Indications for cardiopulmonary bypass in non-cardiac operations.
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Cardiopulmonary Bypass↗
Biomedical subjects
K S Nair
Publications and source records attributed to K S Nair.
Insulin effect on leucine kinetics in type 2 diabetes mellitus.
Insulin-induced glucose disposal is impaired in Type 2 diabetes mellitus (T2DM). To determine whether insulin-induced suppression of protein breakdown also is impaired, we measured leucine flux (an index of protein breakdown) in diabetic and nondiabetic subjects during a hyperinsulinemic euglycemic clamp. To avoid the confounding effects of a difference in baseline glucose, glucose concentration in the diabetic subjects was normalized by means of an overnight insulin infusion. Despite higher plasma insulin levels (33.5+/-0.05 vs 132+/-2.7 pmol/l, p<01) diabetic subjects had similar amino acid concentrations and leucine flux (96.9+/-5.8 vs 93.4+/-3.7 micromol/kg/h) as nondiabetic subjects. Infusion of insulin (0.5 mU/kg/min) increased insulin levels (p<0.01) to identical levels in both groups (218+/-16 vs 222+/-19), but the glucose infusion required to maintain euglycemia was higher (p<0.01) in nondiabetic than in diabetic subjects, indicating insulin resistance to glucose disposal in the diabetic subjects. In contrast, leucine flux (81.3+/-4.8 vs 81.6+/-3.4 micromol/kg/h) reached identical levels in both groups. The individual and total amino acid levels also were comparable in both groups. We conclude that suppression of whole body protein turnover in response to an acute increase in insulin is normal in people with T2DM. However, chronic adaptation to high insulin levels occurs, thereby enabling protein breakdown and amino acid concentration to remain within the normal range in people with T2DM.
Blood Glucose↗
Adhesion of neutrophils to fibronectin: role of the cd66 antigens.
Adhesion of neutrophils to substrate is initiated by receptor-ligand interactions that induce outside-in signaling. Inside-out signals and lateral interactions between surface molecules further fine tune the response. This study investigates the role of CD66 in adhesion of neutrophils to fibronectin, using domain-mapped monoclonal antibodies to CD66. Neutrophils express CD66a, CD66b, and CD66c on their surface. The neutrophil surface molecules that bind to fibronectin are the alpha(4)beta(1) and alpha(5)beta(1) integrins. Our results show that the monoclonal antibody Kat4c, which recognizes the AB domain of CD66a, b, and c and the polyclonal anti-CD66 (anti-carcinoembryonic antigen), augments neutrophil adhesion to fibronectin, while monoclonal antibodies to the individual CD66 antigens, the Fab fragment of Kat4c, and a mixture of the individual antibodies to CD66 antigens were unable to affect the adhesion. Thus heterodimerization of CD66a, b, and c is required for promoting neutrophil adhesion to fibronectin. The increased adhesion in presence of Kat4c was inhibited by antibodies to the beta(1) and beta(2) integrins. Antibody ligation of CD66 antigens causes their clustering and concomitant coclustering of the alpha(M) subunit of the beta(2) integrin, thereby activating the integrin. The sugar alpha-methyl mannoside inhibited anti-CD66-mediated clustering, indicating that a carbohydrate-lectin interaction may exist between CD66 and alpha(M) integrin. It also reduced the increased adhesion of neutrophils to fibronectin, suggesting that beta(2) integrin activation precedes beta(1) integrin activation. Further, the anti-CD66-mediated adhesion to fibronectin is accompanied by increased localization of Src family kinases (lyn and hck) to the cytoskeleton and an increase in their kinase activity. These results suggest that crosslinking of CD66a, CD66b, and CD66c promotes activation of the beta(2) integrin and in turn an alteration in the affinity of the beta(1) integrin, which enhances the adhesion of neutrophils to fibronectin.
Antibodies, Monoclonal↗
Sarcopenia.
