Lowering of plasma glucose concentration in septic cancer-bearing patients: metabolic significance.

Previous work has indicated that 40-50% of glucose intake is oxidized in normal humans with protein-sparing effect. In contrast, the catabolic stressed patient is hyperglycaemic with decreased glucose oxidation and protein wasting. This study evaluated whether the plasma glucose concentration alone would be a reliable indicator of efficient glucose utilization and protein sparing in the critically ill septic cancer patients receiving glucose infusions. Glucose turnover, glucose concentration, nitrogen excretion, oxygen consumption, and glucose oxidation were measured in 8 septic cancer-bearing patients during a glucose infusion of 4.0 mg/kg/min followed by the infusion of insulin with the same glucose load. During glucose infusion without insulin the glucose concentration was 11.8 +/- 1.4 mmol/l, glucose oxidation 10 +/- 5% of glucose tissue uptake, and nitrogen excretion 9.0 +/- 1.3 mg/kg/h. During the euglycaemic clamp the glucose concentration was 3.8 +/- 0.2 mmol/l, glucose oxidation increased to 45 +/- 6% of glucose tissue uptake (p < 0.001), and nitrogen excretion dropped to 6.8 +/- 1.2 mg/kg/h (p < 0.001). The glucose concentration was greater than 10 mmol/l in 4 patients and between 6.9 and 9.3 mmol/l in 4 patients after glucose infusion alone. Despite this difference in initial glucose concentration, normalization of plasma glucose to less than 5 mmol/l with insulin resulted in the same decrease in nitrogen excretion and improvement in glucose oxidation. We conclude that, independent of the initial glucose concentration, maintenance of euglycaemia with insulin appears to be a good indicator of efficient glucose utilization and protein sparing in septic cancer-bearing patients receiving glucose as the primary mode of nutritional support.     

Relationship between glucose oxidation and glucose tolerance in man

The study was performed to determine the influence of peripheral glucose utilization on glucose tolerance. Glucose oxidation was measured in a group of 6 normal subjects by means of continuous indirect calorimetry during a 100 g oral glucose tolerance test for 3 hr, comparing the control state with experimental inhibition or stimulation of glucose oxidation. Suprabasal oxidation, corresponding to oxidation in response to the load, mainly by insulin-dependent tissue, was obtained by subtracting basal oxidation (essentially by non-insulin dependent tissues) from total oxidation. Suprabasal oxidation of glucose was inhibited by a neutral fat infusion, and stimulated by means of dichloracetate. In the control test, from the 100 g glucose administered, 18 g participated to suprabasal oxidation during the 3 hr of the test. A neutral fat infusion, started 2 hr before the glucose load and lasting throughout the test, decreased suprabasal oxidation to 7.5 g, i.e. to 42% of the control value. With the fat infusion, a larger fraction of the energy consumption was shown to originate from lipid oxidation (37% versus 25% in controls, p < 0.05) at the expense of carbohydrate (CHO) oxidation (44% versus 60% in controls, p < 0.05). However, these major changes in peripheral glucose oxidation were accompanied by only a moderate decrease in glucose tolerance. Dichloracetate administered prior to the test increased suprabasal oxidation to 25 g glucose oxidized in the 3 hours following the glucose load, i.e. an increment of 39% above the control value. A larger fraction of energy consumption was derived from carbohydrates (77% versus 60% in controls, p < 0.05). However, no significant change was observed in glucose tolerance. These results indicate that marked changes of peripheral glucose oxidation have little influence on glucose tolerance and suggest that another mechanism, i.e. glucose storage, plays a larger role in regulating plasma glucose levels during oral glucose tolerance tests.     

Effect of interaction between insulin and glucagon on glucose turnover and FFA concentration in normal and depancreatized dogs

We showed previously that arginine increased glucose production (R_a) and utilization (R_d) synchronously in normal dogs and suggested that this was due to concurrent insulin and glucagon release. In order to investigate the metabolic effects of coincidently elevated insulin and glucagon levels on R_a and R_d, glucagon was infused (1.55 μg/kg/hr) into normal dogs and into depancreatized dogs coincident with graded amounts of insulin (250–3000 μU/kg/min) until the metabolic response of the normal dog was achieved in depancreatized dogs. Main observations: Concurrent insulin and glucagon elevations increased glucose turnover (100%) in normal and depancreatized dogs while maintaining normoglycemia. Glucagon had no appreciable effect on peripheral glucose clearance in depancreatized dogs maintained on basal insulin. The effect of glucagon on R_a was not inhibited by concurrent insulin infusion at rates up to 3000 μU/kg/min. The effect of glucagon on R_a waned with time, indicating that a given insulin/glucagon ratio did not have a sustained effect. Near normal metabolic effects with respect to glucose turnover and FFA concentration were achieved in depancreatized dogs when the normal IRI response to glucagon was reproduced, indicating that the spike pattern of insulin release reflects not only the inherent secretory characteristic of β cells, but also serves an important glucoregulatory function. Glucagon induced an increase in ¹⁴C-glucose recycling, suggesting that it enhanced gluconeogenesis.     

