The essential action of propranolol in hypertension.

The unique action of propranolol and other beta blockers in lowering raised arterial pressure is discussed. Although the onset of the antihypertensive effect is not immediate, many trials have confirmed the efficacy of these drugs. Animal experiments have thrown little light on the mechanism of action of beta blockers in hypertension: this may be because in animals, especially the rat, peripheral beta adrenoceptor vasodilatation is relatively more important than in man. Five principal theories have been advanced to explain the antihypertensive effect. None of these, the renin, central nervous system, cardiac, baroceptor or metabolite theory, is totally satisfactory. A new theory is proposed suggesting that the essential action is to diminish sympathetic nerve output by damping sensory input to the central nervous system from a heart whose capacity to respond to exercise and stress is blunted by beta adrenoceptor blockade.     

Insulin resistance and insulin pulsatility in essential hypertension

OBJECTIVE: Studies in normal humans and in patients with type 2 diabetes mellitus have demonstrated a close inverse relationship between peripheral insulin sensitivity and the frequency of short-term insulin secretory pulses in the systemic circulation. Our objective was to study this relationship in essential hypertension. DESIGN: Study of insulin sensitivity and insulin pulse characteristics in hypertensive subjects and normotensive controls using well-established techniques. METHODS: Twelve subjects with essential hypertension and 12 age- and sex-matched normotensive controls were recruited. Insulin action was measured using the glucose clamp technique combined with isotope dilution methodology. Insulin pulsatility in the peripheral circulation was assessed by sampling every 2 min for 90 min after an overnight fast Pulses were identified using the computer program Pulsar. RESULTS: Insulin sensitivity index (glucose infusion rate/ serum insulin) was lower in the hypertensive patients (P= 0.01) and fasting insulin was increased (P= 0.008) compared to controls. The frequency and amplitude of insulin pulses were similar in the two groups. Insulin pulse frequency and insulin sensitivity were inversely related in the normotensive group (r= -0.68, P= 0.015), but not in the hypertensive group (r= -0.23, P= 0.48). Insulin clearance was reduced in the hypertensive group (P= 0.03), and was inversely related to insulin pulse frequency in the two groups combined (r = -0.51, P= 0.01). CONCLUSIONS: Insulin action was not related to insulin pulse frequency in essential hypertension, in contrast to the situation in normal man.     

高血压病患者胰岛素抵抗及其关联因素

目的 :探讨高血压患者同时存在多种代谢异常时胰岛素的敏感性。方法 :高血压组 79例 ,健康对照组 78例 ,分别进行口服葡萄糖耐量试验 （OGTT）、同步血清胰岛素释放试验 ,血清总胆固醇 （TC）、甘油三酯 （TG）、低密度脂蛋白胆固醇 （L DL- C）、高密度脂蛋白胆固醇 （HDL- C）及体质量指数 （BMI）测定 ,以胰岛素敏感性指数 （ISI）和胰岛素曲线下面积 （IS- AU C）作为胰岛素敏感性的判定指标。结果 :高血压组空腹胰岛素 （FINS）及餐后 2 h胰岛素 （15± 7及 70± 10 m U/L）均显著高于正常对照组 （8± 3及 9± 4 m U/L） ,均为 P<0 .0 1;OGTT显示葡萄糖耐量降低 ,P<0 .0 1。 TC、TG、L DL- C显著升高 ,均 P<0 .0 1,HDL- C升高 ,P<0 .0 5 ;ISI（绝对值 ）和 IS- AUC均显著增高 ,分别为 P<0 .0 5与 P<0 .0 1。二组 BMI与 ISI呈显著负相关 ,r分别为 - 0 .4 9,- 0 .37,P<0 .0 5 ;与 FINS呈显著正相关 ,r分别为 0 .5 3,0 .38,P<0 .0 1。结论 :高血压患者存在着高胰岛素血症 ,同时存在着糖代谢及脂蛋白代谢异常。血糖、血脂、体质量指数均影响胰岛素敏感性。     

