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The results of octreotide scintigraphy, performed in two patients with malignant endocrine pancreatic tumors, were compared with the effect of somatostatin-14 and its analogue octreotide on hormonal levels and clinical outcome. Radiolabeled octreotide failed to demonstrate any tumor localisation in a patient with a malignant insulinoma. Nevertheless, IV injection of somatostatin and octreotide resulted in a significant decrease in peripheral insulin levels. Moreover in this patient, chronic treatment with a high dose of octreotide subcutaneously was able to transiently lower the incidence of hypoglycemic events. In a second patient with metastatic PP-oma, 111In-octreotide disclosed a pancreatic tumor in the tail of the pancreas and metastatic supraclavicular lymph nodes. In this patient IV administration of somatostatin and octreotide inhibited the hormonal secretion of the tumor but subcutaneous injection of octreotide induced hardly any decrease in plasma PP levels and failed to affect tumor growth. These observations find a possible reason for this in the heterogeneous affinity of the somatostatin receptors in endocrine pancreatic tumors. They indicate that octreotide scintigraphy alone should not be used to select patients with neuroendocrine tumors who can benefit from chronic treatment with the somatostatin analogue.

In Type 1 diabetes an increased total body sodium and an impaired ability to excrete a sodium load have been described. A possible involvement of the renal dopaminergic system in this abnormal sodium handling was evaluated through measurements of the urinary output of dopamine, sodium, the dopamine/sodium correlation, and through examining the effect of a dopamine infusion on urinary sodium excretion. Twenty-four hour urinary dopamine excretion was significantly lower in Type 1 diabetic patients as compared to normal controls. A significant correlation between urinary dopamine and sodium excretion was present in normoalbuminuric Type 1 diabetic patients and in normal controls. However, no such correlation could be found in microalbuminuric patients. The increase in fractional excretion of sodium during a 1 h low-dose dopamine (3 micrograms kg-1 min-1) infusion in Type 1 diabetic patients was negatively correlated with diabetes duration. Patients with short duration of diabetes (less than 15 years) had a comparable dopamine-induced increase in fractional excretion of sodium as normal controls. However, patients with longer duration of diabetes (more than 15 years) and microalbuminuric patients displayed no significant changes in sodium output during dopamine infusion. These findings suggest that in Type 1 diabetes mellitus a deficiency of renal dopamine production could be responsible for the impaired sodium handling. Longer duration of the disease and microalbuminuria seem to be associated with an uncoupling of the urinary dopamine/sodium relationship.

The hitherto identified hallmarks of the autoimmune aspects in Type 1 diabetes are reviewed. Their implication in the disclosure of the pre-clinical phase of the disease is put forward. The possible delineation of this pre-diabetic phase can lead to an early immunotherapeutic approach. The effect of immunomodulation by agents such as azathioprine, cyclosporin A and nicotinamide in newly diagnosed diabetes and the use of some of these drugs in clinical trials on pre-diabetic individuals are discussed.

Both delayed and accelerated gastric emptying rate (GER) have been reported in patients with diabetes mellitus. Delayed GER has been attributed to autonomic neuropathy in established diabetes but rapid GER was demonstrated in early Type 2 diabetes. The aim of the study was to investigate rapid gastric emptying in a group of people with long-duration Type 2 diabetes. GER of a radiolabelled liquid meal was studied scintigraphically in 20 Type 2 patients with a mean (+/-SEM) duration of diabetes 13 (+/-1) years. The 50% emptying time (t50) for the liquid meal was shorter in diabetic patients (29.6+/-2.1 min) than in controls (39.2+/-1.9 min; p

PMID: 7556811 [PubMed - indexed for MEDLINE]

