Biomedical subjects
Publications and source records attributed to D E Andersson.
We report on a case of malignant insulinoma occurring in a patient with genuine insulin-dependent diabetes mellitus (IDDM). A review of cases concerning patients with diabetes mellitus and insulinomas is presented, and reveals only patients with non-insulin-dependent diabetes mellitus (NIDDM). Our case appears to be the first in showing the combination of IDDM and a functioning malignant insulinoma.
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OBJECTIVES: Melatonin (MT) undergoes circadian changes in response to external light conditions and has been implicated in the control of other circadian hormone variations. Alcohol inhibits MT secretion in healthy subjects. The purpose of the present investigation was to elucidate whether patients with Wernicke-Korsakoff syndrome (WKS) also have impaired MT secretion after a period of prolonged alcohol abstention. If so, it would be of interest to find out whether this affects cortisol rhythmicity. DESIGN: Seven patients with WKS and 8 healthy controls were included in the study. Venous blood was sampled every 2nd h between 18.00 and 08.00 hours, and urine collected between 22.00 and 07.00 hours. SETTING: Department of Internal Medicine, Endocrinology Section, Södersjukhuset, Stockholm. MAIN OUTCOME MEASURES: Peak serum MT values during the night, total nocturnal MT secretion (estimated by MT incremental areas), and urinary excretion of MT were determined in each participant. Serum cortisol levels were determined in the patients at 18.00, 02.00 and 08.00 hours. RESULTS: Patients with WKS had a markedly reduced nocturnal secretion of MT compared to healthy volunteers (MT incremental areas 0.33 +/- 0.21 vs. 1.60 +/- 0.29 nmol L-1 h-1, mean +/- SEM; P < 0.005). Amongst the patients, the serum cortisol level was higher in the morning than in the afternoon (331 +/- 46 vs. 240 +/- 52 nmol L-1; P < 0.01), and showed a nadir during the night (138 +/- 45 nmol L-1) as in normal individuals. CONCLUSION: Patients with WKS have markedly reduced nocturnal secretion of MT. The exact mechanism behind this finding has to be further elucidated. However, it is of interest to note that despite the lack of clearcut circadian MT changes. WKS patients retain normal cortisol secretion, thus suggesting that MT rhythm may not be obligatory for the proper control of circadian cortisol rhythmicity.
To determine whether ethanol inhibits nocturnal melatonin (MT) secretion, three experiments (A, B, and C) were performed in seven normal subjects. In A, ethanol at a dose of 0.34 g/kg was administered orally at 6:00, 8:00, and 10:00 PM. Each dose was increased to 0.52 g/kg in B. In C, water was substituted for ethanol. Blood samples for determination of serum MT levels were drawn every second hour between 6:00 PM and 8:00 AM. Urinary excretion of MT during the night was also determined. In A, serum ethanol reached a maximal level of 13 +/- 1 mmol/L at 12 midnight. In B, the corresponding maximum was 25 +/- 1 mmol/L. The higher alcohol dose inhibited nocturnal MT secretion by 20% +/- 5% (P < .01), whereas the lower dose lacked such effect. Urinary excretion of MT was left unaffected by alcohol at both doses. Five additional normal subjects were given alcohol as described above at a dose of 0.52 g/kg (experiment D). This induced mild nocturnal hypoglycemia as evidenced by a glucose decremental area (5.9 +/- 1.8 mmol/L.h) that differed significantly from zero (P < .05). To determine whether a reduced glucose delivery to pinealocytes might contribute to the decreased MT secretion in alcohol-intoxicated subjects, two experiments (E and F) were performed in eight healthy individuals. In E, ethanol was given orally as in B; three small oral doses of glucose were also given at 8:00 PM, 10:00 PM, and 12 midnight. In F, water was substituted for ethanol and glucose.(ABSTRACT TRUNCATED AT 250 WORDS)
Determination of serum prolactin can help distinguish between epileptic and pseudo-epileptic attacks since generalized tonic-clonic and complex partial seizures frequently are accompanied by a transient rise in prolactin. In status epilepticus, however, serum prolactin levels are well within the normal range: cellular depletion due to the prolonged seizure activity has been suggested as a mechanism for this finding. The control of prolactin secretion is complex. Among several possible regulators, inhibitory dopamine and stimulatory thyrotropin-releasing hormone (TRH) may take part in the regulation of prolactin levels in connection with epileptic activity. There may be subpopulations of prolactin-producing cells that react differently in response to various regulators. A dopamine receptor blocker given during status epilepticus brings forth a distinct increase in prolactin levels. In order to add to the understanding of prolactin changes in connection with status epilepticus, we injected TRH i.v. during status epilepticus in seven consecutive patients. All patients had prolactin levels within the normal range (< 25 micrograms/l) before injection of TRH which resulted in at least a two-fold increase in prolactin levels. Our results contradict the hypothesis of cellular depletion of prolactin in connection with status epilepticus. The mechanism behind prolactin values within the normal range after prolonged seizure activity remains unknown.
