Role of insulin receptor in the regulation of glucose uptake in neonatal hepatocytes

The liver plays a major role in the regulation of glucose homoeostasis. Evidence from liver-specific insulin receptor knockout mice (LIRKO) suggested that insulin's direct and indirect effects on glucose utilization by the liver both require the presence of hepatic insulin receptors (IR). To address this issue, we have generated immortalized neonatal hepatocytes bearing (HIR LoxP) or not (HIR KO) IR. The lack of IR significantly decreased basal glucose uptake in neonatal hepatocytes from 3- to 14-d-old mice, and the expression of glucose transporter 1 (GLUT1), GLUT2, and glucokinase (GK) remained unchanged throughout development. HIR KO reconstituted hepatocytes with IRA but not with IRB isoform and restored basal glucose uptake up to the levels observed in HIR LoxP cells. However, both IR isoforms associated with GLUT1 or GLUT2. Overexpression of IGF-I receptor (IGF-IR) increased basal glucose uptake in neonatal hepatocytes lacking or not IR. This effect was also accompanied by its association with GLUT1 or GLUT2. Exogenous expression of GLUT4 had no effect on basal glucose uptake in neonatal hepatocytes. However, HIR LoxP hepatocytes expressing exogenous GLUT4 increased glucose uptake in the presence of insulin without showing association between GLUT4 and IR. Our data clearly indicate that IR plays a direct role in the regulation of basal glucose uptake/transport by the hepatocytes, and either type A IR or IGF-IR works on glucose uptake as a GLUT1- or GLUT2-associated cotransporter. Thus, IR mediates glucose uptake through its specific association with endogenous, but not with exogenous, glucose transporters in neonatal hepatocytes.     

Role of substance P in the regulation of glucose metabolism via insulin signaling-associated pathways

Substance P (SP), encoded by the tachykinin 1 (Tac1) gene, is the most potent tachykinin ligand for the high-affinity neurokinin-1 receptor (NK-1R). We previously reported that NK-1R-deficient mice show less weight gain and reduced circulating levels of leptin and insulin in response to a high-fat diet (HFD) and demonstrated the presence of functional NK-1R in isolated human preadipocytes. Here we assessed the effects of SP on weight gain in response to HFD and determined glucose metabolism in Tac1-deficient (Tac1(-/-)) mice. The effect of SP on the expression of molecules that may predispose to reduced glucose uptake was also determined in isolated human mesenteric, omental, and sc preadipocytes. We show that although weight accumulation in response to HFD was similar between Tac1(-/-) mice and wild-type littermates, Tac1(-/-) mice demonstrated lower glucose and leptin and increased adiponectin blood levels and showed improved responses to insulin challenge after HFD. SP stimulated phosphorylation of c-Jun N-terminal kinase, protein kinase C, mammalian target of rapamycin, and inhibitory serine insulin receptor substrate-1 phosphorylation in human preadipocytes in vitro. Preincubation of human mesenteric preadipocytes with the protein kinase C pseudosubstrate inhibitor reduced insulin receptor substrate 1 phosphorylation in response to SP. Lastly, SP also induced insulin receptor substrate-1 phosphorylation in mature human sc adipocytes. Our results demonstrate an important role for SP in adipose tissue responses and obesity-associated pathologies. These novel SP effects on molecules that enhance insulin resistance at the adipocyte level may reflect an important role for this peptide in the pathophysiology of type 2 diabetes.     

Role of glucose reabsorption from bile on hyperglycaemia-induced cholestasis in the rabbit

The effect of glucose administration on bile secretion of glucose and bile flow and composition was studied in the rabbit. After intravenous glucose infusion at 83 mumol/kg/min a mean bile concentration of 12.7 +/- 1.8 mg/dl was reached. Intraportal administration of phlorizin enhanced bile glucose concentration to 169.6 +/- 18.1 mg/dl, suggesting the presence of a system for transferring glucose from bile to liver in the biliary tree of the rabbit. A significant correlation between bile flow and plasma glucose levels could be demonstrated. A cholestatic effect appeared in glucose-infused rabbits with a decrease in bile flow by about 40% during the second hour of infusion. Both bile acid and inorganic electrolyte output were significantly lowered. Cholestasis was maintained after phlorizin administration. Possible explanations for this effect are discussed.     