老年高血压病患者胰岛素抵抗及药物干预的观察

观察了１６例老年高血压病（ＥＨ）患者及１０例健康老年人口服葡萄糖耐量试验（ＯＧＴＴ）的血糖、胰岛素和Ｃ－肽浓度变化。结果显示，ＥＨ组空腹及ＯＧＴＴ后胰岛素、Ｃ－肽及胰岛素／血糖比值明显高于对照组，Ｃ－肽／胰岛素比值明显降低，糖耐量明显下降。老年ＥＨ组经伊拉地平治疗６周后，空腹及ＯＧＴＴ后胰岛素，Ｃ－肽和胰岛素／血糖比值较治疗前上明显下降，Ｃ－肽／胰岛素比值升高，糖耐量改善，但仍未完全恢复正常。提示老年ＥＨ患者存在胰岛素抵抗（ＩＲ），伊拉地平能在一定程度上改善ＥＨ患者的ＩＲ。     

Insulin hypersecretion: a distinctive feature between essential and secondary hypertension.

Several studies have demonstrated that patients with hypertension have greater plasma insulin levels than normotensive subjects. The aim of the present study was to clarify if hyperinsulinemia in hypertension is a consequence of either increased pancreatic secretion or decreased hepatic clearance, and to determine whether abnormalities of glucose metabolism are equally present in essential and secondary hypertension. In an observational cross-sectional study, fasting blood glucose, plasma insulin, and plasma C-peptide levels were measured in five patient groups: 34 lean normotensive, 19 overweight normotensive, 25 lean essential hypertensive, 27 overweight essential hypertensive, and 20 secondary hypertensive subjects. The blood glucose/plasma insulin and plasma insulin/plasma C-peptide ratios were calculated as indexes of insulin sensitivity and hepatic insulin clearance, respectively. Subjects with essential hypertension and, to a greater extent, those who were overweight, exhibited significantly higher fasting insulin and C-peptide levels and significantly lower glucose/insulin ratios as compared with lean normotensive subjects. In contrast, no differences were observed between secondary hypertensive and control subjects. Mean blood pressure was significantly and independently correlated to body mass index, plasma insulin and plasma C-peptide levels, and the glucose/insulin ratio. In lean essential hypertensive and secondary hypertensive subjects, the insulin/C-peptide ratios were comparable to controls, indicating normal hepatic insulin clearance. In both overweight groups, a trend to increased insulin/C-peptide ratios was observed. This study shows that in essential hypertensive subjects, hyperinsulinemia is caused by insulin hypersecretion, whereas in overweight subjects, both increased insulin secretion and decreased hepatic insulin clearance might be involved.(ABSTRACT TRUNCATED AT 250 WORDS)     

胰岛素样生长因子1与原发性高血压

目的:探讨原发性高血压病的发病机制。方法:对28例原发性高血压患者和16名正常人测定了血清胰岛素样生长因子1(IGF1),并与高血压分级进行了相关分析。结果:原发性高血压患者IGF1水平显著低于正常人(分别为26.22μg/L±20.23μg/L和48.02μg/L±33.43μ/L,P<0.05),且IGF1水平与临床分级呈负相关(=-0.437,P<0.05)。 结论:IGF1可能参与了原发性高血压的病理生理过程。     

Insulin secretion and action in different stages of glucose tolerance in Asian Indians.

