Splanchnic and peripheral glucose and amino acid metabolism in diabetes mellitus

Splanchnic and leg exchange of glucose, lactate, pyruvate, and individual plasma amino acids was studied in diabetics 24 hr after withdrawal of insulin and in healthy controls. Measurements were made in the basal postabsorptive state and during the administration of glucose at a rate of 2 mg/kg per min for 45 min.In the basal state, net splanchnic glucose production did not differ significantly between diabetics and controls. However, splanchnic uptake of alanine and other glycogenic amino acids was 1(1/2)-2 times greater in the diabetics, while lactate and pyruvate uptake was increased by 65-115%. Splanchnic uptake of these glucose precursors could account for 32% of hepatic glucose output in the diabetics, as compared to 20% in the controls. This increase in precursor uptake was a consequence of a two- to threefold increment in fractional extraction of these substrates inasmuch as arterial levels of alanine, glycine, and threonine were reduced in the diabetics, while the levels of the remaining substrates were similar in the two groups. Peripheral output of alanine and other glycogenic amino acids as reflected in arterio-femoral venous differences was similar in both groups. An elevation in arterial valine, leucine, and isoleucine was observed in the diabetics, but could not be accounted for on the basis of alterations in splanchnic or peripheral exchange of these amino acids.Administration of glucose (2 mg/kg per min) for 45 min resulted in an 80% reduction in splanchnic glucose output in controls, but failed to inhibit hepatic glucose release in the diabetics despite a twofold greater increment in arterial glucose levels. In both groups no consistent changes in arterial glucagon were observed during the infusion.It is concluded that in nonketotic diabetics (a) total splanchnic output of glucose is comparable to controls, but the relative contribution of gluconeogenesis may be increased by more than 50%; (b) accelerated splanchnic uptake of glucose precursors is a consequence of increased hepatic extraction of available substrates rather than a result of augmented substrate supply; and (c) the failure of glucose infusion to inhibit hepatic glucose output suggests that the exquisite sensitivity of the liver to the infusion of glucose in normal man is a consequence of glucose-induced insulin secretion.     

Insulin time-dependent effects on the leg exchange of glucose and amino acids in man

Time-dependent effects of insulin on the leg exchange of glucose, lactate, glycerol, free fatty acids (FFA) and amino acids were measured in relation to oxygen uptake (leg and whole body) and whole body glucose assimilation including oxidation. Seven healthy males (58 +/- 3 years of age) were investigated before operation of uncomplicated inguinal hernia or varicose veins. Euglycaemic glucose clamp investigations with systemic hyperinsulinaemia between 100-120 mU1(-1) were used. Metabolic measurements were performed before and during hyperinsulinaemia at 2 and 6 h following the start of glucose clamp to evaluate the time-dependency of insulin actions. Whole body glucose uptake increased continuously for up to 6 h (from 4.7 +/- 0.7 to 8.0 +/- 0.8 mg/kg/min, P less than 0.01) despite stable plasma concentrations of glucose and insulin. This was also true for glucose oxidation. Whole body oxygen uptake did not change significantly during the clamp while the leg exchange of oxygen uptake did (from 5.9 +/- 0.86 mumol/100 g/min to 11.6 +/- 2.4, P less than 0.01). Insulin effect on leg blood flow was time-dependent and increased two-fold (2.3 +/- 0.4 ml/100 g/min to 4.4 +/- 0.9, P less than 0.001) during clamp. The leg production of lactate increased continuously, accounting for approximately 15% of the glucose uptake across the leg, but the rise in arterial lactate did not reach the level of statistical significance. Plasma FFA concentrations decreased in a time-dependent manner during clamp, while the leg exchange of FFA switched rapidly to a stable net uptake.(ABSTRACT TRUNCATED AT 250 WORDS)     

Plasma glucose, non-esterified fatty acids and amino acids in Huntington's chorea.

1. The metabolic responses to an oral glucose tolerance test (100 g) and an intravenous insulin provocation test (0-1 i.u./kg) were studied in nine control subjects and nine patients with Huntington's chorea. 2. Plasma glucose responses to these stimuli were identical in both groups. 3. High fasting concentrations of non-esterified fatty acid (NEFA) were recorded in the choreic patients when compared with control subjects. This difference was maintained under hypoglycaemic conditions. However, during hyperglycaemia the differences in NEFA concentrations between the groups was abolished. 4. Total plasma tryptophan concentrations were equal in the two groups. Free plasma tryptophan, however, was markedly reduced in the choreic group, and this appeared to be a result of a disturbed relationship between free tryptophan and NEFA concentrations. The abnormalities in free tryptophan values were sensitive to plasma glucose concentrations, as hyperglycaemic conditions markedly reduced the differences between the choreic and control group. 5. Patients with Huntington's chorea showed reduced fasting plasma concentrations of leucine, isoleucine and valine.     

