Chloroquine inhibits the insulin production of isolated pancreatic islets.
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Biomedical subjects
Publications and source records attributed to A Andersson.
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The effects of metabolic inhibition on the kinetics of glucagon release by pancreatic islets from normal guinea pigs have been studied in a perfusion system. All three metabolic inhibitors, malonate, iodoacetate and 2,4-dinitrophenol, induced a marked stimulation of glucagon secretion, each displaying its own characteristic pattern of response. This was accompanied by a rapid and marked decrease in the ATP concentration of the A2-cell as evidenced by measurements performed in A2-cell rich islets, isolated from guinea pigs treated with streptozotocin. The ATP levels were reduced by about 90% following iodoacetate and 2,4-dinitrophenol exposure and by about 60% after exposure to malonate. The data support the hypothesis that the inhibition of glucagon release from the A2-cell is regulated via an intracellular, energy-dependent mechanism.
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Sixty-six patients with primary adenocarcinomas of the duodenum recorded by the Swedish Cancer Register during 1958-1973 are reviewed. The mean age was 66 years, and female:male ratio 1.2:1.0. The predominant symptom was duodenal obstruction. Correct diagnosis was made in 68% by conventional barium meal examination. Hypoton duodenography and duodenoscopy are necessary diagnostic aids. In 25% of the patients the diagnosis was first made at postmortem examination. Thirty-two patients had metastases at first diagnosis. Forty-three per cent were radically operated and 43% palliatively. The operative mortality after curative operations was 25% with no difference correlated to operative methods with the exception of pure polyp extirpation where no patient died. The overall one-year survival was 67% and five-year 18%. There was a tendency for longer survival time for patients with more distally situated carcinomas. Duodenopancreatectomy gave a longer survival time than duodenal resection.
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The uptake of 14C-chloroquine by isolated mouse pancreatic islets in vitro was investigated. The islets were found to have a very high capacity to accumulate the substance. The uptake of 14C-chloroquine in the islets was a saturable process. Metabolic inhibitors, ouabain, anaerobic conditions and absence of glucose did not inhibit the uptake of 14C-chloroquine in the islets, suggesting that the substance is accumulated by some means other than energy-dependent active transport or pinocytosis. The uptake of 14C-chloroquine was inhibited by low temperature and low pH and in the presence of mepacrine, chlorpromazine, imipramine and desmethylimipramine. Only a small part of the 14C-chloroquine which had been taken up in the islets left the cells during 45 min. incubation in non-radioactive media. Two possible mechanisms for the uptake of 14C-chloroquine in the islets are considered: (1) The accumulation may be due to a binding of the substance to cellular constituents. (2) Chloroquine may be trapped by protonation within lysosomes or other membrane-surrounded organelles with low pH.
Four patients were found to react to occupational exposure to grinding of hard metal (tungsten carbide). Three of the patients had symptoms and signs compatible with an allergic alveolitis, the symptoms disappearing and the chest radiograph clearing when they were absent from work for a few months. Re-exposure to the offending agent led to new signs and symptoms. The first patient was re-exposed twice and each time reacted a little more seriously. After the last episode her chest radiograph has not cleared completely, in contrast to the first two times. The fourth patient had more typical occupational asthma. All the cases occurred in the part of the factory where air concentrations of cobalt were the lowest. The cobalt there is dissolved in the coolant necessary for grinding the hard metal. It occurs mainly in the ionised form, which is known to react with proteins and therefore presumably acts as a hapten. Protective measures, including choosing a coolant with minimal ability to dissolve cobalt and an effective exhaust system, should minimise the risk of this occupational disease in the future.