Role of glucose and insulin in the dynamic regulation of glucagon release by the perfused rat pancreas

The effect of glucose upon the release of glucagon and insulin from the perfused rat pancreas in vitro was studied by varying both the concentration of glucose (from 3.3 to 4.6, 8.5, or 11.1 mmol/l) and the time of exposure to an elevated concentration of the sugar (5, 10 or 23 min). The results suggest that the amount of insulin released during the early period of stimulation could contribute to both the speed and extent of the inhibition in glucagon release. The rate of recovery from inhibition in the A cell, however, appeared to be independent of insulin and was related, in a dose-dependent and time-dependent manner, only to the glucose stimulus. It is suggested that a direct effect of glucose upon the A cell is involved in the physiological regulation of glucagon secretion. An indirect effect of glucose, as mediated via insulin release, may contribute to the rapidity and magnitude of inhibition in A cell secretory activity.     

Hypouricemia by defect in the tubular reabsorption.

Two patients with hypouricemia with high levels of uric acid in their urine were given pyrazinamide and probenecid. The uric acid clearance decreased to low or normal values after pyrazinamide administration. In both cases, probenecid produced a slight increment in the uric acid excretion. This type of response suggests a defect in the reabsorption component. It is tempting to speculate on a postsecretory reabsorption defect based on the results of pyrazinamide and probenecid tests.     

Enhanced tubular reabsorption of phosphate.

Individual kidney functions were studied during water diuresis in eight patients, following the relief of unilateral ureteral obstruction. Fractional excretion of phosphate was diminished in four of the patients, presumably due to enhanced tubular reabsorption of phosphate in the diseased side. Glomerular underperfusion may be the main factor responsible for the hypophosphaturia in the postobstructive kidney. Fractional excretion of sodium and water was increased in the obstructed side in six of the eight patients. In two of the four patients with hypophosphaturia, there was enhanced fractional sodium excretion, suggesting a dissociation of renal handling of sodium and phosphate in some patients with this condition.     

Dysfunction of tubular phosphate reabsorption related to glomerular filtration and blood glucose control in diabetic children

Summary The renal handling of inorganic phosphate was studied by measuring the urinary excretion rate of phosphate ( ), phosphate-(Cr⁵¹) EDTA clearance ratio ( ) and maximal tubular reabsorption of phosphate per litre glomerular filtrate ( ) during fasting in 26 ambulatory Type 1 (insulin-dependent) diabetic children without clinical signs of microangiopathy (age: 7–14 years; duration of disease: 3–14 years). Similar measurements were made in 28 healthy schoolchildren (age: 8–14 years). and were significantly enhanced in the diabetic children (p<0.001) and correlated with the degree of hyperglycaemia (p<0.005). was significantly suppressed in the diabetic children (1.23 versus 1.73 mmol/1, p<0.001). This disturbance was neither related to changes in serum parathyroid hormone nor to growth hormone concentrations but was inversely correlated with the degree of hyperglycaemia (r=-0.61, p<0.001) and with tubular reabsorption of glucose in the diabetic subjects, the mean maximal ( ) and absolute tubular phosphate reabsorption rates were equal to those of the 28 healthy subjects. Both in the diabetic and healthy subjects, these parameters were positively correlated with glomerular filtration rate which was significantly elevated in the diabetic children (138 versus 109 ml/min per 1.73 m², p<0.01). The study demonstrates a dysfunction in tubular phosphate reabsorption in diabetic children which is related to glycaemic regulation.     

下丘脑对血糖的调节

下丘脑腹内侧核(VMH)中存在的血糖感受神经元参与全身血糖稳定状态的调节。其中分为两种不同功能的血糖感受神经元:葡萄糖兴奋神经元——当细胞外周环境中葡萄糖浓度升高时能降低其代谢率;葡萄糖抑制神经元——当外周葡萄糖浓度升高时能提高其代谢率。除VMH外,脑中还有更高级的血糖调节中枢,能和VMH部位通过促肾上腺皮质激素释放因子(CRF)、尿皮质醇及促肾上腺皮质激素释放因子受体(CRFRs)相互作用。1型糖尿病患者对低血糖的负调节反应(CRRs)存在缺陷,导致在胰岛素治疗的过程中发生低血糖事件。研究VMH部位对血糖调节的机制能为其治疗提供新的线索。     