游离脂肪酸与子痫前期和妊娠期糖尿病发生的相关性

目的:探讨孕晚期游离脂肪酸对子痫前期和(或)妊娠期糖尿病(GDM)发病率的影响。方法:选择417例孕晚期子痫前期和(或)GDM为观察组,另选2 018例正常妊娠孕妇为对照组。检测并比较2组血清总胆固醇(TC)、三酰甘油(TG)、高密度脂蛋白胆固醇(HDL-C)、低密度脂蛋白胆固醇(LDL-C)和游离脂肪酸(FFA)。采用logistic回归模型分析血脂子痫前期和(或)GDM的关系。结果:校正混杂因素[孕妇年龄、孕前体质指数(BMI)和采血时的孕周]后,孕晚期FFA浓度升高会增加子痫前期、GDM和子痫前期合并GDM的风险(P0.01)。孕晚期TG水平升高会增加子痫前期、GDM发生的风险(P0.001)。结论:孕晚期FFA水平升高可使子痫前期和(或)GDM发生风险增加。     

The exchange of blood-borne amino acids in the leg during abdominal surgical trauma: effects of glucose infusion

The exchange of plasma amino acids and glucose, lactate, glycerol and 3-hydroxybutyrate in the leg was studied in otherwise healthy patients undergoing elective cholecystectomy. Seven patients were given a constant intravenous infusion of glucose at a rate of 1.1 mmol/min throughout the study. Seven other patients who received normal saline only served as a control group. Measurement of leg blood flow and arterio-femoral venous differences of amino acids and other energy metabolites were made on four occasions: (I) before surgery, (II) 10 min after skin incision, (III) at the end of surgery, and (IV) 30 min after the end of anaesthesia. The release of amino acids from the leg was comparable in the two groups before and during the early part of surgery. At the end of surgery the release of several individual amino acids, as well as the total release of amino acids, from the leg was higher in the patients given glucose infusion compared with the control patients. The infusion of glucose prevented the intraoperative rise in arterial levels and uptake of 3-hydroxybutyrate in the leg. A high release of amino acids at the end of surgery was thus associated with low arterial levels of 3-hydroxybutyrate while the reverse pattern was seen in the control patients. These effects of glucose infusion were qualitatively different from those seen in uninjured postabsorptive man.     

罗格列酮对2型糖尿病游离脂肪酸的影响

目的观察罗格列酮对2型糖尿病游离脂肪酸（FFA）的影响。方法60例2型糖尿病患者,随机分为罗格列酮组与二甲双胍组。治疗前和治疗3个月后,测量身高和体质量,计算体质量指数（BMI）,观察空腹血糖（FBS）、甘油三酯（TG）、总胆固醇（TC）、高密度脂蛋白胆固醇（HDL-C）、低密度脂蛋白胆固醇（LDL-C）、FFA、糖化血红蛋白（HbA1c）的变化。结果治疗后两组FBS、HbA1c均下降。罗格列酮组FBS治疗前后（10．34±3．08）mmol／L vs（7．75±1．46）mmol／L（P〈0．01）,HbA1c（8．85±2．28）％vs（7．28±1．33）％（P〈0．01）;二甲双胍组FBS（9．51±2．89）mmol／Lvs（7．36±1．40）mmol／L（P〈0．01）,HbA1c（9．26±2．45）％vs（7．61±1．23）％（P〈0．01）。但两组之间比较无统计学意义（P〉0．05）。罗格列酮组治疗前后FFA（0．65±0．24）mmol／Lvs（0．54±0．19）mmol／L（P〈0．05）。而二甲双胍组治疗前后FFA无明显下降。结论罗格列酮治疗降低FFA的水平,有助于减少2型糖尿病大血管并发症的发生。     

Leg exchange of amino acids during exercise in patients with arterial insufficiency