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Human fetal pancreas preserved in culture was used as a donor organ in a 45-yr-old man with diabetes of 14-yr duration complicated by severe retinopathy and nephropathy. Renal failure had been successfully treated by a cadaveric renal transplant 2 yr earlier. Six fetal pancreases, obtained within 30 min of delivery after prostaglandin-induced abortion at 14--20 wk of gestation, were minced and placed in tissue culture for 3 h at the earliest and 15 days at the longest duration. The cultures were harvested 2--3 h before transplantation. Approximately 3 ml of tissue was infused into a right portal vein branch. Azathioprine was continued at 2 mg/kg and prednisolone increased from 10 mg to 100 mg/day on the day of transplantation and gradually reduced to 25 mg/day. Only two doses of antilymphocytic globulin were given because of a severe reaction. During the 40 days since transplantation, insulin requirements have not changed, but C-peptide has appeared in the urine, suggesting function of the transplanted tissue.
An unusual case of aortoenteric fistulation, 5 years after surgery for renal artery stenosis, is presented. A stenotic right renal artery had been reimplanted into the aorta in a 4 1/2 year old boy. No signs of infection had been present, nor had any synthetic material been used. The fistula was found to originate from the ligated renal artery, not from the reconstruction. It was successfully corrected without compromising the kidney.
To further investigate the regulation of glucagon biosynthesis in mammalian A2-cells, we have studied the incorporation of [3H]-tryptophan into acid alcohol extracts of isolated pancreatic islets of guinea pig and mouse. Gel chromatography on Sephadex G-50 indicated that labelled proteins, migrating either with the void volume (peak I) or in region (peak II) between the void volume and the insulin marker, were formed during a 6h incubation of the islets. However, a period of at least two days in tissue culture was required before the islets showed any significant accumulation of labelled protein eluting in a position corresponding to that of pancreatic glucagon (peak III). Addition of glucose (16.7 mM) enhanced the incorporation into all chromatograph fractions during the culture period. Binding of gel chromatographed proteins Sepharose coupled anti-glucagon antibodies indicated that both guinea pig and mouse islets contained only small amounts of labelled, immunoreactive proteins eluting with either peak I or peak II. However, proteins eluting with peak III contained 6-8 times more lbelled, immunoreactive material than any of the other peaks. Total glucagon immunoreactivity was abundant in peaks I and II but less evident in peak II. The results of pulse-chase experiments provided no convincing evidence for a precursor-product relationship between larger proteins and glucagon. However, the heterogeneity of the putative precursor pool, as evidenced both by SDS-polyacrylamide gel electrophoresis and by the low immune binding, might have masked a conversion process. The combined data show that glucagon is, indeed, synthesized in isolated islets of guinea-pig and mouse, but that this process occurs slowly.
Glipizide was found to stimulate the insulin release from isolated mouse pancreatic islets incubated at 5.5 mM glucose. The rate of insulin biosynthesis under similar conditions was, however, markedly depressed except at the lowest glipizide concentration tested (5 ng/ml), where the drug stimulated insulin secretion but was without effect on the biosynthetic rate. The inhibition of insulin biosynthesis was also observed in experiments with islets maintained in tissue culture, despite the fact that insulin accumulation in the culture medium was increased throughout the culture period. The present data suggest that glipizide has a transient beta-cytotropic effect, which could suggest that extra-pancreatic factors may be involved in the long-term therapeutic action of the drug.
Purine ribonucleosides were found to be as potent stimulators of proinsulin biosynthesis as glucose, adenosine being effective at very low concentrations (0.1 mM). Some pyrimidine nucleosides together with 2-deoxyribonucleoside (thymidine) were also potent stimulants. The single components of nucleosides (pentoses and bases) had no, or only slight, stimulatory effects. Nucleosides added to a low-glucose culture medium were found to replace glucose as a long-term stimulant of the insulin biosynthesis of islets in culture. Adenosine-stimulated insulin secretion from perifused islets was biphasic, although kinetic differences were observed as compared with glucose stimulation. The rate of oxidation of [U-14C]-adenosine was dose dependent, whereas no production of 14CO2 was obtained during incubation of islets in [8-14C]-adenosine. Oxidation of 14C-labelled glucose was depressed by addition of adenosine. The results add further support to the view that nucleoside-stimulated insulin secretion and biosynthesis are modulated through metabolic signals.