AIMS: To evaluate the sequence of changes in insulin secretion and action in different stages of glucose tolerance and the effect of obesity on insulin profile in South Indian adults. Blood samples from 260 consecutive cases with no known history of diabetes were collected. Plasma insulin levels were measured during a 75-g oral glucose tolerance test. Insulin resistance (IR) was calculated, using the homeostasis model assessment (HOMA). An index of insulin secretion was derived as the ratio of incremental insulin at 30 min divided by 30 minute plasma glucose (delta I/G). RESULTS: Normoglycaemia was present in 164, impaired glucose tolerance (IGT) in 60 and diabetes in 36 subjects. Fasting and 2 h insulin secretion showed bell shaped curves with increasing plasma glucose. The peak values corresponded to the cut-off values used for the diagnosis of clinical diabetes. IR was higher in obese than in nonobese, nondiabetic subjects but the effect of obesity on IR was not found in subjects with diabetes. IGT was associated with higher IR, but not with evidence of a beta-cell defect. CONCLUSIONS: Evaluation of insulin resistance and beta-cell function in different stages of glucose tolerance indicate that insulin resistance is manifested in the early stage of glucose intolerance in South Indians, i.e. IGT. A beta-cell defect was mostly found in people with diabetes. The beta-cell defect is more common in diabetes among the nonobese.     

游离脂肪酸增高对肝糖产生、葡萄糖循环和总葡萄糖输出率的影响

目的 探讨FFA增加肝脏葡萄糖生成和肝脏胰岛素抵抗(IR)的作用位点. 方法分别给清醒大鼠输注24h脂肪乳+肝素和盐水,在输注的最后2h行高胰岛素正葡萄糖钳夹试验,测定肝脏葡萄糖生成率(HGP)、总葡萄糖输出率(TGO)和葡萄糖循环(GC). 结果 脂肪乳使血浆FFA升高3倍.在基础状态,脂肪乳使HGP和TGO增高(P<0.01).在钳夹状态,脂肪乳降低了胰岛素(Ins)增加GC的作用(P<0.01),并使Ins抑制HGP和TGO的作用下降(P<0.01). 结论 FFA能使Ins增加GC和抑制HGP与TGO的作用下降,说明FFA在不同位点诱导了肝脏IR.     

1193例住院高血压病患者胰岛素分泌和敏感性情况

目的用口服葡萄糖耐量试验中各点血糖和胰岛素的值来计算反映胰岛素敏感性及β细胞功能的参数,回顾性研究住院高血压病人糖代谢情况。方法根据WHO和美国糖尿病协会标准计算血糖分布情况,去除新诊断的糖尿病病人后,分成正常血糖(NGT)、单纯性空腹血糖升高(IFG)、单纯性餐后血糖升高(IGT)和空腹、餐后血糖均升高(IFG,／IGT)组进行比较。再分别以口服75g葡萄糖后30min或60min血糖正常值为标准对NGT组和IGT组进行分组。用HOMA-IR和Composite胰岛素敏感性指数(ISI)计算胰岛素敏感性,HOMA-B和△I／AG计算β细胞功能。结果1193例住院的原发性高血压病人中,新诊断的糖尿病病人为11．1％,其中57．9％仅有餐后血糖升高。IGT、和IFG／ICT组的HOMA-IR高于NGT组,Composite ISI和AI／AG低于NGT组。无论是否30min或60min血糖升高,IGT组的Composite ISI均低于30min和60min血糖正常的NGT组。30min和(或)60min血糖升高的NGT组△I／AG低于30min和60min血糖正常的NGT组。结论IGT或IFG／IGT的高血压患者同时存在空腹和总体胰岛素敏感性的下降和糖负荷后早期β细胞分泌功能的受损。30min和(或)60min血糖升高的NGT高血压病人存在糖负荷后早期β细胞分泌功能的受损。     

