Peripheral glucose metabolism in human hyperprolactinaemia

OBJECTIVE Prolactin has important biological actions in several species which include metabolic control and waterlelectrolyte balance. However, human PRL has generally been characterized as a mammotrophic hormone and it is unknown whether PRL has any important metabolic actions. This study was thus conducted to evaluate the effect of hyperprolactinaemia on peripheral muscle glucose metabolism. DESIGN The study was designed to determine forearm muscle glucose uptake and utilization (oxidative and non-oxidative metabolism) in normal and hyperprolactinaemic subjects in the post-absorptive state and lor 3 hours after the ingestion of 75 g of glucose. Peripheral glucose metabolism was analysed by the forearm technique to estimate muscle exchange of substrates combined with local indirect calorimetry. PATIENTS Eight hyperprolactinaemic patients (HP group, 6 females and 2 males) and ten normal sublects (N group, 7 females and 3 males) were studied. The hyperprolactinaemic patients showed no clinical or laboratory evidence of acromegaly or hypothyroidism and were not using any PRL releasing drugs. MEASUREMENTS Forearm blood flow was measured by capacitance plethysmography and arterial and venous blood samples were drawn simultaneously to determine plasma glucose, serum FFA, total blood CO₂ and O₂ and serum insulin in the post-absorptive state (0 time) and at 30, 60, 120 and 180 minutes after glucose Ingestion. RESULTS No significant difference in glucose uptake by the forearm muscle tissue was observed between the N and HP groups (823 plusmn; 103 vs 828 ± 110 μmol/100 ml forearm 3h, respectively), nor were any significant differences observed in the intracellular utilization of glucose (oxidative and non-oxidative metabolism). However, the serum insulin levels after glucose ingestion were significantly higher in hyperprolactinaemic patients than in normal subjects, especially at 30 (N 283 ± 46 vs HP 581 ± 133 pmol/l) and 60 minutes (N 291 ± 37 vs HP 544 ± 61 pmol/l). Furthermore, after glucose ingestion the suppression of serum FFA levels was smaller in the hyperprolactinaemic patients than in normal subjects. CONCLUSIONS This study demonstrated that insulin resistance is associated with the presence of spontaneous human hyperprolactinaemia. The hyperinsulinaemia detected in the hyperprolactinaemic patients after the oral glucose stimulus did not determine a proportional Increase in forearm glucose uptake and utilization, which were similar to the normal levels. The suppression of serum free fatty acid concentrations was also smaller in hyperprolactlnaemlc patients during the oral glucose challenge, suggesting an impaired antilipolytic effect of Insulin.     

Peripheral glucose metabolism in acromegaly

The present study was designed to determine the effect of chronic GH excess on forearm muscle glucose uptake and oxidation during the postabsorptive state and after an oral glucose challenge. Nine normal subjects and 10 nondiabetic acromegalic patients (5 of them with normal glucose tolerance) were studied after an overnight fast (12-14 h) and for 3 h after the ingestion of 75 g glucose. Peripheral glucose metabolism was analyzed by the forearm technique to estimate muscle exchange of substrate combined with indirect calorimetry. Decreased forearm glucose uptake was observed in the acromegalic patients compared to that in the normal subjects (380 +/- 84 vs. 709 +/- 56 mumol/100 mL forearm.3 h) with diminished nonoxidative glucose metabolism (262 +/- 81 vs. 572 +/- 53 mumol/100 mL forearm.3 h). The acromegalics with normal glucose tolerance also showed decreased forearm glucose uptake and nonoxidative glucose metabolism compared to normal subjects (271 +/- 124 vs. 709 +/- 56 and 133 +/- 110 vs. 572 +/- 53 mumol/100 mL forearm.3 h, respectively). Muscle glucose oxidation did not differ significantly in normal subjects, the entire group of acromegalic patients, and the acromegalics with normal glucose tolerance (137 +/- 18 vs. 118 +/- 22 vs. 138 +/- 34 mumol/100 mL forearm.3 h, respectively). Serum FFA levels and lipid oxidation rates were similar in the normal subjects and the acromegalic patients, and declined in a similar fashion after glucose ingestion. Insulin levels were significantly higher in acromegalic patients than in normal subjects before and after glucose loading. In conclusion, this study showed that the insulin resistance occurring in the presence of chronic GH excess is accompanied by impaired muscle glucose uptake and nonoxidative glucose metabolism, which are early derangements because they are also observed in acromegalic patients with normal glucose tolerance.     