The case of a woman suffering from progressive diaphyseal dysplasia is presented. Characteristic symptoms of crippling pain in both legs, severe aching in both forearms, and episodic temporofrontal and occipital headache were only partially regulated by corticosteroid treatment. However, pregnancy resulted in a progressive disappearance of these symptoms, allowing withdrawal of steroid treatment. Tc-99m MDP scintigraphy performed immediately after delivery showed a decrease of the intense uptake in the forearms, tibiae, and skull, which had been documented prior to pregnancy. However, widespread pain recurred within 6 weeks after delivery, accompanied by a recurrence of multiple severely hyperactive foci on bone scintigraphy. Alterations of immune modulated processes and changes in bone mineral homeostasis and in endogenous cortisol metabolism during pregnancy can be considered as possible explanations for the temporary improvement in clinical and scintigraphic signs of progressive diaphyseal dysplasia in this patient.

Three patients are reported with false positive enzyme-linked immunosorbent assay (ELISA) for IgG antibodies against Borrelia burgdorferi, respectively associated with undifferentiated connective tissue disease or systemic lupus erythematosus. These cases further document that Lyme serology should be interpreted with caution and within the clinical context.

The hitherto identified hallmarks of the autoimmune aspects in Type 1 diabetes are reviewed. Their implication in the disclosure of the pre-clinical phase of the disease is put forward. The possible delineation of this pre-diabetic phase can lead to an early immunotherapeutic approach. The effect of immunomodulation by agents such as azathioprine, cyclosporin A and nicotinamide in newly diagnosed diabetes and the use of some of these drugs in clinical trials on pre-diabetic individuals are discussed.

Clinical improvement during pregnancy in a case of progressive diaphyseal dysplasia.

Two cases of hepatic artery aneurysm are reported. The first presented as obstructive jaundice, the second as an upper gastrointestinal bleeding. The diagnosis was made by performing ultrasound, CT-scan and angiography. In both cases surgery was the treatment. However, in some cases, interventional angiography with embolisation of the affected vessel offers an alternative treatment.

The relationship between metabolic control and leukocyte glycogen content in diabetes mellitus was re-evaluated, blood glycogen being measured by an enzymatic procedure. In 30 healthy subjects, fasting blood glycogen averaged 50.6 ± 2.8 mg l−1 or 7.45 ± 0.42 ng 103-cells−1, the latter value being unaffected during a 60-min period of induced hyperglycaemia. Comparable levels were found in 18 Type 1 insulin-treated diabetic patients (blood glycogen 50.4 ± 4.6 mg l−1, leukocyte glycogen 6.92 ± 0.50 ng 103-cells−1), 6 insulin-treated diabetic patients presenting with chronic pancreatitis (blood glycogen 62.2 ± 9.3 mg l−1, leukocyte glycogen 6.69 ± 0.70 ng 103-cells−1) and 12 Type 2 insulin-treated patients (blood glycogen 53.7 ± 4.3 mg l−1, leukocyte glycogen 7.51 ± 0.44 ng 103-cells−1). In severely ketotic patients, leukocyte counts and blood glycogen (160.8 ± 29.6 mg l−1, p < 0.01 vs stable diabetic patients) were increased, but the leukocytic glycogen content was not significantly affected either before or during intensive insulin therapy and rehydration. The leukocyte glycogen content was abnormally low, however, in 9 untreated Type 2 diabetic patients (5.29 ± 0.39 ng 103-cells−1, p < 0.02 vs healthy subjects) and abnormally high (10.77 ± 0.65 ng 103-cells−1, p < 0.005 vs healthy individuals) in 30 Type 2 patients treated by sulphonylurea, alone or in combination with insulin. No correlation was found between leukocyte glycogen and either fasting plasma glucose or HbA1c. These findings indicate that blood glycogen is not a reliable index of metabolic control in diabetic patients, and may be affected by factors such as insulin concentration or efficacy, blood glucose level, and sulphonylurea administration.