Insulin binding to erythrocyte receptors in patients with essential hypertension

Recently many researchers have described the presence of insulin resistance and hyperinsulinemia in a substantial number of patients with essential hypertension. Reduced insulin binding to the receptors may play important role in development of insulin resistance in these patients. The study was aimed to assess the value of insulin binding to erythrocyte receptors in the patients with essential hypertension and compare to values in healthy persons. Additional purpose was the evaluation of insulin degradation by erythrocytes in patients with essential hypertension. 23 patients with essential hypertension (BMI 22.7 +/- 3.2) and 21 healthy persons (with BMI value 23.3 +/- 2.9) were studied. In all examined individuals the blood glucose and blood insulin concentrations were determined, insulin binding to erythrocyte receptors and insulin degradation by erythrocytes were measured by the method of Gambhir and al. Insulin concentration was significantly higher in patients with essential hypertension than in healthy subjects. We demonstrated a statistically significant positive correlation between body weight and insulin concentration in blood serum only in healthy people. Insulin binding to the receptors of red blood cells was significantly stronger (p < 0.001) in healthy persons than in patients with essential hypertension (0.972 +/- 0.395 pg 10(11) RBC and 0.446 +/- 0.14 pg 10(11) RBC respectively). In patients with hypertension insulin binding to receptors of red blood cells does not depend on body weight and insulin concentration in blood serum. Values of insulin degradation by erythrocyte in patients with essential hypertension and healthy persons were not significantly different. It seems that decreased insulin binding to insulin receptors is an important mechanism of insulin resistance patients with essential hypertension.     

Insulin resistance and upper-normal glucose levels in hypertension: a review

Reduced insulin-mediated glucose disposal, indicative of insulin resistance, has been demonstrated in lean male hypertensives both with the hyperinsulinaemic euglycaemic clamp and the insulin suppression test. In lean hypertensives, insulin resistance was not accompanied by increases in fasting plasma insulin and glucose levels; but with modest hyperglycaemia and hyperinsulinaemia after a glucose load. Population studies (no stratification) reveal that: (1) insulin sensitivities vary widely in normotensives and hypertensives, (2) there are hypertensives and normotensives with similar degrees of insulin resistance, (3) not all hypertensives are insulin resistant, and (4) insulin resistance does not contribute to the blood pressure level of the hypertensive population. In large cross-sectional studies, the clustering of obesity, dyslipidaemia and type 2 diabetes is largely responsible for the observed associations between insulin or insulin resistance and hypertension. Recent studies indicate a role of glucose in blood pressure control. Glucose has been shown to elevate blood pressure in the presence of endothelial dysfunction and glucose values in the upper-normal range have been shown to be associated with increased cardiovascular mortality. Since endothelial dysfunction is present in hypertensives, dyslipidaemic, obese and in glucose intolerant individuals, lowering of high-normal glucose levels becomes a new, additional therapeutic target in the management of these patients. Hyperglycaemia together with endothelial dysfunction may account for the increased incidence of hypertension in obesity and diabetes mellitus. Because of the strong association between insulin resistance, hyperglycaemia and endothelial dysfunction, and the clustering of risk factors in these subjects, we propose the lowering of high normal glucose levels as part of the therapeutic strategy to prevent cardiovascular and metabolic disease.     

Dietary patterns and 1-h post-load glucose in essential hypertension

Background and aimsNormoglucosetolerants (NGT) are considered at low risk, even if a 1-h post-load glucose (PLG) value ≥ 155 mg dl⁻¹ identifies NGTs at high risk of type-2 diabetes (T2D) and sub-clinical organ damage. Specific dietary factors may affect insulin sensitivity and the risk of T2D. However, it is unknown whether dietary components affect 1-h PLG in hypertensive NGT. Therefore, we investigate the effect of dietary patterns on 1-h PLG.Methods and resultsWe selected 188 subjects (94 NGTs < 155 mg dl⁻¹ and 94 NGTs ≥ 155 mg dl⁻¹ PLG), well matched for age, gender and body mass index (BMI). Insulin sensitivity was evaluated using the Matsuda index. Dietary intake was quantified by a semiquantitative food frequency questionnaire (FEQ) validated in the European Investigation into Cancer and Nutrition (EPIC) study. The NGT ≥ 155 group had significantly reduced insulin sensitivity (40.3 ± 19.8 vs. 73.3 ± 28.8; P < 0.0001). With the exclusion of total calories, lipids, alcohol and fiber consumption we observed a significant difference, between groups, in starch (214.1 ± 52.4 vs. 268.8 ± 71.8 g; P < 0.0001), saturated (27.4 ± 8.7 vs. 24.1 ± 8.5 g; P = 0.009), monounsaturated (45.5 ± 8.9 vs. 48.8 ± 10.7 g; P = 0.023) and polyunsaturated fatty acids (FAs) (14.5 ± 4.0 vs. 16.8 ± 4.7 g; P < 0.0001), fructose (14.5 ± 5.3 vs. 11.2 ± 4.8 g; P < 0.0001), and oligosaccharides (103.2 ± 26.6 vs. 89.9 ± 29.2 g; P = 0.001) consumption. In the whole population, starch was the major predictor of 1-h PLG, explaining 23.2% of variation (P < 0.0001). In the NGT < 155 group, fructose was the strongest predictor, accounting for 15.4% of the variation; BMI, gender and polyunsaturated FAs added another 6.6%, 3.6% and 3.2%, respectively. In the NGT ≥ 155 group, saturated and polyunsaturated FAs were retained as the major predictors of 1-h PLG, explaining 18.2% and 11.4% of the variation.ConclusionsThe present data demonstrate that dietary patterns affect 1-h PLG, remarking the importance of both quantitative and qualitative composition of a diet.     