Effects of carbocromene on performance and oxidation of FFA and glucose in isolated atria

Conclusions Carbocromene inhibits only inhypoxic injured atria the palmitate oxidation (–32%), whereas glucose oxidation-rate (+17%) increased at the incubation with the combination of these 2 substrates. In thenormoxic controls, however, the competition of substrates in the biological oxidation after the positive inotropic effect of C. was dependent on the V_max-and K_m-values of the oxidation-rate of each substrate as well as its concentration.If carbocromene inhibits the palmitate oxidation in the stage of its penetration through the cell membrane or in the mitochondrial membrane or by other interference in the hypoxic injured atria cannot be decided yet.

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Wirkungen von Carbocromen auf Funktion und Oxidation von FFA und Glukose in isolierten Herzvorhöfen

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Paper, presented at the Erwin Riesch Symposium, Tübingen, April 3–7, 1979

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With 1 figure     

肥胖患者血清单核细胞趋化蛋白1浓度与葡萄糖钳夹试验胰岛素敏感性的关系

血清单核细胞趋化蛋白1(MCP-1)浓度随正常人[(65.6±17.7)ng/L]、体重指数＞25 kg/m2的糖耐量正常者[(136.8±57.4)ng/L]和超重或肥胖的2型糖尿病患者逐步升高[(189.4±72.1)ng/L,均P＜0.01],胰岛素介导的葡萄糖代谢率(Rd)则降低[(10.66±1.68,6.11±2.06,4.86±1.38)mg·kg-1·min-1,P＜0.05或P＜0.01].部分2型糖尿病患者(n=13)经12周罗格列酮治疗后,MCP-1降低[(113.0±35.7vs186.9±64.3)ng/L,P＜0.01],Rd升高[(6.34±1.18vs4.97±1.51)mg·kg-1·min-1,P＜0.01].     

Free fatty acid turnover and lipolysis in septic mechanically ventilated cancer-bearing humans

Loss of body fat and lean body mass are features of critical illness, and anabolism is difficult to achieve despite parenteral nutrition. Resting energy expenditure (REE), free fatty acid turnover (FFT) and glycerol turnover (glyTO) were measured in septic, mechanically ventilated cancer-bearing patients, both fasting and immediately following or during a glucose infusion providing 87% of REE. No patient was in septic shock nor required pressor support. In the fasting state, REE was greatly elevated compared with basal energy expenditure calculated using the Harris-Benedict equations. Fasting FFT (14.2 +/- 0.9 mumol/kg/min) and glyTO (4.7 +/- 0.5 mumol/kg/min) were elevated compared with normal humans. Fasting respiratory quotient (RQ) was 0.68 +/- 0.02 and did not rise significantly with glucose. Fat appears to be the preferred calorie source in septic, cancer-bearing humans even in the presence of glucose. As similar, but less pronounced, changes have been seen in septic and injured humans without cancer, it is likely that these changes are not cancer-specific.     

Relationship between fractional pancreatic beta cell area and fasting plasma glucose concentration in monkeys

Aims/hypothesis

We sought to establish the relationship between fasting plasma glucose concentrations and pancreatic fractional beta cell area in adult cynomolgus monkeys (Macaca fascicularis).

Methods

Fasting plasma glucose and pancreatic fractional beta cell area were measured in 18 control and 17 streptozotocin-treated adult primates (17.0?±?1.2 vs 15.4?±?1.2 years old).

Results

Fasting plasma glucose was increased (12.0?±?2.0 vs 3.4?±?0.1 mmol/l, p?<?0.01) and fractional beta cell area was decreased (0.62?±?0.13% vs 2.49?±?0.35%, p?<?0.01) in streptozotocin-treated monkeys. The relationship between fasting plasma glucose and pancreatic fractional beta cell area was described by a wide range of beta cell areas in controls. In streptozotocin-treated monkeys there was an inflection of fasting blood glucose at ～50% of the mean beta cell area in controls with a steep increase in blood glucose for each further decrement in beta cell area.

Conclusions/interpretation

In adult non-human primates a decrement in fractional beta cell area of ～50% or more leads to loss of glycaemic control.     