Transient elevation of serum prolactin frequently follows generalised tonic-clonic and complex partial seizures. However, the levels of prolactin during status epilepticus are not increased above the normal range. Exhaustion of central prolactin supplies has been proposed as a possible mechanism for the absence of prolactin increase during status epilepticus. To test this hypothesis we injected intravenous metoclopramide (10 mg) in eight consecutive patients with status epilepticus. One patient had generalised tonic-clonic status epilepticus. Seven patients had EEG-verified non-convulsive status epilepticus, consisting of one typical absence status, one atypical absence status and five complex partial status epilepticus. Metoclopramide raised the mean (SD) prolactin levels at least five-fold in all patients, from 5.8 (8.0) micrograms/l to 87.0 (39.0) micrograms/l, within 60 minutes after the injection. Thus the mechanism for low prolactin values in status epilepticus is not cellular depletion of stored prolactin, but more likely an altered regulation, presumably induced by prolonged seizure activity.
The serum concentration of prolactin is frequently increased after single epileptic seizures and has therefore been used as a method to differentiate between hysterical attacks and epileptic seizures. We determined plasma prolactin concentrations in fifteen patients with status epilepticus. Seven patients had absence status, five complex partial and three generalised tonic-clonic status epilepticus. Prolactin levels were normal in all patients which indicates that, in contrast to single seizures, status epilepticus is not associated with an increase in serum prolactin.
Studies have indicated that verapamil inhibits insulin release from pancreatic beta cells in vitro. Studies in this clinic, however, showed that both oral pretreatment with verapamil for 1 week and intravenous infusion of the drug over a period of 3 hours improved oral glucose tolerance in patients with type II diabetes without affecting insulin release. In contrast, verapamil failed to increase further the hypoglycemic effect of oral glibenclamide therapy when administered intravenously in diabetic patients. This hypoglycemic effect of verapamil does not appear to be caused by reduced glucose absorption from the gut because intravenous infusion of verapamil left the portal vein glucose response to glucose ingestion unaffected in normoglycemic patients who underwent portal vein catheterization for diagnostic purposes. It is more likely that verapamil affects the liver, leading to decreased hepatic glucose output, which supports previous reports that have shown an inhibitory influence of verapamil on enzymes involved in the gluconeogenetic and glycogenolytic processes.
The current study was performed in order to investigate whether verapamil would affect the basal blood glucose concentration in a metabolic state characterized by an increased hepatic gluconeogenesis. For that purpose verapamil (5 mg/h) was infused i.v. during three hours in a group of healthy subjects fasted for 36 h, and for comparison also in healthy subjects fasted overnight. Verapamil was found to lower the basal blood glucose concentration in the 36 h fasted subjects. No effect of verapamil was seen in the overnight-fasted group. Since both the insulin and the glucagon concentrations remained unaffected by verapamil after the 36 h fast, other glucose-regulatory factors must have been responsible for the blood glucose lowering effect of the drug. An effect upon the cytosolic calcium concentration in the hepatocytes causing a decrease in the hepatic gluconeogenesis, is a feasible mechanism by which verapamil might have lowered the blood glucose concentration in the individuals subjected to a prolonged fast.