Bile acid metabolism in human hyperthyroidism

Decreased levels of serum cholesterol are a well-recognized finding in hyperthyroidism. Since the conversion to bile acids is an important pathway for the elimination of cholesterol, we studied primary bile acid kinetics in seven hyperthyroid patients before and after medical treatment. Pool sizes, fractional turnover and synthesis rates of cholic acid and chenodeoxycholic acid were determined after oral administration of 50 mg [13C]cholic acid and 50 mg [13C]chenodeoxycholic acid. 13C/12C isotope ratios in serum were measured by capillary gas chromatography/electron impact mass spectrometry. Compared with the euthyroid state, serum cholesterol levels were distinctly lower in hyperthyroidism (150 +/- 33 vs. 261 +/- 51 mg per dl, p less than 0.01). Thyroid hormone excess caused a 34% reduction in cholic acid synthesis (5.8 +/- 2.8 vs. 7.9 +/- 4.2 mu moles per kg per day, p less than 0.02), which was associated with a 47% decrease in cholic acid pool size (11.7 +/- 3.4 vs. 22.0 +/- 5.2 mu moles per kg, p less than 0.01). Chenodeoxycholic acid kinetics exhibited no apparent changes. Thus, total primary bile acid synthesis was diminished by 20% in hyperthyroidism. After normalization of thyroid function, the ratio of cholic acid/chenodeoxycholic acid pool size increased in all patients. This was paralleled by a rise in the ratio of concentrations of cholic acid/chenodeoxycholic acid in serum. The depression of cholic acid synthesis in the presence of unaltered subjects is compatible with an inhibition of hepatic 12 alpha-hydroxylation by thyroid hormone. Furthermore, evidence is provided that, in man, the low serum cholesterol levels found during hyperthyroidism are not caused by an increased conversion of cholesterol to bile acid.     

Peripheral glucose metabolism is altered by epileptic seizures

The aim of the present study was to investigate the status of jejunal absorption and peripheral metabolism of glucose in Wistar Audiogenic Rats (WAR), a genetic model of epilepsy, after seizures induced by intensive sound exposure. The jejunal loop of rats was isolated and infused (0.5 mL min⁻¹) with Tyrode solution containing twice the normal concentrations of glucose, sodium, and potassium. Samples were taken at 5 or 10-min intervals over a 40-min period. At the end of the experiment, samples of liver and gastrocnemius muscle were taken to measure the levels of glycogen, glucose-6-phosphate, fructose-6-phosphate and glucose transporter-4 (GLUT4). Hepatic glucose-6-phosphate increased in WAR submitted to audiogenic seizure (21.90 ± 3.08) as compared to non-susceptible Wistar rats (8.12 ± 0.87) and to WAR not submitted to audiogenic stimulation (5.17 ± 0.97). In addition, an increase in hepatic fructose-6-phosphate, an intermediate metabolite of the glycolytic pathway, was observed in WAR submitted to audiogenic seizure (5.98 ± 0.99) compared to non-susceptible Wistar rats (2.38 ± 0.53). According to the present results, jejunal absorption of glucose was not changed by seizures. However, generalized tonic–clonic seizures produced by sound stimulation resulted in a decrease in muscle glycogen content. In addition, our results demonstrated that the concentration of GLUT4 in the gastrocnemius muscle of WAR was 1.6-fold higher than that observed in resistant rats and that the audiogenic stimulus led to decreased concentration of this receptor in the muscle of WAR animals.     