The rates of oxygen consumption and glucose oxidation were measured in isolated pancreatic islets of obese-hyperglycemic or normal mice. Sufficient analytical sensitivity was achieved by incubating islets in Cartesian divers, allowing accurate measurements of oxygen uptake in the range of 1 to 10 mug dry islet weight. The endogenous islet respiration proceeded at a constant rate for more than one hour. Glucose effected a rapid and lasting elevation of the respiratory rate which corresponded to the observed rate of glucose oxidation. An extended period of starvation led to a reduction in both oxygen uptake and glucose oxidation. Isolated islets maintained for seven days in tissue culture at a glucose concentration of 5.5 mM showed a pronounced increase in oxygen consumption when they were incubated with the nonmetabolizable insulin secretagogue b (+/-) BCH in the absence of glucose. The respiratory stimulation was less marked after culture at 3.3 mM glucose and only faint after culture at 16.7 mM glucose. A common feature of islets exposed to BCH in the absence of glucose was a gradual decline of respiration commencing 30 to 40 minutes after addition of BCH. Islets incubated with BCH in the presence of glucose displayed, however, no respiratory retardation. BCH produced only a weak stimulation of the islet glucose oxidation. It is concluded that BCH stimulates the endogenous substrate oxidation of the B-cells, possibly by affecting a noncarbohydrate pool of substrate. The observations add further support to the idea that the regulation of insulin release is linked to metabolic events in the B-cell.
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Benign tumors of the papilla of Vater are unusual; fewer than 100 cases have been reported. Six cases with adenomyosis of the papilla of Vater are presented. In two patients, the adenomyosis was an incidental finding at laparotomy or autopsy. In two patients, adenomyosis produced symptoms, and the lesions were successfully excised. There was no recurrence of biliary symptoms postoperatively. In two patients adenomyosis was associated with adenocarcinoma of the papilla of Vater. Adenomyosis can be a premalignant condition. Frozen section for histologic examination should be done when a tumor is encountered in the papilla of Vater. Adequate local excision of a benign tumor should result in cure. The patient must, however, be followed-up carefully, and a reexploration should be performed if there is the slightest indication of recurrence. The recurrence is often malignant.
To facilitate detailed studies of the B-cytotoxic action of alloxan we developed a model using isolated pancreatic islets of normal mice. An essential feature of this model is the low temperature employed during exposure to alloxan, which minimizes the degradation of the drug. The islets were incubated with alloxan for 30min at 4 degrees C and subsequently various aspects of their metabolism were studied. The O(2) consumption was measured by the Cartesian-diver technique. Islets exposed to 2mm-alloxan and control islets had the same endogenous respiration, whereas the O(2) uptake of the alloxan-treated islets was inhibited and that of the control islets stimulated when they were incubated with 28mm-glucose as an exogenous substrate. The islet glucose oxidation was estimated by measurement of the formation of (14)CO(2) from [U-(14)C]glucose at 37 degrees C. Compared with the controls, alloxan-treated islets showed a decrease in the glucose-oxidation rate in a dose-dependent manner. Pretreatment of the islets with 28mm-glucose for 30min at 37 degrees C completely protected against this effect, whereas preincubations at glucose concentrations below 16.7mm failed to exert any protective effect. The glucose utilization was estimated as the formation of (3)H(2)O from [5-(3)H]glucose. Alloxan (2mm) failed to affect islet glucoseutilization rate in the presence of either 2.8 or 28mm-glucose. In contrast, islets exposed to 5 or 10mm-alloxan exhibited lowered glucose utilization. It is concluded that in vitro alloxan has an acute inhibitory effect on the islet glucose metabolism, and that this action can be prevented by previous exposure to a high glucose concentration. The results are consistent with the idea that the B-cytotoxicity of alloxan reflects an interaction with intracellular sites involved in the oxidative metabolism of the B-cell.