Verapamil has previously been found to inhibit insulin release from pancreatic beta-cells in laboratory animals. In our department, however, both oral pretreatment with verapamil for one week and a 3-hour iv infusion of the drug improved the tolerance to oral glucose in type II diabetics without affecting insulin release. It failed, however, to potentiate the hypoglycaemic effect of oral glibenclamide therapy in patients with type II diabetes. Since iv infusion of verapamil left the portal vein glucose response to glucose ingestion unaffected in normoglycaemic patients (being portal vein catheterised for diagnostic purposes), it seems unlikely that the hypoglycaemic effect of verapamil could have been due to reduced glucose absorption from the gut. More likely is that verapamil, in the diabetic patients, influenced metabolic processes inside the hepatocytes that are of importance for glucose homeostasis. In-vitro experiments have shown that calcium affects factors of importance for the glucose metabolism. Accordingly, calcium triggers the stimulus-secretion coupling process which leads to insulin release from the pancreatic beta-cells (1). Calcium also tightens cell membranes, thereby decreasing their permeability to various substances, including glucose (2). Finally, calcium mediates cellular responses to glucagon stimulation (3,4) and thus affects the hepatic glucose output. Calcium apparently influences glucose metabolism by several pathways and different overall effects on the blood glucose concentration may be forthcoming depending on which of these pathways is the dominating one.(ABSTRACT TRUNCATED AT 250 WORDS)
To investigate whether anterior pituitary function is disturbed in chronic alcoholic men after a period of alcoholic abuse, TSH and PRL secretagogues were given to such patients in the acute and late withdrawal states (1 and 8 days after admission to hospital, respectively). The TSH and PRL responses were compared with those obtained in a group of control patients without a history of alcohol abuse. Twenty five micrograms of TRH, injected iv in six alcoholic men during acute withdrawal, raised TSH by 1.6 +/- 0.8 (SEM) microU/ml and PRL by 18 +/- 7 ng/ml. In the seven control patients the corresponding responses were significantly larger (7.8 +/- 1.4 microU/ml, P less than 0.01; and 56 +/- 10 ng/ml, P less than 0.02, respectively). When the alcoholics were reinvestigated in the late withdrawal state their TSH and PRL responses increased significantly to 2.9 +/- 1.1 microU/ml (P less than 0.05) and 41 +/- 9 ng/ml (P less than 0.05), respectively. To determine whether dopaminergic inhibition contributed to the reduced TSH and PRL responsiveness in the acute withdrawal state, six additional chronic alcoholic men were tested with oral metoclopramide. This drug, which has dopamine D2-receptor blocking properties, induced similar PRL responses (7- to 8-fold PRL increments) in the acute and late withdrawal states but did not alter TSH. Furthermore, TRH, injected 90 min after oral priming with metoclopramide in six additional alcoholics, elicited TSH and PRL increments in the acute withdrawal state which did not differ significantly from those obtained in the late withdrawal state (TSH, 3.5 +/- 0.9 vs. 4.1 +/- 1.2 microU/ml; PRL, 27 +/- 3 vs. 24 +/- 6 ng/ml). These findings suggest that dopaminergic inhibition of the thyrotrophs and lactotrophs may be responsible for the blunted TSH and PRL responses to TRH during the acute withdrawal period in chronic alcoholic patients.