甲亢糖代谢紊乱与红细胞胰岛素受体的改变

对未经治疗的Ｇｒａｖｅｓ病人２０例及正常人２０例进行血糖、胰岛素、胰岛素受体检测。Ｇｒａｖｅｓ病人均有不同程度高胰岛素血症（Ｐ＜０．０１）。甲亢ＯＧＴＴ异常组红细胞胰岛素受体的四个参数Ｑ１、Ｋ１、Ｑ２、Ｋ２均减低，后两个参数与正常组比较有显著性差异（Ｐ＜０．０１），且甲亢ＯＧＴＴ异常组餐后２小时血糖与Ｋ２值呈显著负相关（ｒ＝－０．４１９０，Ｐ＜０．０５）。提示甲亢糖代谢异常可能是由于胰岛素受体的结构改变，使胰岛素与ＩＲ的结合位点数减少及亲合力降低而致胰岛素抵抗引起。     

Graves病患者糖代谢紊乱与红细胞胰岛素受体变化的关系

目的　探讨Graves病 (GD)患者糖代谢紊乱的可能机制。方法　应用受体放射分析法测定 33例GD患者治疗前后红细胞胰岛素受体数目及亲和力 ,同时测定糖耐量和胰岛素水平。结果　GD患者治疗前存在高血糖、高胰岛素血症 ,其红细胞胰岛素受体数目显著减少 ,服糖后 12 0min时受体数目与相应时间的血糖成显著负相关。治疗后红细胞胰岛素受体数目与正常对照组无差异 ,糖耐量基本恢复正常。结论　红细胞胰岛素受体数目的减少可能是GD患者糖代谢紊乱的机制之一。当甲状腺功能恢复正常时 ,糖代谢紊乱基本上是可以逆转的。     

Peripheral and hepatic insulin antagonism in hyperthyroidism

Eight hyperthyroid and eight normal subjects underwent 2-h oral glucose tolerance tests (OGTT) and euglycemic clamp studies to assess the presence of peripheral and hepatic insulin antagonism in hyperthyroidism. Although the mean total glucose area during the OGTT was similar in the hyperthyroid patients and normal subjects [16.4 +/- 0.8 (+/- SE) vs. 15.8 +/- 0.7 mmol/L.h], the mean insulin area was significantly elevated in the hyperthyroid group (1413 +/- 136 vs. 1004 +/- 122 pmol/L.h; P less than 0.05). Basal hepatic glucose production was measured during the second hour of a primed [3-3H]glucose infusion. A two-insulin dose euglycemic clamp study with [3-3H]glucose and somatostatin (500 micrograms/h) was carried out during the next 6 h. The insulin infusion rate was 0.05 mU/kg.min during the third, fourth, and fifth hours and 0.60 mU/kg.min during the sixth, seventh, and eighth hours. Hepatic glucose production and glucose utilization were measured during the final 0.5 h of each clamp period. Serum C-peptide concentrations were measured in the initial sample and in the last sample of each clamp period. The mean equilibrium serum insulin concentrations were similar in both groups during the final 0.5 h of the low (90 +/- 8 vs. 79 +/- 6 pmol/L) and high (367 +/- 11 vs. 367 +/- 15 pmol/L) insulin infusion rates. Basal serum C-peptide levels were significantly increased in the hyperthyroid patients (596 +/- 17 vs. 487 +/- 43 pmol/L; P less than 0.05) but were suppressed equally in both groups at the end of both clamp periods. The MCRs of insulin were similar in the hyperthyroid and normal subjects during the low (6.7 +/- 1.1 vs. 5.6 +/- 0.5 mL/kg.min) and high (11.9 +/- 0.4 vs. 12.1 +/- 0.5 mL/kg.mm) insulin infusion rates. Glucose production was significantly increased in the hyperthyroid patients during the basal state (17.6 +/- 0.9 vs. 11.5 +/- 0.5 mumol/kg.min; P less than 0.001) and remained elevated during the final 0.5 h of the low (12.1 +/- 1.1 vs. 5.9 +/- 1.7; P less than 0.01) and high (3.2 +/- 1.2 vs. 0.5 +/- 0.3; P less than 0.05) insulin infusion rates. Peripheral insulin action, assessed by Bergman's sensitivity index, was significantly decreased in the hyperthyroid patients (7.4 +/- 2.2 vs. 15.6 +/- 2.1 L/kg min-1/pmol/L; P less than 0.02). In conclusion, hyperthyroidism is characterized by 1) hyperinsulinemia after oral glucose loading, 2) increased basal hepatic glucose production, 3) impairment of insulin-mediated suppression of hepatic glucose production, and 4) antagonism to insulin-stimulated peripheral glucose utilization.     

