Impaired insulin secretion of aging: role of renal failure and hyperparathyroidism.

Available data indicate that insulin secretion is impaired with aging. Almost all the studies that examined insulin secretion by old animals did not take into consideration the state of renal function or the blood levels of parathyroid hormone (PTH). Old animals may have chronic renal failure (CRF) and secondary hyperparathyroidism, and both of these conditions impair insulin secretion. It is possible, therefore, that the impaired insulin secretion of aging is not due to old age per se, but rather to associated CRF and excess PTH. The present study examined this issue in adult (6 month old) and senescent rats (2 year old) with and without CRF and excess PTH. Senescent rats without CRF had normal renal function and normal blood levels of PTH, and the values were not different from those observed in adult rats. Creatinine clearance in senescent rats with CRF was significantly (P less than 0.01) lower and serum levels of PTH were significantly (P less than 0.01) higher than in senescent animals without CRF and than in the adult rats as well. Only the senescent rats with CRF displayed glucose intolerance during intravenous glucose tolerance test. For any given level of blood glucose, plasma insulin levels were lower in senescent rats with CRF than in the adult rat or senescent animals without CRF.(ABSTRACT TRUNCATED AT 250 WORDS)     

Impaired glucose-induced calcium signal in pancreatic islets in chronic renal failure.

Basal level of cytosolic calcium ([Ca2+]i) is elevated in islets of rats with chronic renal failure (CRF). The high [Ca2+]i level was implicated in the impaired insulin secretion of CRF, and its effect is due, in part, to a reduction in ATP content and impaired glucose metabolism by the islets. However, elevated [Ca2+]i may interfere with insulin secretion via another pathway. Exposure of the islets to glucose causes an acute rise in [Ca2+]i which generates events leading to insulin secretion. It is possible that a sustained rise in [Ca2+]i interferes with the magnitude of glucose-induced calcium signal and the ratio between this signal and basal [Ca2+]i. We examined this question in normal, CRF, normocalcemic CRF-PTX rats and in CRF rats treated with verapamil (CRF-V). Basal [Ca2+]i was higher (p less than 0.01) in CRF (130 +/- 7.0 nM) than in normal (82 +/- 5.5 nM), CRF-PTX (75 +/- 3.6 nM) and CRF-V rats (84 +/- 3.8 nM). Glucose-induced calcium signal (95 +/- 10.4 nM) and the ratio between this signal and basal [Ca2+]i (0.73 +/- 0.07) in CRF rats were lower (p less than 0.01) than in normal (153 +/- 14.4 nM; 1.90 +/- 0.24), CRF-PTX (130 +/- 16.7 nM; 1.75 +/- 0.25) and CRF-V (124 +/- 5.8 nM; 1.90 +/- 0.12) rats despite high PTH in the latter. The data indicate that a sustained rise in [Ca2+]i of islets interferes with the glucose-induced calcium signal which in turn plays a role in impaired insulin secretion.     

Impaired phagocytosis in chronic renal failure is mediated by secondary hyperparathyroidism.

Patients with chronic renal failure (CRF) display impaired phagocytosis by the polymorphonuclear leucocytes (PMNL), and these cells have elevated basal levels of cytosolic calcium ([Ca2+]i) and reduced ATP content. It has been suggested that these changes in PMNL metabolism and function are mediated by the state of secondary hyperparathyroidism of CRF. To examine the role of excess PTH in these derangements of PMNL, we studied [Ca2+]i, ATP and phagocytic ability of PMNL in five groups of rats including: CRF, CRF normocalcemic parathyroidectomized (CRF-PTX), CRF and normal animals treated with verapamil (CRF-V), and normal-V, respectively. The level of [Ca2+]i in the PMNL of CRF rats (149 +/- 2.7 nM) was significantly (P less than 0.01) higher and the ATP content (4.2 +/- 0.17 nmol/5 x 10(6) PMNL) significantly lower (P less than 0.01) than in normal (108 +/- 2.4 nM; 9.5 +/- 0.15 nmol/5 x 10(6) PMNL), CRF-PTX (103 +/- 2.9 nM; 9.2 +/- 0.19 nmol/5 x 10(6) PMNL), CRF-V (107 +/- 2.2 nM; 9.0 +/- 0.2 nmol/5 x 10(6) PMNL) and normal-V (106 +/- 1.8 nM; 9.2 +/- 0.2 nmol/5 x 10(6) PMNL), despite sustained elevation in blood PTH in the CRF-V group. Phagocytosis was significantly (P less than 0.01) impaired in CRF animals (5.6 +/- 0.25 micrograms oil/10(7) PMNL/min) but was normal in CRF-PTX (9.3 +/- 0.21 micrograms oil/10(7) PMNL/min) and CRF-V (9.5 +/- 0.22 micrograms oil/10(7) PMNL/min) rats. The values of phagocytosis in normal and normal-V rats were 9.6 +/- 44 and 9.6 +/- 0.18 micrograms oil/10(7) PMNL/min, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)     