The influence of iv administration of 0.2 mg thyrotropin-releasing hormone (TRH) on serum calcium was examined in 20 subjects divided into three different groups: one, comprising patients with primary hypothyroidism (A), another, containing euthyroid patients with various diseases (B), and a third, including healthy volunteers (C). Ninety min after the TRH injection total serum calcium (T-Ca) had fallen by 0.19 +/- 0.03 mmol/l in group A (p less than 0.01), by 0.10 +/- 0.02 mmol/l in group B (p less than 0.01), and by 0.08 +/- 0.02 mmol/l in group C (p less than 0.02). Ionized serum calcium (I-Ca) fell in parallel with T-Ca in group A and B. In contrast, serum magnesium was unaffected in all groups. Neither the renal excretion of calcium nor the serum concentration of parathyroid hormone, glucagon or calcitonin changed significantly in response to TRH. These results indicate that TRH has a slight hypocalcemic effect in man which is not caused by plasma dilution, direct influence on the kidneys, or TRH effects on the major calcium regulating hormones. Whether TRH per se, or an increased serum TSH level, induces calcium to leave the vascular space remains to be elucidated.
The aim of the present study was to test whether cimetidine (Cim) influences PIF (prolactin inhibitory factor), and thereby indirectly affects the release of prolactin (PRL) from the pituitary lactotrophs. For that purpose 10 mg metoclopramide (Met), known for its dopamine-receptor blocking properties, were first given orally to 6 subjects. This raised the PRL level from 13 +/- 2 to 97 +/- 12 ng/ml in 60 min (p less than 0.001). PRL tended to plateau at this level until 120 min. An additional 7 subjects were then injected iv with 400 mg Cim, 90 min after oral administration of placebo. Placebo did not change the basal PRL level, but the subsequent Cim injection raised the PRL level from 14 +/- 4 to 66 +/- 9 ng/ml (p less than 0.01). When, in the same subjects, an oral dose of Met was given (10 mg) PRL increased from 19 +/- 4 to 112 +/- 10 ng/ml (p less than 0.001). A subsequent Cim injection, given on top of the PRL plateau, 90 min after the Met ingestion, however, failed to induce any further increase in PRL. To exclude that this failure was not merely a reflection of a Met-induced depletion of the PRL stores, 25 micrograms thyrotropin-releasing hormone (TRH) were given iv to an additional 6 subjects, 90 min after ingestion of either placebo or Met. Also in these subjects placebo left basal PRL unaffected. The subsequent TRH injection, however, raised PRL from 10 +/- 2 to 55 +/- 6 ng/ml (p less than 0.001). Met increased PRL from 17 +/- 4 to 133 +/- 19 ng/ml (p less than 0.01) in these subjects, and TRH, subsequently injected, induced a further PRL increase to 174 +/- 18 ng/ml (p less than 0.01). The observation that Cim fails to elicit an increase in PRL after priming with Met thus indicates that Cim, under normal conditions, stimulates the PRL release via a reduced dopaminergic inhibition of the lactotrophs.
The present investigation was carried out in order to study the acute effects of hypercalcemia on the carbohydrate metabolism in healthy subjects and in patients with non insulin-dependent diabetes mellitus (NIDDM). The combined effect of hypercalcemia and a calcium-antagonistic agent (verapamil) was also studied in healthy subjects, in patients with chronic hypercalcemia, e.g. primary hyperparathyroidism (PHPT). Calcium, infused intravenously to fasting diabetic patients, induced a significant decline in the blood glucose concentration. This was not the case in healthy individuals. When glucose was administered orally during exogenous hypercalcemia, glucose tolerance decreased significantly in the diabetic as well as in the healthy individuals. Verapamil, however, abolished this hypercalcemia effect, and even improved the tolerance for oral glucose when administered intravenously together with calcium in the patients with NIDDM. No such effect of verapamil was seen in the healthy subjects or in the patients with PHPT. Insulin activity was left unaffected by hypercalcemia and/or verapamil in all experimental situations. These findings thus imply that hypercalcemia decreases the tolerance for oral glucose in normoglycemic subjects, and further deteriorates the glucose tolerance in patients with an already impaired carbohydrate metabolism. Verapamil, on the other hand, appears to counteract this effect of hypercalcemia in diabetic patients. Since insulin remains unaffected by calcium and verapamil in the above mentioned situations, it is reasonable to assume that the calcium- and verapamil-induced effects on the glucose tolerance are due to glucose-regulatory factors other than insulin.
