studies, human fetal metabolism can be unraveled (3-7). To add to the very scarce knowledge bank, our aim was to investigate several aspects of human fetal essential amino acid metabolism. In this study, we were interested in fetal kinetics of the branched chain amino acids (leucine and valine) and of another essential amino acid, methionine. Previously, fetal kinetics of phenylalanine and tyrosine were described. These two amino acids together with those studied here were chosen both scientifically as well as practically. First, they are often subject of debate when it comes to (parenteral) neonatal nutrition. Second, their stable isotopomers are affordable, and our laboratory has much experience analyzing them accurately. Metabolism was determined after the infusion of stable isotopically labeled amino acids into pregnant women undergoing ele...

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Section: Discussionmentioning

confidence: 99%

Amino Acid Metabolism in the Human Fetus at Term: Leucine, Valine, and Methionine Kinetics

et al. 2011

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“…Although leucine is transaminated mainly in skeletal muscle, it is possible that activity of BCKD in the liver may change with dietary protein intake since the liver is the main site of KIC decarboxylation (31,32,38). Animal studies have shown that total BCKD activity and percentage of the active enzyme are not influenced by the dietary protein intake (6 or 20% casein) in skeletal muscle of rats (30), although a small and transient increase in total BCKD activity was observed in rat skeletal muscle after a 50% protein diet was fed for 10 days (7).…”

Section: Discussionmentioning

confidence: 99%

Functional impact of high protein intake on healthy elderly people

Walrand¹,

Short²,

Bigelow³

et al. 2008

American Journal of Physiology-Endocrinology and Metabolism

102

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Decline in muscle mass, protein synthesis, and mitochondrial function occurs with age, and amino acids are reported to enhance both muscle protein synthesis and mitochondrial function. It is unclear whether increasing dietary protein intake corrects postabsorptive muscle changes in aging. We determined whether a 10-day diet of high [HP; 3.0 g protein ⅐ kg fat-free mass (FFM) Ϫ1 ⅐ day Ϫ1 ] vs. usual protein intake (UP; 1.5 g protein ⅐ kg FFM Ϫ1 ⅐ day Ϫ1 ) favorably affects mitochondrial function, protein metabolism, and nitrogen balance or adversely affects insulin sensitivity and glomerular filtration rate (GFR) in 10 healthy younger (24 Ϯ 1 yr) and 9 older (70 Ϯ 2 yr) participants in a randomized crossover study. Net daily nitrogen balance increased equally in young and older participants, but postabsorptive catabolic state also increased, as indicated by higher whole body protein turnover and leucine oxidation with no change in protein synthesis. Maximal muscle mitochondrial ATP production rate was lower in older people, with no change occurring in diet. GFR was lower in older people, and response to HP was significantly different between the two groups, with a significant increase occurring only in younger people, thus widening the differences in GFR between the young and older participants. In conclusion, a short-term high-protein diet increased net daily nitrogen balance but increased the postabsorptive use of protein as a fuel. HP did not enhance protein synthesis or muscle mitochondrial function in either young or older participants. Additionally, widening differences in GFR between young and older patients is a potential cause of concern in using HP diet in older people. dietary protein; protein metabolism; mitochondrial function; kidney function; aging AGE IS ASSOCIATED WITH A PROGRESSIVE DECLINE in body protein content, as reflected by declining fat-free mass (FFM) (33). The reduction in FFM is attributed mainly to loss of skeletal muscle, i.e., sarcopenia, and is associated with reduced muscle strength and exercise endurance as well as predisposition to many metabolic disorders (33). The disabilities related to sarcopenia and associated disorders are not fully assessed but result in substantial health care costs (25).One of the potential mechanisms contributing to sarcopenia is reduced muscle protein synthesis, which was shown to decline by 3.5% per decade (49). Aging is also associated with reductions in the skeletal muscle mitochondrial ATP production and the abundance of mitochondrial DNA and transcripts of genes that encode mitochondrial proteins (44,47). Reduced ability to produce ATP, the key chemical form of energy for cellular functions, could potentially contribute to the vitality of the aging population and may contribute to the overall reduction in many muscle functions (33). The reduced ability to maintain muscle proteins may result from decreased sensitivity of muscle to efficiently use exogenous amino acids for protein anabolism. It has been reported (56) that skeletal muscle protein s...

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“…Albumin-bound [9, H]-palmitate (GE Healthcare, Brøndby, Denmark) was infused (0.3 mCi/min) at t = 200-260 min and analyzed in triplicate as previously described (9).…”

Section: Outcomes and Analytical Methodsmentioning

confidence: 99%

“…Experimental studies primarily have used insulin withdrawal to assess the precipitating events in type 1 diabetic DKA. These studies have shown increased lipolysis/FFA availability and increased levels of glucagon to be important triggers of ketogenesis (7)(8)(9), whereas proinflammatory cytokines in general have not been measured, and levels of cortisol, epinephrine, and growth hormone (GH), when measured, have not been increased. Studies in subjects without diabetes have showed that administration of tumor necrosis factor-a (TNF-a) or endotoxin (lipopolysaccharide [LPS]), as a model for acute inflammation, increases circulating levels of stress hormones and stimulates lipolysis (10)(11)(12)(13).…”

mentioning

confidence: 99%

Combined Insulin Deficiency and Endotoxin Exposure Stimulate Lipid Mobilization and Alter Adipose Tissue Signaling in an Experimental Model of Ketoacidosis in Subjects With Type 1 Diabetes: A Randomized Controlled Crossover Trial

et al. 2016

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Most often, diabetic ketoacidosis (DKA) in adults results from insufficient insulin administration and acute infection. DKA is assumed to release proinflammatory cytokines and stress hormones that stimulate lipolysis and ketogenesis. We tested whether this perception of DKA can be reproduced in an experimental human model by using combined insulin deficiency and acute inflammation and tested which intracellular mediators of lipolysis are affected in adipose tissue. Nine subjects with type 1 diabetes were studied twice: 1) insulin-controlled euglycemia and 2) insulin deprivation and endotoxin administration (KET). During KET, serum tumor necrosis factor-α, cortisol, glucagon, and growth hormone levels increased, and free fatty acids and 3-hydroxybutyrate concentrations and the rate of lipolysis rose markedly. Serum bicarbonate and pH decreased. Adipose tissue mRNA contents of comparative gene identification-58 (CGI-58) increased and G0/G1 switch 2 gene (G0S2) mRNA decreased robustly. Neither protein levels of adipose triglyceride lipase (ATGL) nor phosphorylations of hormone-sensitive lipase were altered. The clinical picture of incipient DKA in adults can be reproduced by combined insulin deficiency and endotoxin-induced acute inflammation. The precipitating steps involve the release of proinflammatory cytokines and stress hormones, increased lipolysis, and decreased G0S2 and increased CGI-58 mRNA contents in adipose tissue, compatible with latent ATGL stimulation.

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Renal amino acid, fat and glucose metabolism in type 1 diabetic and non-diabetic humans: effects of acute insulin withdrawal

Cited by 24 publications

References 30 publications

Amino Acid Metabolism in the Human Fetus at Term: Leucine, Valine, and Methionine Kinetics

Amino Acid Metabolism in the Human Fetus at Term: Leucine, Valine, and Methionine Kinetics

Functional impact of high protein intake on healthy elderly people

Combined Insulin Deficiency and Endotoxin Exposure Stimulate Lipid Mobilization and Alter Adipose Tissue Signaling in an Experimental Model of Ketoacidosis in Subjects With Type 1 Diabetes: A Randomized Controlled Crossover Trial

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