Glyceraldehyde is known to stimulate insulin release. Its influence on various parameters of islet function was investigated in order to assess the possible significance of glycolsis in the insulinotropic action of glucose. In the absence of glucose, glyceraldehyde (5-20 mM), but neither dihydroxyacetone nor glycerol stimulated insulin release in rat isolated islets. The glucose-like effect glyceraldehyde (10 mM) was characterized by a shift to the left of the curve relating insulin release to glucose concentration, without any significant increase in the maximal velocity of the secretory process. In the isolated perfused rat pancreas, glyceraldehyde provoked a biphasic secretory response. Glyceraldehyde-induced insulin release was inhibited in the absence of calcium or in the presence of epinephrine, unaffected by mannoheptulose or 3,3-tetramethyleneglutaric acid, and enhanced by theophylline and cytochalism B. Glyceraldehyde also stimulated to pro-insulin biosynthesis and 45Ca net uptake by isolated islets, the latter effect being apparently due, in part at least, to inhibition of calcium outward transport across the cell membrane. At concentrations of nearly equivalent insulinotropic potency, glucose and glyceraldehyde were metabolized at rates yielding comparable output of both lactate and 14CO2. The data indicate that glyceraldehyde mimics many effects of glucose on islet function, suggesting that the insulinotropic action of glucose may be related to its metabolism through the glycolytic pathway.

The modality of Ba2+-induced insulin release was investigated in the isolated perfused rat pancreas. The insulinotropic action of Ba2+ was antagonized by Ca2+, Mg2+ and verapamil, and enhanced by EGTA, theophylline, glucose and cytochalasin B. Likewise the net uptake of 133Ba2+ by isolated islets was inhibited by Ca2+, Mg2+ and verapamil. Glucose increased 133Ba2+ net uptake, but only when sufficient Ba2+ had accumulated in the islets. Theophylline failed to affect 133Ba2+ net uptake. These data suggest that (i) Ba2+-induced insulin release is dependent on the accumulation of this cation in the B-cell; (ii) Ba2+ inward transport in the B-cell occurs through a verapamil-sensitive channel characterized by competition between Ba2+, Ca2+ and Mg2+; and (iii) the enhancing effect of theophylline upon insulin release could be due to an intracellular translocation of alkaline-earth cations rather than to an increase in their net uptake. The present findings also support the idea that insulin release can be triggered by the accumulation of suitable divalent cations in a critical site of the B-cell, leading to the activation of a cytochalasin B-response effector system.

Extracellular Ca2+, at concentrations exceeding 10 mmol/l, causes a dose-related stimulation of insulin release. The dynamics of Ca2+-induced insulin release are characterized by a quick onset, a progressive build-up and a later return towards basal secretory rate. The release of insulin evoked by Ca2+ is inhibited in the presence of either Mg2+ (10 mmol/l) or the organic Ca2+-antagonist verapamil (81 μmol/l), both of which are known to inhibit Ca2+ entry in the B-cell. Glucose and theophylline, which are thought to affect the net uptake or intracellular distribution of Ca2+ in the B-cell, both enhance Ca2+-induced insulin release. As little as 2.7 mmol/l glucose is sufficient to augment Ca2+-induced insulin secretion. Exposure of the pancreas to somatostatin significantly retards the secretory response to Ca2+. Cytochalasin B potentiates the insulin release evoked by Ca2+ (12 mmol/l) and lowers the threshold concentration of Ca2+ required to stimulate secretion. These data suggest that high extracellular Ca2+ concentrations may sufficiently increase the amount of Ca2+ accumulated in the B-cell to eventually trigger insulin release. Agents known to cause a remodelling of Ca2+ fluxes across membrane systems in the B-cell interfere with Ca2+-induced insulin release, a process also dependent on the integrity of the cytochalasin B-sensitive microfilamentous effector system.