Serum resistin level in essential hypertension patients with different glucose tolerance.

AIMS: To investigate resistin concentrations in patients with essential hypertension and different glucose tolerance and the relationship between serum resistin level and blood glucose. METHODS: Sixty-five patients with essential hypertension [13 with Type 2 diabetes mellitus (DM), 26 with impaired glucose tolerance (IGT), and 26 with normal glucose tolerance (NGT); 30 males, 35 females] were studied. Fasting serum resistin concentrations were measured by enzyme immunoassay (EIA). Oral glucose tolerance tests and insulin release tests were used to calculate glucose area under the curve (AUCG), the ratio of insulin to glucose (DeltaI30/DeltaG30), and insulin sensitivity index (ISI) according to Cederholm's formula. RESULTS: Fasting serum resistin concentrations (microg/l) in DM (34.9 +/- 10.2) patients were significantly higher than those in IGT (25.1 +/- 10.4) (P < 0.05) and in NGT (21.5 +/- 7.9) (P < 0.05) patients. Pearson correlation showed that fasting serum resistin concentration was correlated with AUCG (r = 0.445, P < 0.001), ISI (r = -0.322, P < 0.01) and DeltaI30/DeltaG30 (r = -0.366, P < 0.01), but not body mass index and waist-hip ratio. After adjustment for gender, age and body mass index (BMI), partial correlation analysis showed that the fasting serum resistin concentrations were still correlated with AUCG (r = 0.327, P < 0.01) and DeltaI30/DeltaG30 (r = -0.348, P < 0.01), but ISI. CONCLUSION: Resistin may be involved in the development of diabetes in humans.     

Insulin and glucose suppress hepatic glycogenolysis by distinct enzymatic mechanisms

Both insulin and hyperglycemia can effectively suppress hepatic glucose output (HGO). We examined whether insulin and hyperglycemia specifically suppress liver net glycogen breakdown in a rat model in which glycogen is the major source of HGO. We further examined whether insulin and hyperglycemia act by similar or distinct enzymatic mechanisms. HGO, the rate of net glycogen loss, and glycogen phosphorylase and synthase activities were measured in fed, anesthetized rats infused with saline or insulin (7 mU/min/kg) while either maintaining plasma glucose at basal (7.8 ± 0.2 mmol/L, euglycemic clamp [EC]) or at 10 mmol/L above basal (18 ± 0.4 mmol/L, hyperglycemic clamp [HC]). During the basal period, the rate of HGO in each group was comparable to the rate of net glycogen breakdown, averaging 76 ± 9 and 75 ± 5 μmol/min/kg, respectively. Thus glycogen breakdown appeared to be a major source of ongoing HGO. Over the last 60 minutes of the experimental period, the rate of glycogenolysis averaged 69 ± 8 μmol/min/kg in saline-treated rats; this could account for about 80% of the total HGO. During both EC and HC studies, HGO was suppressed (5.5 ± 3 and −3.6 ± 10 μmol/min/kg, respectively; P < .001 for each). Net glycogen breakdown decreased by 50% in EC rats (P < .05) and ceased in HC rats (P < .001). Glycogen synthase was predominantly in the active form in all three experimental groups (87% ± 2%, 89% ± 2%, and 95% ± 3% in saline, EC, and HC rats, respectively). The fraction of glycogen phosphorylase in the active form was similar in saline (41% ± 2%) and EC (40% ± 2%) rats, but lower (23% ± 5%, P < .03) in HC rats. In summary, insulin fully suppresses HGO and partially inhibits net glycogenolysis in vivo without affecting the phosphorylation state of glycogen phosphorylase. Addition of hyperglycemia enhances phosphorylase a to b conversion and fully suppresses net glycogenolysis. Glucose produced by residual glycogenolysis during EC does not reach the systemic circulation and must be disposed of glycolytically in liver.     