Serum gliclazide concentration in diabetic patients. Relationship between gliclazide dose and serum concentration

Serum levels of gliclazide were determined by radioimmunoassay in seven healthy controls and in 18 diabetic in-patients receiving single oral dosing and consecutive dosing over 5 days. Following a single oral dose of 40 mg in the seven controls and eight diabetic patients, and 120 mg in ten diabetic patients, the serum levels of gliclazide peaked on average at 2 h, followed by a slow decline, the t1/2 being 16.5 h in the volunteers, 12.3 h in the diabetic patients receiving 40 mg, and 10.5 h in those receiving 120 mg. During consecutive administration, the serum levels both at fasting and at the peak reached a plateau in 2 days and no further accumulations were observed. The steady-state peak levels of gliclazide in the diabetic patients revealed a strongly positive correlation with the dose per m2 body surface area (r = 0.78, P less than 0.001), and their steady-state fasting levels correlated positively but weakly with the dose per m2 body surface area (r = 0.48, P less than 0.05). Thus, measuring either the fasting or the peak concentration of gliclazide will be useful for monitoring drug concentration in the serum. Pharmacokinetics of gliclazide will contribute to the elucidation of the relationship of serum level and clinical effectiveness in diabetic subjects.     

Interaction between serum calcium concentration and glucose tolerance in normal and azotaemic patients

Summary The effect of calcium infusion on the intravenous glucose tolerance was tested in hypocalcaemic patients suffering from renal insufficiency. It was shown that the delayed glucose disappearance rate in uraemics could be improved (p < 0.005) by the infusion of calcium gluconolactobionate despite the fact that the serum concentrations of potassium, urea nitrogen, and the blood pH were not altered. The basal insulin concentration was significantly depressed by the calcium infusion (p < 0.02). The serum calcium concentration was significantly correlated to the glucose assimilation coefficient in the uraemic patients (p < 0.01). — 3 hypocalcaemic patients without renal failure had a normal glucose tolerance and a normalization of the serum calcium concentration had no discernable effect. — A slight but significant decrease of the serum calcium concentration (p < 0.01) by EDTA-Na₂ in normocalcaemic patients did not change the intravenous glucose tolerance. — It is concluded that hypocalcaemia may be one of the causes for the abnormal glucose tolerance in chronic renal failure.     

不同甲状腺功能状态下游离脂肪酸与胰岛素抵抗的关系

44例甲状腺功能亢进症(甲亢)、23例甲状腺功能减退症(甲减)和30例甲状腺功能正常人的研究显示,甲亢患者存在胰岛素抵抗,甲亢和甲减患者HOMA-IR与游离三碘甲状腺原氨酸(FT3)和游离甲状腺素(FT4)正相关,甲状腺功能正常者HOMA-IR与游离脂肪酸正相关。     

高龄糖尿病患者血糖与胃排空的相互关系

目的研究高龄糖尿病(DM)患者胃排空与血糖间的关系。方法将63例2型糖尿病(T2DM)患者根据血糖控制情况分成2组(血糖控制正常组DM1和血糖异常组DM2),均给予99mTc标记的试餐,测定固相胃排空时间,并与30例正常对照组比较,对DM2组中胃排空延迟者给予莫沙比利5 mg,3次/d,服药4 w后再测放射性核素胃排空及血糖。结果DM2组胃半排空时间延迟,平均(106.9±29.5)m in,与正常对照组(78.1±19.6)相比,P<0.05,DM1组胃半排空时间(76.5±17.1)m in,与正常对照组相比,P>0.05。DM2组中17例血糖异常胃排空延迟者服用莫沙比利后,胃半排空时间明显改善,平均为(81.3±15.2)m in;服药后空腹血糖无变化,8例餐后血糖降低,4例上升,平均餐后血糖与服药前相比,变化无显著差异。结论高龄DM患者高血糖时可延迟胃排空;改善胃排空后可降低部分病人的餐后血糖,空腹血糖无变化。     

原发性高血压患者肾素-血管紧张素-醛固酮系统活性与空腹血糖水平的关系

目的 探讨原发性高血压患者肾素-血管紧张素-醛固酮系统（RAAS）活性与FPG水平的关系. 方法 选择符合要求的研究对象664例,观察RAAS活性和FPG水平的关系. 结果 将肾素活性（PRA）、ACE、ATⅡ和醛固酮（ALD）水平按四分位数分组后,随着PRA、ACE水平和ATⅡ水平的升高,原发性高血压患者体内FPG水平亦升高,差异有统计学意义（P＜0.05）.相关分析结果显示,PRA（r=0.19,P＜0.05）、ACE（r=0.10,P＜0.05）和ATⅡ （r=0.10,P＜0.05）均与FPG呈正相关.校正其他影响因素后,PRA和ATⅡ水平仍与FPG水平相关. 结论 原发性高血压患者RAAS活性和FPG水平之间存在一定相关性.RAAS活性越高,FPG水平也越高.     