Sarcopenia is a term utilized to define the loss of muscle mass and strength that occurs with aging. Sarcopenia is believed to play a major role in the pathogenesis of frailty and functional impairment that occurs with old age. Progressive muscle wasting occurs with aging. The prevalence of clinically significant sarcopenia is estimated to range from 8.8% in young old women to 17.5% in old old men. Persons who are obese and sarcopenic (the "fat frail") have worse outcomes than those who are sarcopenic and non-obese. There is a disproportionate atrophy of type IIa muscle fibers with aging. There is also evidence of an age-related decrease in the synthesis rate of myosin heavy chain proteins, the major anabolic protein. Motor units innervating muscle decline with aging, and there is increased irregularity of muscle unit firing. There are indications that cytokines-especially interleukin-1beta, tumor necrosis factor-alpha, and interleukin-6-play a role in the pathogenesis of sarcopenia. Similarly, the decline in anabolic hormones-namely, testosterone, dehydroepiandrosterone growth hormone, and insulin-like growth factor-I-is also implicated in the sarcopenic process. The role of the physiologic anorexia of aging remains to be determined. Decreased physical activity with aging appears to be the key factor involved in producing sarcopenia. An increased research emphasis on the factors involved in the pathogenesis of sarcopenia is needed.
Aging↗
Does aging adversely affect muscle mitochondrial function?
Muscle oxidative function appears to decline with aging, and evidence suggests that this is related to reduced synthesis of mitochondrial and other muscle proteins. Causes for these events may include mtDNA damage or reduced mtDNA copy numbers, reduced oxidative enzyme activities and ATP production, and increased proton leak.
Adenosine Triphosphate↗
Muscle protein metabolism and the sarcopenia of aging.
Loss of muscle mass, strength, and oxidative capacity accompanies normal aging in humans. The mechanisms responsible for these changes remain to be clearly defined. Muscle protein mass and function depend on protein turnover. Synthesis rate of the major muscle contractile protein, myosin heavy chain (MHC), and transcript levels of fast MHC isoforms decrease in association with strength reductions, while mitochondrial protein synthesis rate declines in parallel with activities of mitochondrial enzymes and maximal oxidative capacity (VO2max). Resistance exercise training increases the synthesis rate of MHC and transcript levels of the slow MHC isoform in older humans, along with increasing muscle strength. The relationship between the synthesis of muscle proteins, and muscle size and function, with aging and exercise training are discussed in this review.
Aged↗
Age effect on transcript levels and synthesis rate of muscle MHC and response to resistance exercise.
Experimental evidence indicates that a lower synthesis rate of muscle contractile protein myosin heavy chain (MHC) occurs in age-related muscle wasting and weakness. To determine the molecular mechanism of this lower synthesis of MHC, we measured transcript levels of isoforms of MHC (MHCI, MHCIIa, and MHCIIx) in muscle biopsy samples of 7 young (20-27 yr), 12 middle-aged (47-60 yr), and 14 older (>65 yr) people. We further determined the effect of 3 mo of resistance exercise training (exercise) vs. nonintervention (control) on transcript levels of MHC isoforms on these subjects and the fractional synthesis rate (FSR) of MHC in 39 people aged 46-79 yr. MHCI mRNA levels did not significantly change with age, but MHCIIa decreased 38% (P < 0.05) from young to middle age and further decreased 50% (P < 0.05) from middle to old age. MHCIIx decreased 84% (P < 0.05) from young to middle age and 48% from middle to old age (P < 0.05). Exercise increased FSR of MHC by 47% (P < 0.01) and mixed muscle protein by 56% (P < 0.05). Exercise training results in an increase (85%) in transcript levels of MHCI and a decrease in the transcript levels of MHCIIa and MHCIIx. In conclusion, an age-related lowering of the transcript levels of MHCIIa and MHCIIx is not reversed by exercise, whereas exercise results in a higher synthesis rate of MHC in association with an increase in MHCI isoform transcript levels.
Adult↗
Changes in uncoupling protein-2 and -3 expression in aging rat skeletal muscle, liver, and heart.
Uncoupling protein (UCP)-2 and -3 mediate mitochondrial (mt) proton leak in vitro and are potential regulators of energy expenditure and ATP production. Aging is associated with alteration of tissue functions, suggesting impaired mtATP production. To determine whether age-related changes in UCP expression occur, we measured the transcript levels of UCP-2 and -3 in skeletal muscle, liver, and heart in 6- and 27-mo-old rats. UCP-2 transcripts were higher in old animals in the white (+100%) and red (+70%, both P < 0.04) gastrocnemius muscle and in the liver (+300%, P < 0.03), whereas they were comparable in the heart in both age groups. UCP-2 transcript levels correlated positively with mitochondrial-encoded cytochrome c oxidase transcripts normalized for mtDNA (P < 0.01) and negatively with mtDNA copy number (P < 0.001). UCP-3 transcripts were lower in the less oxidative white (-50%, P < 0.04) and unchanged in the more oxidative red (-15%, P = 0.41) gastrocnemius muscle in old animals. Similar changes at protein level were confirmed by UCP-2 protein in aging liver (+300%, P < 0.01) and UCP-2 (+85%, P < 0.05) and UCP-3 (-30%, P = 0.4) protein in aging mixed gastrocnemius muscle. Aging is thus associated with tissue-specific changes of UCP-2 and -3 gene expression. Increased UCP-2 expression may limit ATP production and is related to mitochondrial gene expression in aging muscles and liver. Different age-related changes may reflect differential regulation of UCP-2 and -3 in skeletal muscle. The current data suggest a potential role of uncoupling proteins to alter energy production in aging tissues.