Impaired left ventricular diastolic function in children with chronic renal failure

BACKGROUND: Diastolic dysfunction is frequent in adults with renal failure. However, in children with mild-to-moderate chronic renal insufficiency (CRI), it has not been evaluated. We compared diastolic function and assessed risk factors associated with diastolic dysfunction in children with CRI with those on dialysis. METHODS: Thirty-three children with CRI, 17 on chronic dialysis, and 33 control patients, had echocardiography performed. Early diastole was assessed using indices of left ventricular (LV) relaxation derived from transmitral and tissue Doppler, and reported as the peak E/A wave ratio, and septal mitral annular velocities (Em). Late diastole was determined using an index of LV compliance (E/Em ratio). Left atrial (LA) dimension was also determined. RESULTS: Children with CRI had worse diastolic function (lower Em, and higher E/Em ratio than control patients, P < 0.001). Dialysis patients had worse diastolic function (lower E/A ratio and Em, and higher E/Em ratio, P < 0.001) than CRI children. LA dimension was higher in renal patients when compared with control patients (P < 0.001). In children on dialysis, LV relaxation (Em) was significantly related to left ventricular mass (LVM) index (r=-0.58, P= 0.04), and LV compliance (E/Em) was significantly associated with LA index (r= 0.67, P= 0.01), LVM index (r= 0.75, P < 0.01), hemoglobin level (r=-0.65, P= 0.02), serum phosphorus (r= 0.56, P= 0.05), and calcium-phosphorus ion product (r= 0.59, P= 0.04). CONCLUSION: Our results indicate that diastolic dysfunction is already present in children with mild-to-moderate CRI. Worse diastolic function in dialysis patients might be related to LV hypertrophy. The results suggest that children with advanced renal failure and diastolic dysfunction may be at risk for ultimate worsening of cardiac function over time.     

Impaired endothelium-dependent vasodilatation in renal failure in humans.

BACKGROUND: The main causes of death in patients with chronic renal failure (CRF) are cardiovascular complications. The aim of the present study was to compare endothelium-dependent vasodilatation (EDV) in patients with chronic renal failure with a control population controlling for hypertension, diabetes mellitus and hypercholesterolaemia. METHODS: Fifty-six patients with moderate CRF (mean creatinine clearance 29.4 ml/min/1.73 m(2)) underwent evaluation of EDV and endothelium-independent vasodilatation (EIDV) by means of forearm blood flow (FBF) measurements with venous occlusion plethysmography during local intra-arterial infusions of methacholine (Mch, 2 and 4 microg/min evaluating EDV) and sodium nitroprusside (SNP, 5 and 10 microg/min evaluating EIDV). Fifty-six control subjects without renal impairment underwent the same investigation. RESULTS: Infusion of Mch increased FBF significantly less in patients with renal failure than in controls (198 vs 374%, P<0.001), whereas no significant difference was seen regarding the vasodilatation induced by SNP (278 vs 269%). The differences in EDV between the groups were still significant after controlling for hypertension, blood glucose, and serum cholesterol in multiple regression analysis (P<0.001). EDV was related to serum creatinine (r=-0.37, P<0.01), creatinine clearance (r=0.45, P<0.005) and to serum triglyceride levels (r=-0.29, P<0.005) in the CRF group. CONCLUSIONS: Patients with moderate CRF have an impaired EDV even after correction for traditional cardiovascular risk factors and this impairment is related to the degree of renal failure.     

Impaired insulin secretion and enhanced insulin sensitivity in cholecystokinin-deficient mice

OBJECTIVE

Cholecystokinin (CCK) is released in response to lipid intake and stimulates insulin secretion. We hypothesized that CCK deficiency would alter the regulation of insulin secretion and glucose homeostasis.