The role of endothelial insulin signaling in the regulation of glucose metabolism

The skeletal muscle is one of the major target organs of insulin and plays an essential role in insulin-induced glucose uptake. Some evidence indicates that insulin delivery to skeletal muscle interstitium through the endothelial cells is the rate-limiting step in insulin-stimulated glucose uptake. Researchers have also found that this process is impaired by insulin resistance in type 2 diabetes and obesity. A recent study of ours demonstrated that insulin signaling in the endothelial cells plays a pivotal role in the regulation of glucose uptake by the skeletal muscle. Specifically, impaired insulin signaling in the endothelial cells, with reduction of insulin-induced eNOS phosphorylation, causes attenuation of the insulin-induced capillary recruitment and insulin delivery, which, in turn reduces glucose uptake by the skeletal muscle in high-fat diet-fed mice. Moreover, restoration of the insulin-induced eNOS phosphorylation in the endothelial cells completely reverses the reduction in the capillary recruitment and insulin delivery, and as a result, significantly restores glucose uptake by the skeletal muscle. In the present review, we describe the recent progress in research on the physiological and pathophysiological roles of endothelial insulin signaling in the regulation of insulin-induced glucose uptake by the skeletal muscle.     

Renal tubular reabsorption of calcium in familial hypocalciuric hypercalcaemia

To investigate the nephron site of the enhanced tubular calcium reabsorption in familial hypocalciuric hypercalcaemia (FHH), the renal plasma clearance of lithium and calcium and the glomerular filtration rate were determined simultaneously after an overnight fast in nine FHH patients and ten healthy controls. As the renal plasma clearance of lithium equals the rate of the proximal tubular fluid delivered into the thin descending loop of Henle's loop, the reabsorption of calcium in the proximal and distal tubule, respectively, could be calculated. We found that the FHH patients had a significantly higher fractional calcium reabsorption in the proximal tubule (77.6 +/- 4.7 (%) vs 73.3 +/- 3.1, P less than 0.05). The same held true for the absolute proximal calcium reabsorption (1.49 +/- 0.12 (mmol/l) vs 1.07 +/- 0.05, P less than 0.001). There was a significant linear correlation between the increased tubular capacity for calcium reabsorption and the absolute proximal calcium reabsorption (r = 0.70, P less than 0.05). The distal tubular calcium reabsorption did not differ in the two groups. Our results therefore suggest that the enhanced tubular calcium reabsorption in FHH takes place exclusively in the proximal renal tubule.     

糖调节受损个体胰岛β细胞功能和胰岛素抵抗观察

评价152例人选者[正常糖耐量、空腹血糖受损和(或)糖耐量受损]胰岛β细胞功能和胰岛素抵抗.结果 显示空腹血糖受损者主要表现胰岛素早期分泌功能缺陷和基础分泌不足,胰岛素抵抗严重;糖耐量受损者则胰岛素早期和晚期分泌功能显著下降伴轻度胰岛素抵抗.     

糖调节受损不同亚型胰岛素敏感性和胰岛素分泌的特点

糖调节受损包括单纯空腹血糖受损、单纯糖耐量受损和混合糖调节受损三个亚型.流行病学资料及病理生理研究提示各个亚型具有不同的胰岛素分泌和胰岛素敏感性特点.了解这些特点有助于早期干预以阻止或延缓糖调节受损向2型糖尿病发展的进程.     

Role of glucagon and insulin in control of glucose turnover

The effects of a concurrent supply of glucagon and insulin were investigated in five conscious postabsorptive dogs whose insulin secretion was replaced by a near-basal intraportal insulin infusion of 240 μU/kg/min. An infusion of 29 mμg/kg/min of glucagon with a simultaneous 12-fold increase in the rate of insulin supply doubled the turnover of glucose with a small change in its concentration. This minicked the effect of glucagon infusions in five normal dogs. In contrast, four- to eightfold increases in insulin supply did not match the effect of glucagon in the depancreatized dogs. The rate of glucose production exceeded its rate of utilization and hyperglycemia resulted promptly.