The active role played by beta-cell microfilamentous structures in the dynamics of insulin secretion was investigated by examining the influence of cytochalasin B upon various parameters of hormonal release by the isolated perfused rat pancreas. The view that the cytochalasin-induced changes in insulin release are due to a primary biophysical effect on microfilaments, rather than to an unrelated biochemical alteration of the beta-cell glucose-sensor device, was strengthened by the following observations: (1) the onset and disappearance of the cytochalasin B-induced facilitating action upon insulin release followed a time-course parallel to that characterizing the ultrastructural changes provoked by the drug in the distribution of beta-cell microfilamentous material; and (2) cytochalasin B facilitated leucine-induced insulin release in the presence of a very low glucose concentration. The mold metabolite was also found to transform transient secretory responses into biphasic ones and to prevent the reduction that normally affects the early response to insulinotropic agents when the pancreas is stimulated a few minutes after a prior and short exposure to glucose. The release of insulin evoked by either glucose or gliclazide was abolished in the absence of extracellular calcium, whether in the presence or absence of cytochalasin B. Theophylline and cytochalasin B exerted a synergistic effect upon glucose-induced insulin release. These data support the concept that calcium-dependent contractile events involving cytochalasin B-sensitive microfilamentous structures provide the motive force for both the intracellular translocation and exocytotic release of beta granules.

The role of extracellular Ca2+ in the regulation of islet function is investigated. Decreasing extracellular Ca2+ concentrations cause a dose-related inhibition of glucose-induced insulin release. Whereas the efflux of 45Ca from perifused islets is transiently increased on exposure to Ca2+-deprived media, it is unaffected by a partial lowering of the extracellular Ca2+ concentration. Under the latter condition, therefore, the observed reduction in the size of the islets' exchangeable calcium pool(s) appears to be due to reduced Ca2+ entry. The proper effect of glucose on Ca handling by the islets is apparently not affected by a lowering in the extracellular Ca2+ concentration. Nevertheless, in islets exposed to glucose and incubated in Ca2+-deprived media, glucose uptake and oxidation and lactate output are decreased, whereas the islet ATP level is increased, as if extracellular Ca2+ shortage were to affect not only the cellular pool of Ca regulating insulin release, but also energy-consuming processes possibly located at the cell membrane.

1. In isolated pancreatic islets, pyruvate causes a shift to the left of the sigmoidal curve relating the rate of insulin release to the ambient glucose concentration. The magnitude of this effect is related to the concentration of pyruvate (5–90 mM) and, at a 30 mM concentration, is equivalent to that evoked by 2 mM-glucose. Pyruvate also enhances insulin release in the presence of fructose, leucine and 4-methyl-2-oxopentanoate. 2. In the presence of glucose 8 mM), the secretory response to pyruvate is an immediate process, displaying a biphasic pattern. 3. The insulinotropic action of pyruvate coincides with an inhibition of 45Ca efflux and a stimulation of 45Ca net uptake. The relationship between 45Ca uptake and insulin release displays its usual pattern in the presence of pyruvate. 4. Exogenous pyruvate rapidly accumulates in the islets in amounts close to those derived from the metabolism of glucose. The oxidation of [2-14C]pyruvate represents 64% of the rate of [1-14C]pyruvate decarboxylation and, at a 30 mM concentration, is comparable with that of 8 mM-[U-14C]glucose. 5. When corrected for the conversion of pyruvate into lactate, the oxidation of 30 mM-pyruvate corresponds to a net generation of about 314 pmol of reducing equivalents/120 min per islet. 6. Pyruvate does not affect the rate of glycolysis, but inhibits the oxidation of glucose. Glucose does not affect pyruvate oxidation. 7. Pyruvate (30 mM) does not affect the concentration of ATP, ADP and AMP in the islet cells. 8. Pyruvate (30 mM) increases the concentration of reduced nicotinamide nucleotides in the presence but not in the absence of glucose. A close correlation is seen between the concentration of reduced nicotinamide nucleotides and the net uptake of 45Ca. Menadione inhibits the effect of pyruvate on insulin release, without altering its rate of oxidation. 9. Pyruvate, like glucose, modestly stimulates lipogenesis. 10. Pyruvate, in contrast with glucose, markedly inhibits the oxidation of endogenous nutrients. The latter effect accounts for the apparent discrepancy between the rate of pyruvate oxidation and the magnitude of its insulinotropic action. 11. Dichloroacetate fails to affect glucose oxidation and glucose-stimulated insulin release. 12. It is concluded that the effect of pyruvate to stimulate insulin release depends on its ability to increase the concentration of reduced nicotinamide nucleotides in the islet cells.