Intermittent claudication is associated with adaptation in muscle metabolism. This study has evaluated the metabolism of amino acids at rest and during non-steady state exercise in patients with arterial insufficiency of at least six months duration in comparison with matched control individuals. The exchange of amino acids were measured during two periods of acute exercise; one initial exercise period with a standardized work load and exercise time and a second exercise period which continued until further exercise was impossible due to pain in the patients and exhaustion in the controls. The maximum blood flow was reduced by 40% in the patients but the maximum oxygen uptake per unit power developed was almost the same in patients and controls. The patients had significantly lower concentrations of glutamine, lysine and taurine at rest compared with the controls. The exchange of amino acids across the resting leg did not differ between the two groups. Exercise increased the efflux of amino acids in both patients and controls. The efflux of glutamine (896 ± 205 vs. 48 ± 359 nmol/100 ml/min/watt) was higher in the patients compared to the controls at the first exercise period with inverse changes in the opposite direction of asparagine (149 ± 105 vs. 799 ± 121 and 27 ± 70 vs. 633 ± 334 nmol/100 ml/min/watt at the first and second exercise, respectively. Alanine release did not differ between the groups. The complementary patterns of glutamine and asparagine during hypoxic exercise in the patients may reflect the fact that these amino acids share a common carrier system. The similarity in the efflux of non-metabolized amino acids, such as methionine, phenylalanine, tyrosine and 3-methylhistidine, indicated that muscle hypoxia in claudication patients did not promote net degradation of either globular or myofibrillar proteins, although exercise increased the efflux of 3-methylhistidine three- to fourfold in both patients and control individuals (from 1 ± 0·4 to 4 ± 1·8 and from 0 ± 0·7 to 6 ± 2·5 nmol/100 ml/min/watt, respectively). The exercise-induced alterations in leg exchange of amino acids were restored within 10–20 min following exercise regardless of hypoxia. The results demonstrate that patients with arterial insufficiency have altered intermediary metabolism of amino acids during exercise. However, muscle hypoxia in such patients does not seem to promote a negative protein balance or induce serious alterations in cell membrane integrity.     

老年2型糖尿病患者血清抵抗素、游离脂肪酸水平研究

目的探讨血清抵抗素、游离脂肪酸与老年糖尿病及胰岛素抵抗的关系。方法测量老年(年龄>60岁)2型糖尿病患者82例(老年糖尿病组),成年(年龄<60岁)2型糖尿病患者70例(成年糖尿病组),老年健康体检者50例(对照组)空腹血清抵抗素、游离脂肪酸、空腹血糖及胰岛素水平,计算胰岛素抵抗指数。结果老年糖尿病组血清抵抗素、游离脂肪酸水平高于对照组与成年糖尿病组(P<0.05或P<0.01)。老年糖尿病组胰岛素抵抗程度较成年糖尿病组明显,并伴有脂代谢紊乱。结论血清抵抗素、游离脂肪酸与老年糖尿病尤其是老年胰岛素抵抗密切相关。     

Splanchnic and peripheral glucose and lactate metabolism during and after prolonged arm exercise.

Splanchnic and peripheral exchange of glucose and gluconeogenic substrates was examined in 12 healthy subjects during 2 h of arm or leg exercise on a bicycle ergometer and during a 40-min postexercise recovery period. The work intensity corresponded to 30% of the maximal pulmonary oxygen uptake. The regional exchange of substrates was evaluated using catheter technique and indicator dilution methods for blood flow measurements. Our findings indicate that prolonged arm exercise as compared with exercise with the legs results in a greater increase in heart rate (25-40%) and a more marked reduction in splanchnic blood flow (10-30%) as well as higher arterial concentrations of lactate, free fatty acids, and catecholamines. The respiratory exchange ratio was consistently higher with arm exercise. In addition, arm exercise results in a greater fractional extraction and utilization of glucose by exercising muscle as well as a greater hepatic gluconeogenesis from lactate and glycerol. During recovery from prolonged arm exercise, leg muscle becomes an important site of lactate release to the splanchnic bed, despite a lack of net glucose uptake by the leg. Simultaneously, arm muscle shows an increase in glucose uptake in the absence of a net release of lactate. These coincident but discordant processes in the leg and arm during recovery suggest the occurrence of a redistribution of muscle glycogen from previously resting (leg) muscle to previously exercising (arm) muscle.     