RESEARCH DESIGN AND METHODS

We used quantitative magnetic resonance imaging to determine body composition and studied plasma glucose and insulin secretion of CCK gene knockout (CCK-KO) mice and their wild-type controls using intraperitoneal glucose and arginine infusions. The area of anti-insulin staining in pancreatic islets was measured by immunohistochemistry. Insulin sensitivity was assessed with euglycemic-hyperinsulemic clamps.

RESULTS

CCK-KO mice fed a low-fat diet had a reduced acute insulin response to glucose but a normal response to arginine and normal glucose tolerance, associated with a trend toward greater insulin sensitivity. However, when fed a high-fat diet (HFD) for 10 weeks, CCK-KO mice developed glucose intolerance despite increased insulin sensitivity that was associated with low insulin secretion in response to both glucose and arginine. The deficiency of insulin secretion in CCK-KO mice was not associated with changes in β-cell or islet size.

CONCLUSIONS

CCK is involved in regulating insulin secretion and glucose tolerance in mice eating an HFD. The impaired insulin response to intraperitoneal stimuli that do not typically elicit CCK release suggests that this hormone has chronic effects on β-cell adaptation to diet in addition to acute incretin actions.Obesity and type 2 diabetes are epidemic in both developing and developed countries, and consumption of high-fat diets (HFDs) is thought to be a contributing factor. In particular, consumption of an HFD promotes excess energy intake and contributes to the development of obesity and insulin resistance (1) and to abnormalities of fat metabolism (2). An HFD also stimulates the release of gastrointestinal hormones including cholecystokinin (CCK), glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) (3–5), all of which are secreted from the intestine as ingested food is being processed for absorption. Each of these gut hormones enhances insulin secretion and facilitates glucose tolerance (6).CCK is secreted by intestinal I cells in response to consumption of lipid and is involved in modulating intestinal motility, stimulating pancreatic enzyme secretion, enhancing gall bladder contraction, and regulating meal size (2,7,8). Pure preparations of natural porcine CCK, the synthetic octapeptide of CCK (CCK-8), or synthetic caerulein, which contains a COOH-terminal pentapeptide identical to CCK, have all been found to stimulate insulin secretion in vivo and in vitro (9,10). CCK-8 and CCK-33 are potent stimuli for insulin release, an effect mediated by the CCK1-receptor (CCK1R) both in vitro and in animal models (11–13). Although the role of CCK action on insulin secretion is controversial in healthy humans (14,15), there is evidence that CCK decreases postprandial glucose levels and potentiates increased insulin levels in humans with type 2 diabetes (15,16). CCK also potentiates arginine- and amino acid–induced insulin in normal human subjects (17). To clarify the role of CCK in insulin and glucose homeostasis, we used mice with a targeted global deletion of the CCK gene (CCK knockout [CCK-KO]) mice and their wild-type controls.     

Parathyroidectomy in chronic renal failure.

During the period 1971-1976, subtotal parathyroidectomy was performed on 34 patients with chronic renal failure, representing 8% of all uraemic patients treated on the Renal Ward. Preoperative treatment of renal failure was conservative therapy in 6, haemodialysis in 20 and renal transplantation in 8 patients. The operation was indicated by grave clinical symptoms (pruritus, bone pains and mental disturbances), gastric ulcer and radiological abnormalities (osteoporosis, fractures, subperiosteal resorption and metastatic calcifications). The serum immunoreactive parathyroid hormone was determined in 13 cases, and the value was elevated in all. The serum calcium level was elevated in 8 out of 34 cases. Less than 500 mg of parathyroid tissue was removed in 12 cases, between 500 and 6000 mg in 19 and over 6000 mg in 3. Nodular hyperplasia was present in 11 patients, diffuse hyperplasia in 23. Postoperatively marked falls in serum parathyroid hormone and serum calcium values were observed. The bone pains, pruritus and mental disturbances were alleviated, and the general condition was favourably influenced. The operation had a lesser and more retarded effect on the radiological changes. Complete recovery was only achieved with successful renal transplant. Parathyroidectomy often had a favourable effect on the grave symptoms and may, therefore, be considered in some cases of severe hyperparathyroidism secondary to chronic renal failure.     