Adenosine Triphosphate↗
T(3) increases mitochondrial ATP production in oxidative muscle despite increased expression of UCP2 and -3.
Triiodothyronine (T(3)) increases O(2) and nutrient flux through mitochondria (Mito) of many tissues, but it is unclear whether ATP synthesis is increased, particularly in different types of skeletal muscle, because variable changes in uncoupling proteins (UCP) and enzymes have been reported. Thus Mito ATP production was measured in oxidative and glycolytic muscles, as well as in liver and heart, in rats administered T(3) for 14 days. Relative to saline-treated controls, T(3) rats had 80, 168, and 62% higher ATP production in soleus muscle, liver, and heart, respectively, as well as higher activities of citrate synthase (CS; 63, 90, 25%) and cytochrome c oxidase (COX; 119, 225, 52%) in the same tissues (all P < 0.01). In plantaris muscle of T(3) rats, CS was only slightly higher (17%, P < 0.05) than in controls, and ATP production and COX were unaffected. mRNA levels of COX I and III were 33 and 47% higher in soleus of T(3) rats (P < 0.01), but there were no differences in plantaris. In contrast, UCP2 and -3 mRNAs were 2.5- to 14-fold higher, and protein levels were 3- to 10-fold higher in both plantaris and soleus of the T(3) group. We conclude that T(3) increases oxidative enzymes and Mito ATP production and Mito-encoded transcripts in oxidative but not glycolytic rodent tissues. Despite large increases in UCP expression, ATP production was enhanced in oxidative tissues and maintained in glycolytic muscle of hyperthyroid rats.
Adenosine Triphosphate↗
Increased concentration of tracee affects estimates of muscle protein synthesis.
Muscle protein synthesis was measured by infusion of L-[2H(5)]phenylalanine in two groups of anesthetized dogs, before and during infusion of insulin with euaminoacidemia, and with differing concentrations of unlabeled phenylalanine (tracee). With the infusion of insulin, muscle protein synthesis increased 39 +/- 12% based on phenylalanyl-tRNA. Calculation with plasma phenylalanine enrichment overestimated insulin stimulation by 40% (56 +/- 12 vs. 39 +/- 12%). Raising the concentration of plasma phenylalanine twofold during infusion of insulin further increased the apparent stimulation of muscle protein synthesis based on plasma relative to phenylalanyl-tRNA by 225% (65 +/- 19 vs. 20 +/- 14%, P < 0.001). In both experiments, the stimulation of synthesis rates calculated from phenylalanine enrichment within the muscle was closer to that from phenylalanyl-tRNA (48 +/- 19%, experiment 1; 30 +/- 14%, experiment 2). Results indicate that the enrichment of a labeled amino acid within plasma and tissue amino acid pools is affected by the concentration of tracee infused. Increasing the concentration of tracee overestimates the insulin-mediated stimulation of muscle protein synthesis when amino acid pools other than aminoacyl-tRNA are used as the precursor enrichment.
Amino Acids↗
Cardiac intraventricular thrombus in protein C deficiency.
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Adult↗
Continuation of growth hormone (GH) substitution during fasting in GH-deficient patients decreases urea excretion and conserves protein synthesis.