Splanchnic glucose and amino acid metabolism in obesity

Arterial concentrations and splanchnic exchange of glucose, lactate, pyruvate, glycerol, free fatty acids, and individual acidic and neutral amino acids were determined in obese and nonobese control subjects in the basal state and during a 45 min infusion of glucose. Glucose was administered to the controls at a rate (2 mg/kg/min; 144 +/- 4 mg/min) known to inhibit splanchnic glucose output without influencing peripheral glucose utilization. The obese subjects received glucose at two dose levels (75 and 150 mg/min) which simulated either the rise in insulin or the inhibition in splanchnic glucose production observed in the controls. In the basal state splanchnic glucose production did not differ significantly between obese and control subjects. However splanchnic uptake of lactate, glycerol, alanine, free fatty acids, and oxygen was 50-160% greater in obese subjects. Splanchnic uptake of glucose precursors could account for 33% of hepatic glucose output in the obese group as compared to 19% in controls. The increase in alanine and lactate uptake was due in part, to a 50% increase in splanchnic fractional extraction. Administration of glucose to the control subjects 144 +/- 4 mg/min) resulted in a 50-60% increment in arterial insulin and a 75% reduction in splanchnic glucose output. In the obese group, infusion of glucose at a rate of 75 mg/min resulted in an equivalent rise in arterial insulin, but was accompanied by a less than 40% inhibition in splanchnic glucose output. Glucose infusion at a rate of 150 mg/min in the obese resulted in a 75% reduction in splanchnic glucose output which was equivalent to that observed in controls, but was accompanied by a significantly greater rise (100-200%) in arterial insulin. It is concluded that in obesity (a) despite basal hyperinsulinemia, splanchnic uptake of glucose precursors is increased, the relative contribution to total glucose release attributable to gluconeogenesis being 70% higher than in controls; (b) infusion of glucose at rates causing equivalent increases in arterial insulin induces a smaller inhibition in splanchnic glucose output than in controls; (c) infusion of glucose at rates causing comparable inhibition in splanchnic glucose output is accompanied by a disproportionately greater increase in endogenous insulin than in controls. These data are compatible with hepatic resistance to insulin in obesity.     

Biological effects of omega-3 fatty acids in diabetes mellitus.

Fish oils exert important biological effects on several pathways predisposing to atherosclerosis. Epidemiological studies provided the initial evidence that omega-3 fatty acids may be the principal factor in fish oils responsible for these effects and have led to several short-term clinical trials in which fish-oil concentrates have been administered to various populations at risk for coronary heart disease, including patients with diabetes mellitus. omega-3 Fatty acids reduce serum lipids and lipoproteins, impair platelet aggregation, increase cell membrane fluidity, and lower blood pressure in humans. In this review, we highlight these and other potentially antiatherogenic properties of marine lipids in diabetic subjects.     

Essential fatty acids and the complications of diabetes mellitus

In animals and humans with diabetes mellitus there is evidence that normal metabolism of essential fatty acids is impaired. The main dietary essential fatty acids, linoleic acid of the n-6 series and alpha-linolenic acid of the n-3 series, must both be 6-desaturated and converted to further metabolites if they are to exert all their desirable effects on the body. 6-desaturation is impaired in diabetes and a lack of adequate rates of formation of the 6-desaturated metabolites may be involved in the abnormalities in membrane function, in lipid metabolism and in haemostasis and the microcirculatory system which are seen in diabetes. Attempts to overcome the block by giving very large amounts of dietary linoleic acid, or to by-pass the block by giving 6-desaturated metabolites such as gamma-linolenic acid and eicosapentaenoic acid, have both given promising results.     

Role of plasma non-esterified fatty acids during and after exercise.

1. The importance of circulating non-esterified fatty acids as a substrate during and after low-grade exercise has been examined by using a nicotinic acid analogue to inhibit lipolysis. Seven healthy men received acipimox or placebo on separate occasions. After 90 min, bicycle exercise was performed for 45 min (40% of pre-determined maximum oxygen uptake), followed by a 60 min recovery period. 2. The plasma concentration of non-esterified fatty acids increased during exercise after placebo (320 +/- 80 to 630 +/- 110 mumol/l) and remained elevated in the post-exercise period. Basal concentrations were lower after acipimox (100 +/- 10 mumol/l; P less than 0.05); they declined to 60 +/- 10 mumol/l during exercise and remained at this level for the rest of the study. 3. Lipid oxidation increased from 0.8 +/- 0.1 to 4.2 +/- 0.5 mg min-1 kg-1 during exercise after placebo (P less than 0.001) and remained elevated in the post-exercise period (1.2 +/- 0.1 mg min-1 kg-1). It was lower after acipimox, but still increased from 0.3 +/- 0.1 to 2.3 +/- 0.2 mg min-1 kg-1 with exercise. Carbohydrate oxidation was increased after acipimox compared with after placebo, but only reached significance during the post-exercise period (P less than 0.05). 4. Although acipimox abolished the rise in the plasma concentration of non-esterified fatty acids during exercise, there was only a 50% decrease in the rate of lipid oxidation. This suggests that an alternative source of non-esterified fatty acids makes an important contribution to the supply of lipid for oxidation during exercise.(ABSTRACT TRUNCATED AT 250 WORDS)     