Melatonin in chronic renal failure.

The melatonin status of patients in end-stage chronic renal failure (CRF) was evaluated by the determination of daytime plasma melatonin levels and by the investigation of the circadian rhythmicity of melatonin secretion. A significant increase in plasma melatonin concentration was found in all CRF patient groups investigated, i.e. CRF patients on conservative treatment (CT; n = 48), CRF patients on maintenance haemodialysis treatment (HD; n = 39) and CRF patients on peritoneal dialysis (PD; n = 32). Successful transplantation led to a marked reduction in plasma melatonin levels. The circadian rhythm of melatonin secretion would appear to be suppressed in CRF as the nocturnal secretory surge was absent in all HD patients and in 80% of the posttransplantation patients studied.     

Endothelin in chronic renal failure.

The aims of the present study were to determine plasma endothelin (ET) in chronically uraemic patients, the renal clearance of endogenous ET in normal dog and man, and the effect of acute volaemic expansion on ET. The mean plasma ET concentration in haemodialysis patients was 57.5 +/- 5 pg/ml before haemodialysis and remained unchanged at 52.5 +/- 5 pg/ml after haemodialysis. They were thus significantly elevated both before and after haemodialysis (P less than 0.01) compared with plasma ET in normal subjects of 20.8 +/- 0.8 pg/ml. There was no evidence of ET clearance across the cuprophane membrane of the dialyser. Resting plasma ET values in the 15 non-dialysed uraemic patients ranged between 20 and 52.5 pg/ml (mean 38.2 +/- 2.3 pg/ml), significantly greater than those observed in controls (P less than 0.01). In CAPD patients, plasma ET was also significantly (P less than 0.01), elevated (63 +/- 10 pg/ml) when compared to controls, and similar to those observed in patients before haemodialysis. In dogs, mean ET did not diminish between the aorta and the renal vein (28.1 +/- 1 versus 28.4 +/- 2 pg/ml). In man mean ET did not significantly decline between the renal artery and the renal vein (17 +/- 3 to 13 +/- 0.8 pg/ml). In the seven healthy subjects who received 2000 ml of isotonic saline intravenously ET remained unchanged (24 +/- 2; 23 +/- 1 and 23 +/- 2 pg/ml before and 1 and 2 h after starting hydration respectively). We have thus shown that plasma ET is elevated in patients with chronic renal failure especially those on dialysis and CAPD.(ABSTRACT TRUNCATED AT 250 WORDS)     

Puberty in chronic renal failure.

Puberty is a period of transition characterized by a sequence of profound physical and psychological changes leading to full sexual maturity. This process is driven and orchestrated by the awakening of the gonadotropic hormone axis. Chronic renal failure and its treatment may interfere with the onset and progress of puberty by numerous mechanisms including endocrine, metabolic and neuropsychological abnormalities, and drug effects. On average, the onset of puberty is delayed by 2 years in children with chronic renal failure, even after successful transplantation. Moreover, pubertal height gain is only 50% of that observed in healthy children. In this report, we discuss the endocrine mechanisms underlying these alterations and highlight new therapeutical options for pubertal growth failure.     

Phrenic neuropathy in chronic renal failure.

BACKGROUND--Peripheral neuropathy and alterations in diaphragmatic muscle function are frequently caused by uraemia. Phrenic nerve function in patients with end stage renal failure, however, has not been examined to date. METHODS--An electrophysiological study of the phrenic nerve was performed to determine its possible involvement in 32 nondiabetic patients with end stage renal disease undergoing chronic haemodialysis. RESULTS--Seventeen patients had electrophysiological signs of peripheral neuropathy in at least one of the investigated nerves and 14 of the 17 showed pathological phrenic nerve latencies. Delayed phrenic nerve latencies correlated clearly with pathological peroneal nerve conduction velocities. CONCLUSIONS--Phrenic neuropathy is a frequent complication of uraemia.     

Back pain in chronic renal failure.