糖代谢与肝性脑病关系的临床观察

目的观察肝硬化患者血糖的改变,探讨糖代谢与肝性脑病（HE）的关系。方法 2008年8月至2010年8月间在嘉定区中心医院消化内科住院的肝硬化患者60人作为肝硬化组,非肝硬化住院患者30人作为对照组。收集一般资料,观察神志,体检有无扑翼样震颤,抽血检测患者血糖,根据患者检查结果,把肝硬化患者分为无扑翼样震颤组和有扑翼样震颤组,对肝硬化组与对照组糖代谢异常发生率进行比较,根据患者血糖情况分为血糖正常组及糖代谢异常组,对两组间扑翼样震颤及HE发生率进行比较。计量资料应用t检验,率的比较应用卡方检验。结果对照组30例,肝硬化组60例中无扑翼样震颤组28例,有扑翼样震颤组32例,对照组糖代谢异常发生率13.33%,肝硬化组糖代谢异常发生率26.67%,肝硬化组患者糖代谢异常发生率高于对照组（χ2=2.058,P〈0.05）。糖代谢正常组扑翼样震颤发生率50.00%,HE发生率34.09%,糖代谢异常组扑翼样震颤发生率62.50%,HE发生率37.50%,两组间差异均无统计学意义（P〉0.05）。结论肝硬化患者存在糖代谢的紊乱,但糖代谢异常不一定易于发生HE,提示存在大脑对糖的利用障碍。     

Nonsuppressability of gluconeogenesis by glucose in septic patients.

The contribution of alanine to the synthesis of glucose and the oxidation of alanine was evaluated in normal and septic patients using (14C)L-alanine. The data indicate that there is a twofold increase in the conversion of alanine into glucose in sepsis and, further, this increase was observed while the patients were receiving a constant glucose infusion (100 mg/min) prior to and during the single injection of (14C)L-alanine. Failure of glucose to decrease this gluconeogenic response in these septic patients clearly indicates that the controlling mechanism for glucose synthesis is modified following injury and undoubtedly plays a role in the abnormal carbohydrate metabolism observed in injury. The contribution of alanine carbon to oxidation was the same in the control and septic group as measured by the per cent of the (14C)L-alanine dose expired in 3 h. Since the control subjects received glucose continuously during the study with and without amino acids, it is clear that nutritional intake and injury has minimal effect on the oxidation of alanine. This suggests that transamination is not affected by sepsis nor is there an inhibition of pyruvate oxidation following sepsis.     

Relationship between endotoxaemia and protein concentration of ascites in cirrhotic patients.

Endotoxaemia was investigated by the Limulus assay in 42 cirrhotic patients with ascites and in 33 without ascites. The incidence of endotoxaemia in the former group (59.5%) was significantly (P less than 0.05) higher than in the latter (36.4%). Correlation between endotoxaemia and specific gravity and concentrations of total protein, albumin, and globulin in ascitic fluid was studied in the group with ascites. The specific gravity of ascites in 25 patients with endotoxaemia was significantly greater than that in 17 patients without endotoxaemia (P less than 0.01). The concentration of total protein in patients with endotoxaemia (13.95 +/- 7.18 milligram, mean +/- SD) was nearly twice as high (P less than 0.01) as in patients without endotoxaemia (7.49 +/- 3.60 milligram). The protein content of those who showed reactions greater or equal to 2(+) in the Limulus assay (16.78 +/- 7.14 milligram) was a significantly (P less than 0.05) higher than in those with 1(+) reaction (11.26 +/- 6.33 milligram). Moreover, the concentration of albumin in patients with endotoxaemia (7.68 +/- 4.60 milligram) was more than twice that of the patients without endotoxaemia (3.39 +/- 1.58 milligram, P less than 0.01). On the other hand, globulin concentration in patients with endotoxaemia was 1.6 times that of patients without endotoxaemia (P less than 0.01). Similar differences were noted between endotoxaemic and non-endotoxaemic patients in the ascites-to-serum ratio in protein, albumin, and globulin. These results suggest that in liver cirrhosis endotoxaemia may cause an increase in protein concentrations in ascitic fluid, and that it may be a precipitating factor in the formation of ascites.     