The consequences of GH deficiency during conditions in which endogenous GH release is acutely stimulated are largely unknown. Short-term fasting constitutes a robust GH stimulus, but the metabolic significance of GH during fasting is uncertain. To address both of these issues, we therefore evaluated the effect of GH on substrate metabolism during fasting in adults with GH deficiency. Seven hypopituitary GH-deficient patients were each studied twice during a 40-h fast: once with GH replacement continued and once with GH discontinued during the fast. After 40 h of fasting, protein synthesis and turnover were higher with than without GH replacement [phenylalanine incorporation (micromol/kg fat free mass/h): 36.6 +/- 1.2 (GH) vs. 32.8 +/- 1.4, P < 0.05; phenylalanine flux (micromol/kg fat free mass/h): 41.3 +/- 1.0 (GH) vs. 38.0 +/- 1.8, P < 0.05]. During continued GH replacement, urea excretion decreased during nighttime [urea excretion (mmol/24 h): 269 +/- 51 (GH) vs. 390 +/- 69, P < 0.05], and a significant decline in urea-N synthesis rate was found [urea-N synthesis rate (mmol/h): 14.7 +/- 1.6 (GH) vs. 21.1 +/- 2.2, P < 0.01]. GH replacement was associated with increased lipid oxidation [lipid oxidation (mg/kg per min): 0.91 +/- 0.07 (GH) vs. 0.70 +/- 0.03, P < 0.05]. Finally, continuation of GH induced moderate elevations in plasma glucose levels without significant changes in total glucose turnover or oxidation. In summary, continued GH substitution during fasting conserves nitrogen, which involves stimulation or maintenance of protein synthesis. Our data support the importance of GH replacement in hypopituitary adults.
Adult↗
The protein-retaining effects of growth hormone during fasting involve inhibition of muscle-protein breakdown.
The metabolic response to fasting involves a series of hormonal and metabolic adaptations leading to protein conservation. An increase in the serum level of growth hormone (GH) during fasting has been well substantiated. The present study was designed to test the hypothesis that GH may be a principal mediator of protein conservation during fasting and to assess the underlying mechanisms. Eight normal subjects were examined on four occasions: 1) in the basal postabsorptive state (basal), 2) after 40 h of fasting (fast), 3) after 40 h of fasting with somatostatin suppression of GH (fast-GH), and 4) after 40 h of fasting with suppression of GH and exogenous GH replacement (fast+GH). The two somatostatin experiments were identical in terms of hormone replacement (except for GH), meaning that somatostatin, insulin, glucagon and GH were administered for 28 h; during the last 4 h, substrate metabolism was investigated. Compared with the GH administration protocol, IGF-I and free IGF-I decreased 35 and 70%, respectively, during fasting without GH. Urinary urea excretion and serum urea increased when participants fasted without GH (urea excretion: basal 392 +/- 44, fast 440 +/- 32, fast-GH 609 +/- 76, and fast+GH 408 +/- 36 mmol/24 h, P < 0.05; serum urea: basal 4.6 +/- 0.1, fast 6.2 +/- 0.1, fast-GH 7.0 +/- 0.2, and fast+GH 4.3 +/- 0.2 mmol/1, P < 0.01). There was a net release of phenylalanine across the forearm, and the negative phenylalanine balance was higher during fasting with GH suppression (balance: basal 9 +/- 3, fast 15 +/- 6, fast-GH 17 +/- 4, and fast+GH 11 +/- 5 nmol/min, P < 0.05). Muscle-protein breakdown was increased among participants who fasted without GH (phenylalanine rate of appearance: basal 17 +/- 4, fast 26 +/- 9, fast-GH 33 +/- 7, fast+GH 25 +/- 6 nmol/min, P < 0.05). Levels of free fatty acids and oxidation of lipid decreased during fasting without GH (P < 0.01). In summary, we find that suppression of GH during fasting leads to a 50% increase in urea-nitrogen excretion, together with an increased net release and appearance rate of phenylalanine across the forearm. These results demonstrate that GH-possibly by maintenance of circulating concentrations of free IGF-I--is a decisive component of protein conservation during fasting and provide evidence that the underlying mechanism involves a decrease in muscle protein breakdown.
Adult↗
Tissue-specific regulation of mitochondrial and cytoplasmic protein synthesis rates by insulin.
In vivo studies have reported conflicting effects of insulin on mixed tissue protein synthesis rates. To test the hypothesis that insulin has differential effects on synthesis rates of various protein fractions in different organs, we infused miniature swine (n = 8 per group) with saline, insulin alone (at 0.7 mU/kg(-1). min(-1)), or insulin plus an amino acid mixture for 8 h. Fractional synthesis rate (FSR) of mitochondrial and cytoplasmic proteins in liver, heart, and skeletal muscle, as well as myosin heavy chain (MHC) in muscle, were measured using L-[1-(13)C]leucine as a tracer. The FSR of mitochondrial and cytoplasmic proteins were highest in liver, followed by heart and then muscle. Mitochondrial FSR in muscle was higher during insulin and insulin plus amino acid infusions than during saline. Insulin had no significant effect on FSR of MHC in muscle. In contrast, FSR of both mitochondrial and cytoplasmic proteins were not stimulated by insulin in liver. Insulin also did not increase FSR of mitochondrial in heart, whereas insulin and amino acid stimulated FSR of cytoplasmic protein. In conclusion, insulin stimulates the synthesis of muscle mitochondrial proteins, with no significant stimulatory effect on synthesis of sarcoplasmic and MHC. These results demonstrate that insulin has different effects on synthesis rates of specific protein fractions in the liver, heart, and skeletal muscle.
