Impaired potassium-induced insulin secretion in chronic renal failure.

Extrarenal disposal of potassium load is impaired in chronic renal failure (CRF). This has been attributed to excess PTH since extrarenal disposition of potassium is normal in CRF-PTX animals. Insulin augments potassium entry into cells and hyperkalemia stimulates insulin secretion. Since glucose-induced insulin secretion is impaired in CRF and normal in CRF-PTX, it is possible that K(+)-induced insulin secretion is also impaired in CRF due to excess PTH. Such a defect would contribute to the abnormality in extrarenal disposal of potassium in CRF. We examined K(+)-induced insulin secretion, cytosolic calcium ([Ca2+]i) and the changes in [Ca2+]i in response to 20 mM KCl of islets from normal, CRF, and CRF-PTX rats; and normal and CRF animals treated with verapamil (normal-V and CRF-V). K(+)-induced insulin secretion by islets isolated from CRF rats was significantly (P less than 0.01) lower than that from normal, CRF-PTX, CRF-V and normal-V rats. Basal level of [Ca2+]i in islets of CRF rats was significantly (P less than 0.01) higher than in islets of the other four groups of animals. The calcium signal (delta [Ca2+]i) and the delta [Ca2+]i/basal [Ca2+]i ratio in response to 20 mM KCl observed in islets from CRF rats were significantly lower than in the other four groups of animals.(ABSTRACT TRUNCATED AT 250 WORDS)     

Impaired activity of alpha-ketoglutarate dehydrogenase of heart mitochondria in chronic renal failure: role of secondary hyperparathyroidism

Chronic renal failure (CRF) is associated with impaired oxidation of alpha-ketoglutarate (alpha-KG) by heart mitochondria, and previous data indicated that this derangement is due to the state of secondary hyperparathyroidism of CRF. A reduction in the utilization of alpha-KG by heart mitochondria implies that the activity of mitochondrial alpha-ketoglutarate dehydrogenase (alpha-KGDH) is impaired; however, direct evidence for such an abnormality is not available. We examined the Vmax and the Km of alpha-KGHD of heart mitochondria obtained from normal rats, CRF animals and normocalcemic parathyroidectomized (PTX) CRF rats. Our data showed that CRF has no effect on the Km of alpha-KGDH for alpha-KG. However, Vmax of the enzyme was significantly (p less than 0.01) reduced and this abnormality was prevented by PTX of CRF rats. Our results provide the evidence that the impaired utilization of alpha-KG by myocardial mitochondria of CRF rats is due to reduced Vmax of alpha-KGDH and that both derangements are mediated by excess PTH or a metabolic consequence of the secondary hyperparathyroidism of CRF.     

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 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.     

Effects of aging on insulin secretion

Aging is associated with hyperinsulinemia, but reports vary on the contributions of altered insulin clearance versus insulin secretion to this phenomenon. To elucidate the role of insulin secretion in the hyperinsulinemia of aging, 10 elderly (age 66 +/- 4 yr, body mass index 25 +/- kg/m2) and 8 young (age 30 +/- 5 yr, body mass index 24 +/- 3 kg/m2) subjects were studied to determine rates of insulin secretion in response to fasting, mixed meals, and intravenous glucose administration. Insulin secretion was determined with a two-compartment model based on individual C-peptide kinetic parameters derived after bolus injection of biosynthetic human C-peptide. Basal insulin secretion rates were increased in elderly subjects (82.5 +/- 9.0 vs. 62.8 +/- 6.1 pmol.min-1.m-2; P less than .05). This was reflected in elevated serum insulin levels in elderly subjects (62.8 +/- 10.1 vs. 41.1 +/- 5.0 pM, P less than .05). During a 24-h mixed-meal profile, elderly subjects had an increase in their glucose response (P less than .01 by analysis of variance [ANOVA]) and total insulin secretion (261 +/- 28 vs. 195 +/- 22 nmol.24 h-1.m-2; P less than .05) compared with young subjects. However, the relative total increases in both glycemia and insulin secretion, calculated as a function of basal levels, were similar between the groups (both NS). To experimentally control for differences in glycemia, both groups underwent a 16.8-mM hyperglycemic clamp and a stepped intravenous glucose infusion to match glycemia. Under these steady-state and dynamic conditions, insulin secretion profiles were nearly identical (NS by ANOVA).(ABSTRACT TRUNCATED AT 250 WORDS)     

Impaired in vivo antibody production in CRF rats: role of secondary hyperparathyroidism.