探究甲亢与糖代谢功能紊乱及胰岛素抵抗的相关性

摘要：目的：探究甲亢与糖代谢功能紊乱及胰岛素抵抗的相关性。方法：将我院2016年8月～2017年8月收治的70例甲亢患者作为观察组,另选同期70例正常体检者作为对照组,在征得两组受试者知情同意下测定并比较其胰岛素、血糖、甲状腺激素、胰岛素抵抗指数、胰岛素敏感指数,利用Pearson检验对甲状腺激素与糖代谢功能紊乱及胰岛素抵抗相关性进行分析。结果：70例甲亢患者中糖代谢功能紊乱者51例（糖耐量异常36例、糖尿病15例）、糖代谢功能正常者19例;观察组游离甲状三碘原氨酸、游离甲状腺素、空腹血糖、餐后2h血糖、糖化血红蛋白、空腹胰岛素、餐后2h胰岛素、胰岛素抵抗指数高于对照组,促甲状腺激素、胰岛素敏感指数低于对照组,差异有统计学意义（P＜0.05）;Pearson检验结果提示,游离甲状三碘原氨酸与胰岛素抵抗呈正相关（r=0.911,P＜0.05）,游离甲状腺素、促甲状腺激素与胰岛素抵抗无相关性（r=-1.243、-2.210,P＞0.05）。结论：糖代谢功能紊乱为甲亢患者临床常见情形,游离甲状三碘原氨酸与胰岛素抵抗呈正相关性,游离甲状腺素、促甲状腺激素与胰岛素抵抗无相关性。     

Hepatic glucose production and splanchnic glucose exchange in hyperthyroidism

Hepatic glucose production (HGP) and net splanchnic glucose balance (NSGB) were simultaneously determined in the basal state in 8 hyperthyroid patients and 10 normal subjects using iv infusion of [3H]3-glucose and the hepatic venous catheter technique. Splanchnic glucose uptake (SGU) was calculated as the difference between the HGP and NSGB. SGU was also measured by determining the splanchnic extraction ratio of [3H]3-glucose across the splanchnic bed. In 5 hyperthyroid patients and 5 normal subjects a renal vein was also catheterized in the basal state. The influence of increased endogenous insulin secretion [stimulated by a low rate iv infusion of glucose (2 mg/kg . min)] on splanchnic and hepatic glucose exchange was also examined. Basal HGP (measured with [3H]3-glucose) was increased by 20% in the hyperthyroid patients [14.2 +/- 0.6 (SEM) mumol/kg . min] as compared to normal subjects (11.9 +/- 0.6, P less than 0.02). In marked contrast, NSGB output was slightly but not significantly decreased in the hyperthyroid group. SGU in the hyperthyroid patients, as determined with both techniques, was more than 2-fold higher than in the normal group (P less than 0.02-P less than 0.005). Splanchnic uptake of gluconeogenic precursors (lactate, pyruvate, glycerol) was increased by 20-120% in the patient group. During iv infusion of glucose, plasma insulin levels increased more in the hyperthyroid group (66% vs. 37%, P less than 0.05). Nevertheless, HGP and NSGB were less markedly suppressed in the patients as compared to the normal subjects (P less than 0.01), whereas the augmented SGU in the hyperthyroid patients reverted to normal. Splanchnic uptake of gluconeogenic precursors was unchanged in both groups. No net renal glucose production could be demonstrated in either group in the basal state. We conclude that in hyperthyroidism, increased HGP occurs in the face of an unchanged or slightly reduced rate of net glucose delivery to extrasplanchnic tissue. This discrepancy can be ascribed to augmented splanchnic uptake of glucose. These findings raise the possibility of futile cycling of glucose in the liver as a mechanism of increased oxygen consumption in hyperthyroidism. The data also demonstrate a diminished inhibitory effect of endogenous insulin on splanchnic glucose production, suggesting the presence of hepatic resistance to insulin in hyperthyroidism.     