Amino Acids↗
Assessment of postabsorptive renal glucose metabolism in humans with multiple glucose tracers.
The contribution of the kidneys to postabsorptive endogenous glucose production is a matter of controversy. To assess whether this could relate to the use of various isotopical methods with different analytical performance capabilities, we measured glucose kinetics in 12 healthy subjects. Blood samples were taken from the femoral artery and the renal vein after 4 h of [6,6-2H2]glucose infusion (for gas chromatography [GC]/mass spectrometry [MS] analysis), and renal plasma flow was determined with paraaminohippurate. In addition, six subjects received uniformly labeled [13C]glucose (for GC/combustion/isotope ratio MS [IRMS]) and [3-3H]glucose (for counting of radioactive disintegrations). Arterial glucose concentrations (means +/- SD) were 4.2+/-0.1 mmol/l, and endogenous glucose production rates using [2H2]glucose were 2.2+/-0.1 mg x kg(-1) x min(-1) or 818+/-50 micromol/min. Dilution of [2H2]glucose across the kidney was 0.79+/-1.32%, and renal glucose production (RGP) rates were 27+/-72 micromol/min. In the six subjects receiving additional tracers, dilutions across the kidney were 2.83+/-0.72 and 0.54+/-1.20 (for [U-13C]glucose and [3-3H]glucose, respectively, the dilution with [U-13C] being higher than that with [2H2] (P = 0.007). Corresponding RGP values were 144+/-39 and 43+/-76 micromol/min for [U-13C] and [3-3H], respectively. In conclusion, we found that the highly sensitive [U-13C] GC/Combustion/IRMS technique showed consistent dilution of label across the kidney, whereas the less sensitive techniques gave some negative values and smaller RGP rates. Thus, depending on which technique is being used, a fivefold difference in calculated RGP values may be encountered. The methodological variability of our data suggests that extrapolation from regional renal measurements to the whole-body level should be perfumed with caution.
Adult↗
Insulin's effect on synthesis rates of liver proteins. A swine model comparing various precursors of protein synthesis.
Insulin's effect on the synthesis of liver proteins remains to be fully defined. Previous studies using various surrogate measures of amino acyl-tRNA have reported variable results of insulin's effect on liver protein synthesis. We determined the effect of insulin with or without amino acid supplementation on the synthesis rates of liver proteins (tissue, albumin, and fibrinogen) using L-[1-13C]Leu as a tracer in 24 male miniature swine. In addition, we compared the isotopic enrichment of different precursors of liver proteins with that of amino acyl-tRNA using L-[1-13C]Leu and L-[15N]Phe as tracers. Although liver tissue fluid enrichment of [13C]Leu and [15N]Phe and that of plasma [13C]ketoisocaproatic acid (KIC) were very similar to that of tRNA, plasma isotopic enrichment of both Leu and Phe were substantially higher (P < 0.01) and VLDL apolipoprotein-B100 enrichment was lower (P < 0.01) than the respective amino acyl-tRNA enrichment. Plasma KIC enrichment most accurately predicted leucyl-tRNA enrichment, whereas plasma Leu enrichment was best correlated with that of tRNA. Neither insulin alone nor insulin plus amino acid infusion had an effect on liver tissue protein synthesis. In contrast, insulin alone decreased the albumin synthesis rate, and insulin with amino acids maintained the albumin synthesis rate. Insulin with or without amino acids inhibited the fibrinogen synthesis rate. These results, based on synthetic rates using amino acyl-tRNA, were consistent with those obtained using KIC or tissue fluid Leu or Phe as precursor pools. These studies demonstrated that plasma KIC enrichment is a convenient and reliable surrogate measure of leucyl-tRNA in liver. We also concluded that insulin has differential effects on the synthesis rates of liver proteins. Whereas insulin with or without amino acid supplement has no acute effect on the synthesis of liver tissue protein, insulin has a substantial inhibitory effect on fibrinogen synthesis. In contrast, insulin administration along with amino supplement is necessary to maintain albumin synthesis rate.
Amino Acids↗
Protein metabolism in clinically stable adult cystic fibrosis patients with abnormal glucose tolerance.