Relationship between serum resistin concentration and proinflammatory cytokines in obese women with impaired and normal glucose tolerance

The aim of this study was to investigate the possible role of resistin in obese women with and without insulin resistance. We compared serum concentrations of resistin with interleukin 6 (IL-6), tumor necrosis factor alpha (TNF-alpha), soluble TNF receptors 1 and 2, and certain anthropometric and metabolic parameters in 26 obese women (body mass index [BMI], 35.8 +/- 4.12 kg/m2) and 15 healthy control women (BMI, 22.32 +/- 1.89 kg/m2). Fasting serum resistin and inflammatory cytokine levels were measured by enzyme immunoassay. Insulin resistance was measured by the homeostasis model assessment of insulin resistance (HOMA-R) formula. Compared with lean controls, obese women showed higher HOMA-R values and levels of insulin and increased values of TNF-alpha, soluble TNF receptors, and IL-6. There was no significant difference in resistin levels between the investigated groups of obese women and lean subjects. The results showed that serum resistin concentrations did not correlate with BMI, HOMA, fasting plasma glucose level, or fasting plasma insulin level. Serum resistin correlated with fat mass and IL-6 in the group with impaired glucose tolerance (obese group) (r = 0.51, P < .05, and r = 0.37, P < .05, respectively) and with low-density lipoprotein cholesterol (r = -0.39, P < .05) in the same group. The groups we examined are relatively small; it is likely that with a larger number of subjects, the correlation in other obese women groups may achieve statistical significance. It seems that resistin may be linked with inflammation and obesity and, indirectly, with insulin resistance.     

Blood glucose control in patients with severe sepsis and septic shock

The main pathophysiological feature of sepsis is the uncontrollable activation of both pro- and anti-inflammatory responses arising from the overwhelming production of mediators such as pro- and anti-inflammatory cytokines. Such an uncontrollable inflammatory response would cause many kinds of metabolic derangements. One such metabolic derangement is hyperglycemia. Accordingly, control of hyperglycemia in sepsis is considered to be a very effective therapeutic approach. However, despite the initial enthusiasm, recent studies reported that tight glycemic control with intensive insulin therapy failed to show a beneficial effect on mortality of patients with severe sepsis and septic shock. One of the main reasons for this disappointing result is the incidence of harmful hypoglycemia during intensive insulin therapy. Therefore, avoidance of hypoglycemia during intensive insulin therapy may be a key issue in effective tight glycemic control. It is generally accepted that glycemic control aimed at a blood glucose level of 80-100 mg/dL, as initially proposed by van den Berghe, seems to be too tight and that such a level of tight glycemic control puts septic patients at increased risk of hypoglycemia. Therefore, now many researchers suggest less strict glycemic control with a target blood glucose level of 140-180 mg/dL. Also specific targeting of glycemic control in diabetic patients should be considered. Since there is a significant correlation between success rate of glycemic control and the degree of hypercytokinemia in septic patients, some countermeasures to hypercytokinemia may be an important aspect of successful glycemic control. Thus, in future, use of an artificial pancreas to avoid hypoglycemia during insulin therapy, special consideration of septic diabetic patients, and control of hypercytokinemia should be considered for more effective glycemic control in patients with severe sepsis and septic shock.     

2型糖尿病患者血清抵抗素水平与血糖和炎症因子的关系

目的探讨2型糖尿病（DM）患者血清抵抗素水平与血糖及炎症因子的相关性。方法采用酶联免疫分析法检测35例初诊2型DM患者、27例血糖控制良好2型DM患者（HbA1C〈7％）、22例呼吸道感染患者及20名糖耐量正常的健康对照者空腹血清抵抗素、白细胞介素6（IL-6）和肿瘤坏死因子α（TNF-α）水平，同时监测空腹血糖、胰岛素、C反应蛋白（CRP）水平及体重指数（BMI）。结果初诊2型DM组血清抵抗素、胰岛素、各炎症因子及血糖水平均高于健康对照组（均P〈0．01），而血糖控制良好2型DM组抵抗素和IL-6水平与健康对照组差异无统计学意义；感染组抵抗素、各炎症因子水平显著高于其它各组（P〈0．01）。相关分析显示抵抗素水平与性别、BMI和空腹胰岛素等均不相关，但与空腹血糖（r=0．38，P=0．03）及炎症因子IL-6（r=0．31，P=0．02）、TNF—α（r=0．48，P=0．03）、CRP（r=0．70，P=0．01）呈显著正相关，与总胆固醇呈显著负相关（r=-0．19，P=0．04）。结论人类空腹血清抵抗素水平在2型DM患者中明显升高，其与血糖浓度有关，并可能受炎症因子的影响，藉此参与2型DM炎症发病机制，但与肥胖关系不明显。