Antibody responses to antigens are impaired in humans and animals with chronic renal failure (CRF), and parathyroid hormone (PTH) inhibits Staphylococcus aureus Cowan I (SAC) or pokeweed mitogen (PWM)-induced antibody production by B cells from normal subjects. Since CRF is associated with secondary hyperparathyroidism and elevated blood levels of PTH, it is possible that impaired humoral immunity in CRF is due to chronic excess of PTH. To test this hypothesis we examined in vivo antibody production in response to sheep red blood cells (SRBC), BSA and influenza vaccine in normal rats, CRF rats and parathyroidectomized CRF rats maintained normocalcemic (CRF-PTX). The blood levels of PTH in CRF rats were elevated and significantly (P less than 0.01) higher than those in normal and CRF-PTX rats. The latter groups of animals did not have elevated blood levels of PTH. The antibody response to all three antigens in CRF rats were significantly (P less than 0.01) and markedly lower than in normal or CRF-PTX rats. The antibody response to SRBC, the IgG anti-BSA and the IgG and IgM anti-influenza vaccine in CRF-PTX rats were not different from normal, while the IgM anti-BSA was lower than in normal rats but higher than in CRF rats. The data demonstrate that the state of secondary hyperparathyroidism of CRF plays a paramount role in the genesis of impaired humoral immunity in CRF.     

Erosive spondyloarthropathy in primary hyperparathyroidism without renal failure.

A patient with erosive spondyloarthropathy (ESA) and primary hyperparathyroidism is described. In the past, ESA has been described exclusively in patients with chronic renal failure (CRF) and has been attributed to crystal deposition, amyloidosis, severe secondary hyperparathyroidism, or other abnormalities of chronic renal failure. This patient with normal renal function suggests that secondary hyperparathyroidism plays the major pathogenetic role in ESA in patients with renal failure.     

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.     

Secondary hyperparathyroidism in chronic renal failure. Role of subtotal parathyroidectomy

Fourteen patients with chronic renal failure and secondary hyperparathyroidism were treated by subtotal parathyroidectomy. Bone pain and hypercalcemia were the main indications to surgery respectively in 13 and 1 patients. Bone pain disappeared or was significantly reduced in 12/14 patients. Two patients had a persistent hyperparathyroidism. Serum alkaline phosphatase returned to normal in 12 patients and PTH in 11 of 12 patients with pretreatment high levels.     

Treatment of hyperkalaemia in renal failure: salbutamol v. insulin

Three groups of patients with acute or chronic renal failure (GFR less than 5 ml/min) and hyperkalaemia (K+ greater than or equal to 6 mEq/l), similar in age, serum creatinine and pretreatment K+. Group A (n = 24) received salbutamol 0.5 mg i.v. in 15 min, group B (n = 10) received glucose 40 g i.v. plus 10 units insulin i.v. in 15 min, and group C (n = 10) received salbutamol 0.5 mg i.v., glucose 40 g i.v. and insulin 10 units i.v. over a 15-min period. Serum potassium was measured at 30, 60, 180 and 360 min after administration of treatment. All treatments reduced serum potassium, maximal at 30 or 60 min, and ranging from -0.5 +/- 0.1 to -1.5 +/- 0.2 mEq/l; patients in group C exhibited a significantly greater decrement in serum potassium, when compared to group B at 60 (-1.5 +/- 0.2 vs -1 +/- 0.1 mEq/l, respectively; P less than 0.01) and 180 min (-1.2 +/- 0.2 vs -0.7 +/- 0.1 mEq/l, respectively; P less than 0.05). There were no significant differences between groups A and C. Patients from group C had moderate tachycardia and more prolonged hyperglycaemia than those from group B, but all treatments were well tolerated.     

Reduced activity of Na(+)-K+ ATPase of pancreatic islets in chronic renal failure: role of secondary hyperparathyroidism.

The activity of Na(+)-K+ ATPase of pancreatic islets modulates their insulin secretion. The study presented here examined the activity of this enzyme in pancreatic islets of chronic renal failure (CRF) rats in an effort to further delineate the mechanisms of impaired insulin secretion in CRF. The Vmax of Na(+)-K+ ATPase, but not its Km, and the ATP content are significantly reduced in islets of CRF rats that have elevated levels of parathyroid hormone (PTH). These derangements are prevented by prior parathyroidectomy of CRF rats (low blood levels of PTH) or by their treatment with the calcium channel blocker verapamil; these latter rats have sustained elevation of blood levels of PTH. The data indicate that the chronic excess blood levels of PTH in CRF initiates events (augmented entry of calcium) that lead to the reduction in ATP content and in Vmax of Na(+)-K+ ATPase of pancreatic islets. Reducing the blood levels of PTH by parathyroidectomy or blocking the action of PTH on calcium entry into cells by verapamil prevents these derangements. The results suggest that chronic inhibition of Na(+)-K+ ATPase may participate in the processes underlying the impaired insulin secretion in CRF.     