Tumor necrosis factor impairs insulin action on peripheral glucose disposal and hepatic glucose output.

The present study examined whether a prolonged infusion of tumor necrosis factor (TNF) into rats could sustain the increased rate of whole body glucose metabolism observed with short term exposure, and whether TNF produced hepatic or peripheral insulin resistance. Basal glucose metabolism was determined with the use of [3-3H]glucose 18 h after initiating a constant infusion of recombinant human TNF (1 microgram/kg.h). Thereafter, a two-step euglycemic hyperinsulinemic clamp was performed to determine whether TNF impaired insulin action. The overnight infusion of TNF minimally elevated plasma glucose concentrations (17%), but produced large increases in the whole body rate of glucose production and utilization (133%). Under hyperinsulinemic conditions, the glucose infusion rate necessary to maintain euglycemia was 30% lower in TNF-treated rats, indicating an insulin-resistant condition. This resulted from an impaired ability of insulin to both suppress hepatic glucose production and stimulate peripheral glucose utilization in TNF-infused animals. A second series of experiments was performed, using the in vivo tracer [U-14C]2-deoxyglucose technique, to elucidate which tissues were responsible for the TNF-induced increase in basal (no exogenous insulin) glucose disposal and peripheral insulin resistance. Under basal conditions, TNF increased glucose uptake by various muscles (gastrocnemius, heart, and diaphragm) as well as nonmuscle tissues (liver, lung, spleen, gut, skin and fat). Because of their relatively large mass and/or high rate of glucose uptake, the increased uptake by skin (25%), intestine (24%), muscle (23%), and liver (15%) accounted for the majority of the TNF-induced increment in whole body glucose disposal. Under euglycemic hyperinsulinemic conditions, the increment in glucose uptake by muscle and skin (85%) accounted for the majority of the glucose disposal in control rats. However, in TNF-infused animals, hyperinsulinemia failed to increase glucose uptake by skin and blunted the insulin-mediated increase in muscle by 73%. These results suggest that sustained elevations of TNF during chronic therapy and prolonged production of TNF by patients and experimental animals with malignancies or infectious diseases may be an important mechanism for the enhanced glucose flux as well as the insulin resistance seen in these conditions.     

Insulin action and secretion in hypertension in the absence of metabolic syndrome: model-based assessment from oral glucose tolerance test