Back pain in chronic renal failure Patient SK, a 40-yr-old female, resident of Bhagalpur villagein Bihar, India, was operated for gallstones 3 years previously.On pre-operative checkup, mild renal dysfunction was detected.She was asymptomatic for renal disease with serum creatinineof 159 µmol/l (1.8 mg/dl), bland urinary sediment     

Pulsatile bioactive luteinizing hormone secretion in men with chronic renal failure and following renal transplantation

We have measured plasma luteinizing hormone (LH), follicle-stimulating hormone (FSH), testosterone (To) by radioimmunoassay (RIA) and bioactive LH (B-LH) by in vitro bioassay at 10-min intervals over 6 h in men treated by haemodialysis for renal failure and in men after renal transplantation. Eleven normal male volunteers acted as controls. Immunoreactive LH (I-LH) and FSH levels were elevated (p less than 0.03) in uraemia (mean +/- SE; 10.0 +/- 1.0 and 4.6 +/- 0.7 IU/l for LH and FSH, respectively) and following renal transplantation (8.1 +/- 1.2 and 5.3 +/- 0.5 IU/l) compared to controls (C) 4.9 +/- 0.5 and 2.7 +/- 0.4 IU/l) whereas B-LH [17.3 +/- 2.5, 14.8 +/- 1.8 and 12.9 +/- 1.3 IU/l in dialysis (D), transplant (T) and C groups, respectively] levels were normal. Prolactin levels were elevated (p less than 0.03) in the D group (median 348, range 162-1,780 mU/l) compared to the T group (161, 91-206 mU/l) and controls (163, 124-312 mU/l) whereas total To levels (mean +/- SE; 17.3 +/- 4.8, 15.5 +/- 1.3 and 19.6 +/- 2.1 nmol/l in the D, T and C groups, respectively) were similar as was the free To index. B-LH (median frequency, 2 and range 1-3 pulses/6 h) and I-LH (median frequency, 2 and range 1-2 pulses/6 h) was pulsatile in all the C group but B- and I-LH pulses were absent in 2 of the 5 subjects treated by dialysis. Following renal transplantation B-LH pulses were detected in all subjects, whilst I-LH pulses were absent in 1 subject.(ABSTRACT TRUNCATED AT 250 WORDS)     

慢性肾衰患者血红蛋白浓度变化对血清细胞因子活性的影响作用

目的为了探讨贫血与慢性肾衰（ＣＲＦ）免疫功能状态的关系。方法检测了ＣＲＦ患者单纯输血及用红细胞生成素（ＥＰＯ）治疗前后细胞因子白细胞介素２（ＩＬ２）、可溶性白细胞介素２受体（ｓＩＬ２Ｒ）、肿瘤坏死因子（ＴＮＦ）及γ干扰素（γＩＦＮ）水平，并与肾功能正常肾小球肾炎患者（ＧＮ）组及对照组（Ｃ）进行比较分析。结果ＣＲＦ组血清ＩＬ２，ＴＮＦ和γＩＦＮ水平均显著低于ＧＮ组及Ｃ组（Ｐ＜００１），ｓＩＬ２Ｒ水平则较ＧＮ组及Ｃ组明显升高（Ｐ＜００１）。ＣＲＦ组血清ＩＬ２，ＴＮＦ和γＩＦＮ水平与血红蛋白浓度存在直线正相关，而ｓＩＬ２Ｒ水平与血红蛋白浓度呈负相关性，单纯输血或应用ＥＰＯ治疗能改变这些细胞因子活性水平。结论ＣＲＦ免疫功能低下与贫血有关，及时治疗和改善贫血状态可部分纠正这种免疫异常。     

Impaired cellular immune responses in chronic renal failure: evidence for a T cell defect

Cellular immune responses in vitro were studied in 24 patients on chronic hemodialysis and 16 healthy volunteers with normal kidney function. Patients on maintenance hemodialysis had lymphopenia with diminished numbers of both T4+ and T8+ T-lymphocytes. The T4/T8 ratios were within the normal range. Peripheral blood lymphocytes (PBL) showed a diminished proliferative response upon stimulation with concanavalin A, phytohemagglutinin and pokeweed mitogen. When cell surface antigens were used for stimulation (mixed lymphocyte culture) uremic lymphocytes also showed a lower proliferation rate. Although without statistical conformation, there was a tendency by uremic PBL to produce less IL-2 as compared to healthy controls. Moreover, in a PWM driven system, peripheral blood lymphocytes from uremics produced significantly less IgG than PBL from normals. These results support the notion that a profound defect in lymphocyte function accounts at least, in part, for the observed immunodeficiency of uremic patients.