Effect of chronic renal failure on heart. Role of secondary hyperparathyroidism

This study examined the effects of chronic renal failure in rats with and without parathyroid glands on myocardial energy production, transfer and utilization as well as on cardiac index. Chronic renal failure was produced by 7/8 nephrectomy in rats weighing between 240 and 350 g with intact parathyroid glands (CRF-control) and in parathyroidectomized (CRF-PTX) rats maintained normocalcemic. The data were compared to results obtained in intact rats and in normocalcemic parathyroidectomized rats with normal renal function. There were significant (p less than 0.01) decrements in myocardial content of ATP and creatine phosphate, mitochondrial oxygen consumption, and in the activity of both mitochondrial and myofibrillar creatine phosphokinase in CRF-control rats as compared to normal animals. The myocardial calcium content and the 45Ca uptake in CRF-control rats were significantly (p less than 0.01) higher than in normal rats. In CRF-PTX animals, the myocardial content of ATP, mitochondrial oxygen consumption, 45Ca uptake and calcium content were normal, but PTX did not normalize the activity of mitochondrial and myofibrillar creatine phosphokinase. Parathyroidectomy in rats with normal renal function was associated with a significant reduction in the activity of creatine phosphokinase of myocardial mitochondria and myofibrils. There was a significant (p less than 0.01) decrease in cardiac index in CRF-control rats as compared to normal animals, and cardiac index did not return to normal in CRF-PTX rats.(ABSTRACT TRUNCATED AT 250 WORDS)     

Reoperation for secondary hyperparathyroidism in chronic renal failure

From 1972 to 1987, 112 parathyroidectomy (PTX) operations were carried out in 105 haemodialysis or transplant patients by the same surgeon. Twelve had to be reoperated on (19 operations in all) for persistent (9 cases) or recurrent (3 cases) hyperparathyroidism. In six patients morphological tests (echography and technetium-thallium scintigraphy) contributed usefully by detecting parathyroid masses. Repeated surgery was finally effective in nine cases.     

Glucose regulation of glutaminolysis and its role in insulin secretion.

Leucine or the nonmetabolized leucine analog +/- 2-amino-2-norbornane-carboxylic acid (BCH) (both at 10 mmol/l) induced biphasic insulin secretion in the presence of 2 mmol/l glutamine (Q2) in cultured mouse islets pretreated for 40 min without glucose but with Q2 present. The beta-cell response consisted of an initial peak of 20- to 25-fold above basal and a less marked secondary phase. However, BCH produced only a delayed response, while leucine was totally ineffective when islets were pretreated with 25 mmol/l glucose plus Q2. With Q2, 10 mmol/l BCH or leucine caused a nearly threefold increase, a twofold increase, or had no effect on cytosolic Ca2+ levels in islets pretreated for 40 min with 0, 5, or 15 mmol/l glucose, respectively. Thus, pretreatment of islets with high glucose inhibited BCH- and leucine-induced cytosolic Ca2+ changes and insulin release. Glucose decreased glutamine oxidation in cultured rat islets when BCH was present at 10 mmol/l, but not in its absence, with a lowest effective level of approximately 0.1 mmol/l, a maximum of 18-30 mmol/l, and an inhibitory concentration, 50%, of approximately 3 mmol/l. The data are consistent with the hypothesis that glucose inhibits glutaminolysis in pancreatic beta-cells in a concentration-dependent manner and hence blocks leucine-stimulated insulin secretion. We postulate that in the basal interprandial state, glutaminolysis of beta-cells is partly turned on because glutamate dehydrogenase (GDH) is activated by a decreased P-potential due to partial fuel depletion and sensitization to endogenous activators such as leucine. Additionally, it may contribute significantly to basal insulin release, which is known to be responsible for about half of the insulin released daily. The data explain "leucine-hypersensitivity" of beta-cells during hypoglycemia and contribute to the elucidation of the GDH-linked syndrome of hyperinsulinism associated with elevated serum ammonia levels. Thus, understanding the precise regulation and role of beta-cell glutaminolysis is probably central to our concept of normal blood glucose control.