Relationship between insulin action and secretion was analyzed in 10 hypertensive patients (H group; 5 male, 5 female; 56.9 ± 2.5 years) compared with 10 normotensive subjects (N group; 5 male, 5 female; 51.7 ± 3.7 years; P > .05) matched for age, sex, and body mass index. All participants (normoglycemic, nonobese, and not affected by metabolic syndrome) underwent a 5-hour, 22-sample, oral (75 g) glucose tolerance test. Insulin sensitivity was quantified by quantitative insulin sensitivity check index and an insulin sensitivity index computed by minimal-model-based “integral equation.” β-Cell responsivity indexes (dynamic, Φ_d; static, Φ_s; and global, Φ_oral) were estimated by C-peptide oral minimal model. Compared with the N group, our H group featured no significant difference (P > .05) in fasting glycemia, significant (P < .02) increase in plasma insulin (93%) and C-peptide (53%) concentrations, and significant (P < .01) reduction in both quantitative insulin sensitivity check index (10%) and insulin sensitivity index (68%). No significant variations of mean Φ_d, Φ_s, and Φ_oral were observed across the 2 groups in response to glucose challenge. Thus, insulin sensitivity deterioration in hypertension was not mirrored by a reciprocal change in β-cell responsivity. Nevertheless, our H group featured a 143% (P < .005) increase in the area under the curve of circulating insulin and a 34% (P < .01) reduction in the ratio between the area under C-peptide curve and the area under the curve of circulating insulin. These results support the hypothesis that decreased insulin clearance in hypertensive patients, not affected by metabolic syndrome, is a further regulatory mechanism, in addition to increased insulin secretion, to compensate for insulin resistance.     

Insulin resistance and hypertension.

Insulin resistance, a common accompaniment of essential hypertension, increases cardiovascular risk both directly, and via its adverse effect on other cardiovascular risk factors. Decreasing insulin resistance by lifestyle modification including diet, weight loss, and physical exercise is an important component of therapy in all patients. With the exception of thiazide diuretics as monotherapy, the currently utilized classes of agent appear equally effective in lowering blood pressure in insulin resistant patients. Currently utilized agents do, however, differ substantially in their effect on insulin resistance and associated risk factors. Agents that diminish insulin resistance may have a rationale in treating insulin resistant patients with hypertension although a decisive recommendation about class of agent in this group of patients must await several prospective large scale trials currently underway. Lower intervention thresholds and lower therapeutic goals would appear to apply to hypertensive patients with insulin resistance especially in the presence of impaired glucose tolerance or overt diabetes mellitus.     

Changes in hepatic glycogen cycling during a glucose load in healthy humans

Aims/hypothesis Glycogen cycling, i.e. simultaneous glycogen synthesis and glycogenolysis, affects estimates of glucose fluxes using tracer techniques and may contribute to hyperglycaemia in diabetic conditions. This study presents a new method for quantifying hepatic glycogen cycling in the fed state. Glycogen is synthesised from glucose by the direct and indirect (gluconeogenic) pathways. Since glycogen is also synthesised from glycogen, i.e. glycogen→glucose 1-phosphate→glycogen, that synthesised through the direct and indirect pathways does not account for 100% of glycogen synthesis. The percentage contribution of glycogen cycling to glycogen synthesis then equals the difference between the sum of the percentage contributions of the direct and indirect pathways and 100. Materials and methods The indirect and direct pathways were measured independently in nine healthy volunteers who had fasted overnight. They ingested ²H₂O (5 ml/kg body water) and were infused with [5-³H]glucose and acetaminophen (paracetamol; 1 g) during hyperglycaemic clamps (7.8 mmol/l) lasting 8 h. The percentage contribution of the indirect pathway was calculated from the ratio of ²H enrichments at carbon 5 to that at carbon 2, and the contribution of the direct pathway was determined from the ³H-specific activity, relative to plasma glucose, of the urinary glucuronide excreted between 2 and 4, 4 and 6, and 6 and 8 h. Results Glucose infusion rates increased (p<0.01) to ∼50 μmol kg⁻¹ min⁻¹. Plasma insulin and the insulin : glucagon ratio rose ∼3.6- and ∼8.3-fold (p<0.001), respectively. From the difference between 100% and the sum of the direct (2–4 h, 54±6%; 4–6 h, 59±5%; 6–8 h, 63±4%) and indirect (32±3, 38±4, 36±3%) pathways, glycogen cycling was seen to be decreased (p<0.05) from 14±4% (2–4 h) to 4±3% (4–6 h) and 1±3% (6–8 h). Conclusions/interpretation This method allows measurement of hepatic glycogen cycling in the fed state and demonstrates that glycogen cycling occurs most in the early hours after glucose loading subsequent to a fast.