新诊断2型糖尿病患者血浆内脂素及FFA水平的变化

目的:探讨新诊断2型糖尿病患者血浆内脂素及游离脂肪酸水平的变化。方法:检测106例T2DM患者(T2DM组)和100例健康体检者(对照组)血浆内脂素、FFA和相关临床指标。结果:T2DM患者血浆内脂素、FFA水平高于正常对照组(P<0.01)。多元线性逐步回归分析显示腰臀比和空腹血糖是影响血浆内脂素水平的独立相关因素。结论:血浆内脂素水平变化与糖脂代谢关系密切,它可能在T2DM的发病机制中起着一定作用。     

Impaired free fatty acid utilization by skeletal muscle in non-insulin-dependent diabetes mellitus.

This study was undertaken to assess utilization of FFA by skeletal muscle in patients with non-insulin-dependent diabetes mellitus (NIDDM). 11 NIDDM and 9 nondiabetic subjects were studied using leg balance methods to measure the fractional extraction of [3H]oleate. Limb indirect calorimetry was used to estimate RQ. Percutaneous muscle biopsy samples of vastus lateralis were analyzed for muscle fiber type distribution, capillary density, and metabolic potential as reflected by measurements of the activity of seven muscle enzyme markers of glycolytic and aerobic-oxidative pathways. During postabsorptive conditions, fractional extraction of oleate across the leg was lower in NIDDM subjects (0.31 +/- 0.08 vs. 0.43 +/- 0.10, P < 0.01), and there was reduced oleate uptake across the leg (66 +/- 8 vs. 82 +/- 13 nmol/min, P < 0.01). Postabsorptive leg RQ was increased in NIDDM (0.85 +/- 0.03 vs. 0.77 +/- 0.02, P < 0.01), and rates of lipid oxidation by skeletal muscle were lower while glucose oxidation was increased (P < 0.05). In subjects with NIDDM, proportions of type I, IIa, and IIb fibers were 37 +/- 2, 37 +/- 6, and 26 +/- 5%, respectively, which did not differ from nondiabetics; and capillary density, glycolytic, and aerobic-oxidative potentials were similar. During 6 h after ingestion of a mixed meal, arterial FFA remained greater in NIDDM subjects. Therefore, despite persistent reduced fractional extraction of oleate across the leg in NIDDM (0.34 +/- 0.04 vs. 0.38 +/- 0.03, P < 0.05), rates of oleate uptake across the leg were greater in NIDDM (54 +/- 7 vs. 45 +/- 8 nmol/min, P < 0.01). In summary, during postabsorptive conditions there is reduced utilization of FFA by muscle, while during postprandial conditions there is impaired suppression of FFA uptake across the leg in NIDDM. During both fasting and postprandial conditions, NIDDM subjects have reduced rates of lipid oxidation by muscle.     

Effect of adrenaline on exchange of free fatty acids in leg tissues and splanchnic area. A comparison with the metabolic response to surgical stress

Summary. The present investigation was aimed at studying the acute effects of an adrenaline infusion on the exchange of free fatty acids in the leg and splanchnic bed. Seven healthy males participated in the study. Adrenaline (40 ng/(min×kg body weight)) (0·22 nmol/(min×kg body weight)) was infused to produce a plasma concentration similar to that seen in connection with surgery (2·77±0·42 nmol/l). Leg and splanchnic blood flow were measured and the femoral and hepatic arterio-venous differences for the total fraction of FFA were determined. 1-¹⁴C-oleic acid was infused intravenously so as to determine uptake and release of FFA. Measurements were made before and between 30 and 40 min after the start of the adrenaline infusion. The FFA concentration rose by 140% and the FFA uptake in the leg and splanchnic region increased about three fold. For 3-hydroxybutyrate the arterial concentrations as well as leg uptake and splanchnic uptake increased about six fold, four fold and eight fold, respectively. Ketogenesis accounted for a large part of the FFA uptake in the splanchnic bed during adrenaline infusion. We conclude that adrenaline infusion results in pronounced changes in FFA and 3-hydroxybutyrate concentrations and in the exchange of these substrates in leg and splanchnic bed. The adrenaline-induced increases in FFA and 3-hydroxybutyrate metabolism were generally more marked than those seen during and immediately after surgery.