To investigate whether exogenous hypercalcemia influences the release of TSH from the anterior pituitary, 25 microgram TRH were injected iv in six healthy subjects who were pretreated orally with either 10 mg metoclopramide or placebo and infused iv with either calcium or saline. Under normocalcemic conditions, TRH raised the serum TSH level from 1.1 +/- 0.1 to 8.0 +/- 3.3 microU/ml (P less than 0.01). Exogenous hypercalcemia reduced this TSH response to TRH by 37 +/- 11% (P less than 0.02). Although metoclopramide was without effect on basal TSH release in an additional five healthy subjects and also left TRH-stimulated TSH release unaffected under normocalcemic conditions, oral pretreatment with the drug counteracted the inhibitory effect of hypercalcemia and restored a normal TSH response to TRH in hypercalcemic subjects. These results indicate that exogenous hypercalcemia may potentiate dopaminergic TSH inhibition in normal individuals.
The current study was performed in order to investigate whether verapamil would affect the glucose response to glucagon differently in patients with non insulin-dependent diabetes mellitus (NIDDM) compared with age-matched normoglycemic controls. For that purpose glucagon was injected intravenously on a background infusion of verapamil, and for comparison also on a background infusion of saline in these two groups. Verapamil was found to blunt the glucose response to glucagon in the patients with NIDDM, whereas it augmented the glucose response to glucagon in the controls. This discrepancy could not be explained on the basis of verapamil-induced changes in the release of insulin, since verapamil did not effect the serum responses to glucagon. However, it could reflect the differences in hepatic handling of glucose, which has been shown to prevail in patients with NIDDM compared with healthy controls.
To study the effect of verapamil on the glucose tolerance and insulin response to oral glucose, 6 healthy subjects and 15 patients with non-insulin-dependent diabetes mellitus (NIDDM) were performed on separate days: 1) A standardized oral glucose load, 2) an identical glucose load during i.v. infusion of verapamil, and 3) a third oral glucose load after one week of oral verapamil treatment. No significant differences were found when the insulin and glucose responses with and without verapamil were compared. The patients with NIDDM were divided into three groups. Two tests were performed on separate days in each patient: group 1, a standardized oral glucose load and an identical glucose load during i.v. verapamil infusion; group 2, a standardized oral glucose load and a similar glucose load after one week of oral verapamil treatment; group 3, the protocol of group 2 was followed but oral placebo was given instead of verapamil. In groups 1 and 2, verapamil improved the tolerance for oral glucose, whereas the insulin response remained unaffected. In group 3, no significant differences were found in the insulin and glucose responses to the two oral glucose loads. These findings thus imply that verapamil improves the tolerance for oral glucose regardless of the route of verapamil administration in patients with NIDDM. They also indicate that this is accomplished by an effect of verapamil on other glucose regulatory factors than insulin.
The effect of verapamil on the tolerance for oral glucose and on the pancreatic release of insulin was investigated in 6 normoglycemic patients admitted to hospital because of abdominal diseases. Each patient was studied twice. On one occasion, 100 g glucose was ingested during simultaneous i.v. infusion of verapamil, on the other, glucose was given during i.v. infusion of saline. Blood samples for insulin and glucose measurements were collected simultaneously via a portal and an antecubital vein catheter. It was found that the blood glucose and serum insulin responses to oral glucose were unaffected by verapamil both in the portal and in the peripheral venous blood. These findings imply that the pancreatic release of insulin, the tolerance for oral glucose, and the intestinal absorption of glucose remain unaffected by i.v. verapamil in normoglycemic individuals.