Cystic fibrosis (CF) patients are reported to experience chronic protein catabolism. Since diabetes or impaired glucose tolerance (IGT) is common in CF, we hypothesized that their protein catabolic state is related to reduced insulin secretion or reduced insulin action. A total of 12 clinically stable adult CF patients with abnormal glucose tolerance and 12 age-, sex-, and lean body mass-matched healthy control subjects underwent protein turnover studies using L-[1-(13)C]leucine, L-[(15)N]phenylalanine, and L-[(2)H(4)]tyrosine, with and without exogenous insulin infusion. In the baseline fasting state, protein metabolism was entirely normal in CF patients, with no evidence of increased protein catabolism. In contrast, striking abnormalities were seen in CF patients when insulin was infused, since they did not experience normal suppression of the appearance rates of leucine, phenylalanine, or tyrosine (indexes of protein breakdown). At an insulin concentration of 45 +/- 2 microU/ml, normal control subjects suppressed the leucine appearance rate by 19 +/- 5% (P < 0.01), ketoisocaproate appearance rate by 10 +/- 3% (P = 0.03), tyrosine appearance rate by 11 +/- 2% (P = 0.03), and phenylalanine appearance rate by 6 +/- 3% (P = 0.07). Phenylalanine conversion to tyrosine decreased by 22 +/- 7% (P = 0.03). At a similar insulin concentration of 44 +/- 3 microU/ml, normal suppression of amino acid appearance did not occur in CF. The leucine appearance rate decreased by 4 +/- 2% (P = 0.65), ketoisocaproate appearance rate by 1 +/- 2% (P = 0.94), tyrosine appearance rate by 0 +/- 6% (P = 0.56), phenylalanine appearance rate by 5 +/- 6% (P = 0.34), and phenylalanine conversion to tyrosine by 5 +/- 6% (P = 0.95). Poor suppression of the amino acid appearance rate in CF was not related to previously documented glucose tolerance status (IGT or CF-related diabetes without fasting hyperglycemia), fasting insulin levels, the acute insulin response, insulin sensitivity, cytokine or counterregulatory hormone levels, resting energy expenditure, caloric intake, pulmonary function, or clinical status. Protein synthesis was not significantly affected by insulin infusion in either normal control subjects or CF patients. In conclusion, clinically stable adult CF patients have normal indexes of protein breakdown and synthesis in the fasting state. In contrast, elevation of plasma insulin to physiological postprandial levels fails to normally suppress indexes of protein breakdown. It is therefore likely that inability to spare protein during the postprandial state is the cause of protein catabolism in these patients.
Adult↗
Type 2 diabetes impairs splanchnic uptake of glucose but does not alter intestinal glucose absorption during enteral glucose feeding: additional evidence for a defect in hepatic glucokinase activity.
We have previously reported that splanchnic glucose uptake, hepatic glycogen synthesis, and hepatic glucokinase activity are decreased in people with type 2 diabetes during intravenous glucose infusion. To determine whether these defects are also present during more physiological enteral glucose administration, we studied 11 diabetic and 14 nondiabetic volunteers using a combined organ catheterization-tracer infusion technique. Glucose was infused into the duodenum at a rate of 22 micromol. kg(-1). min(-1) while supplemental glucose was given intravenously to clamp glucose at approximately 10 mmol/l in both groups. Endogenous hormone secretion was inhibited with somatostatin, and insulin was infused to maintain plasma concentrations at approximately 300 pmol/l (i.e., twofold higher than our previous experiments). Total body glucose disappearance, splanchnic, and leg glucose extractions were markedly lower (P < 0.01) in the diabetic subjects than in the nondiabetic subjects. UDP-glucose flux, a measure of glycogen synthesis, was approximately 35% lower (P < 0.02) in the diabetic subjects than in the nondiabetic subjects. This was entirely accounted for by a decrease (P < 0.01) in the contribution of extracellular glucose because the contribution of the indirect pathway to hepatic glycogen synthesis was similar between groups. Neither endogenous and splanchnic glucose productions nor rates of appearance of the intraduodenally infused glucose in the portal vein differed between groups. In summary, both muscle and splanchnic glucose uptake are impaired in type 2 diabetes during enteral glucose administration. The defect in splanchnic glucose uptake appears to be due to decreased uptake of extracellular glucose, implying decreased glucokinase activity. Thus, abnormal hepatic and muscle (but not gut) glucose metabolism are likely to contribute to postprandial hyperglycemia in people with type 2 diabetes.
Absorption↗