Glutamine and glucose metabolism in human peripheral lymphocytes

The metabolism of glutamine and glucose in resting and concanavalin A-stimulated human peripheral lymphocytes was investigated. Glutamine was metabolized at a high rate by resting and mitogen-stimulated human peripheral lymphocytes and the major end-products of glutamine metabolism were glutamate, aspartate, CO2, and ammonia: the carbon from glutamine may contribute about 21% to respiration. Concanavalin A enhanced the formation of all end-products except glutamate, indicating that more glutamine was metabolized beyond the stage of glutamate in the mitogen-stimulated cells. Mitogenic stimulation caused an increase in the rates of glucose utilization, lactate production and 14CO2 from variously labeled [14C] glucose. Concanavalin A caused an increase in the oxidation of pyruvate as indicated by the enhanced release of 14CO2 from [2-14C]-, [3,4-14C]-, and [6-14C]-glucose. When both glucose and glutamine were presented to the cells, the rates of utilization of both substrates increased and the increased rates of glucose and glutamine utilization could be accounted for mainly by increased rates of lactate and glutamate production, respectively.     

甲状腺功能亢进患者骨代谢变化的研究

目的　进一步探讨甲状腺功能对骨代谢的影响。方法　本文对４４ 例甲状腺功能亢进症（ 甲亢） 患者及４７ 例健康志愿者采用酶联免疫法（ Ｅ Ｌ Ｉ Ｓ Ａ） 测定了尿脱氧吡啶啉（ Ｄ Ｐ Ｄ） ，放射免疫法（ Ｒ Ｉ Ａ） 测定 Ｆ Ｔ３ 、 Ｆ Ｔ４ ，双能 Ｘ 线吸收骨密度仪测定腰椎（ Ｌ２４ ） 、股骨颈（ Ｎｅｃｋ） 、 Ｗａｒｄ’ｓ 三角（ Ｗａｒｄ’ｓ） 、大转子（ Ｔｒｏｃｈ） 部位的骨密度（ Ｂ Ｍ Ｄ） ，以及骨代谢相关指标。结果　尿 Ｄ Ｐ Ｄ 水平为相应年龄对照组的６ 倍（ Ｐ＜ ０ ．００１） ，血清碱性磷酸酶（ Ａ Ｌ Ｐ） 活性为对照组２ 倍（ Ｐ＜ ０ ．００１） ，腰椎及股骨上端 Ｂ Ｍ Ｄ 与对照组同部位比较有不同程度降低，其骨量丢失发生率达５０ ％ 以上，且严重程度及发生率尚随年龄而增加。相关分析还表明，尿 Ｄ Ｐ Ｄ与 Ｆ Ｔ３ 、 Ｆ Ｔ４ 、 Ａ Ｌ Ｐ 之间呈正相关，与骨密度无相关性。结论　甲状腺激素可能直接参与加速骨转换过程，并以增加骨吸收过程为显著，由此导致骨量丢失。     

Peripheral lactate and oxygen metabolism in man: the influence of oral glucose loading

We investigated the influence of oral glucose loading (100 g) on glucose, lactate, and oxygen metabolism by deep (mainly muscle) and superficial (mainly skin and adipose tissue) forearm tissues. In normal men aged 19 to 32 years (mean +/- SE, 24 +/- 1), basal arterialized venous-deep venous (A-DV) and arterialized venous-superficial venous (A-SV) plasma glucose concentration differences were 4.1 +/- 1.0 (P less than 0.001) and 4.7 +/- 1.0 (P less than 0.005) mg/dL, respectively, but increased markedly following glucose loading. During the first, second, and third hours after glucose ingestion, A-DV differences were 54 +/- 6,43 +/- 3, and 20 +/- 4 mg/dL, respectively, while the corresponding A-SV differences were 39 +/- 4, 17 +/- 2, and 8 +/- 2 mg/dL, respectively. Forearm glucose uptake by deep (FGU-D) and superficial (FGU-S) tissues basally was 0.057 +/- 0.010 and 0.012 +/- 0.002 mg/100 mL forearm/min respectively. From 15 to 180 minutes after glucose loading, mean FGU-D and FGU-S rose to 0.524 +/- 0.083 and 0.056 +/- 0.006 mg/100 mL forearm/min, respectively. Basal A, SV, and DV lactate concentrations were 0.55 +/- 0.04, 0.78 +/- 0.03, and 0.57 +/- 0.04 mmol/L, respectively (A-SV, P less than 0.001; SV-DV, P less than 0.001; A-DV, NS). Lactate production by superficial tissues (0.079 +/- 0.015 mumol/100 mL forearm/min) accounted for 62% of concurrent FGU-S.(ABSTRACT TRUNCATED AT 250 WORDS)     

Glucose metabolism in experimental hyperthyroidism: intact in vivo sensitivity to insulin with abnormal binding and increased glucose turnover

The characteristics of the dose response of insulin on the glucose turnover rate and erythrocyte insulin binding parameters were determined in five normal men before and during experimentally induced hyperthyroidism [L-T4 (2 micrograms kg-1 day-1) for 4 weeks with additional L-T3 (1 microgram kg-1 day-1) for the following 3 weeks]. Hyperthyroidism was characterized by significant rises in T3 from 1.92 +/- 0.17 (+/- SEM) to 3.66 +/- 0.17 nmol/liter (P less than 0.01) and resting metabolic rate from 39 +/- 0.7 to 48 +/- 1 watt/m2 (P less than 0.001). While the subjects received a diet adapted to the metabolic rate, blood glucose rose from 3.8 +/- 0.07 to 4.46 +/- 0.11 mmol/liter (P less than 0.05) without a significant change in plasma insulin. During the insulin dose-response study, glucose infusion rates were unaltered by hyperthyroidism, and neither the maximum effect nor the sensitivity to insulin was altered. Glucose turnover rate, measured using [6,6-2H2]glucose as tracer, was determined in the basal state and during the 0.4 mU kg-1 min-1 insulin infusion. In the basal state, it was significantly increased by hyperthyroidism (control, 2.3 +/- 0.1; hyperthyroidism, 3.7 +/- 0.1 mg kg-1 min-1). During the insulin infusion, hepatic glucose production was totally suppressed before T4 and T3 treatment, but was 0.96 +/- 0.39 mg kg-1 min-1 during T4 and T3 treatment. A marked decrease in the insulin binding affinity to erythrocytes was found without a change in the insulin receptor number. In conclusion, glucose metabolism in experimental hyperthyroidism is characterized by 1) increases in basal glucose production and utilization; 2) antagonism between the effect of insulin and hyperthyroidism at the hepatic level; and 3) lack of peripheral insulin resistance in spite of marked alteration in erythrocyte insulin binding affinity.