Peripheral levels of basal and tolbutamide-induced somatostatin have been measured in patients with diabetes or impaired glucose tolerance (IGT) and compared with those in normal individuals. Basal somatostatin was significantly higher in patients with Type 1 diabetes than in age-matched control subjects. This increase was most pronounced at diagnosis, and appeared to be related to metabolic control in insulin-treated patients. No increase was noted in patients with Type 2 diabetes or with IGT. Intravenous bolus injection of tolbutamide enhanced peripheral somatostatin levels in healthy volunteers in a biphasic manner. Patients with IGT also exhibited a biphasic response but the amplitude of the first phase was higher. No secretory response was detected in 27/29 Type 1 diabetic patients at diagnosis; a somatostatin response to tolbutamide became detectable again in Type 1 patients with normalization of their basal somatostatin levels but was then paradoxically related to poor blood glucose control. In Type 2 diabetes, basal somatostatin levels were similar to age-matched control subjects, but decreased upon intravenous tolbutamide administration.

D-erythrose (5.0 to 20.0 mM) stimulates insulin release. This insulinotropic action of erythrose displays several features in common with that of glucose. First, erythrose (20 mM) causes a shift to the left of the sigmoidal curve relating the secretory rate to the glucose eoncentration, but fails to enhance the maximal response to glucose. Second, the secretory response to erythrose occurs as an early peak followed by a phase of sustained release. Third, erythrose increases the output of lactate from the islets. Last, erythrose inhibits the efflux of 45calcium and favours its accumulation in isolated islets. It is suggested that, whether in response to glucose or erythrose, an increase in glycolytic flux may represent the key process involved in the identification of the secretagogue, a subsequent remodeling of calcium fluxes being apparently responsible for the activation of the insulin-releasing system.

The inophore A23187 stimulates the translocation of calcium from an aqueous Hepes buffer into an organic immiscible phase. At saturating calcium concentrations, 2 molecules of ionophore seem to complex each atom of calcium. Consistent with such a stoichiometric behaviour, the apparent ratio of calcium-ionophore association to dissociation rate constants increases as the concentration of ionophore is raised. As a result, at low calcium concentrations, the amount of translocated calcium increases as a power function of A23187 concentration. When allowance is made for such a phenomenon, the relation between calcium translocation and concentration is characterized by usual substrate-receptor binding kinetics.

The effect of colchicine upon glucose induced insulin release by the isolated perfused rat pancreas was examined in order to characterize the participation of the β cell microtubular apparatus in the biphasic insulin secretory response to glucose. After a short pretreatment (25 min) with a low colchicine concentration (2 x 10 -5 M), both the early and late phases of glucose induced insulin secretion were markedly enhanced. As either the concentration of colchicine or the length of the pretreatment period with this mitotic spindle inhibitor were increased, the facilitating effect faded out and partial inhibition of insulin release was observed. However, colchicine, even at high concentration, markedly enhanced the residual early release of insulin evoked by glucose in the presence of diazoxide (0.05 mg/ml). These findings suggest that a fraction of the early phase of insulin secretion completely escapes from the inhibitory effect of colchicine and may correspond, therefore, to a modality of hormonal release which does not involve the oriented intracellular translocation of secretory granules; and extensive disruption of the microtubular apparatus is associated with inhibition of insulin release, especially during the late phase of the secretory response to glucose.

A duodenal somatostatinoma is described in a patient suffering from a tumoral obstruction of the bile duct. The diagnosis was based upon histologic and immunocytochemical characterization of tumoral fragments and later confirmed by immunochemical analysis of liver metastases. Basal peripheral somatostatin immunoreactivity levels were normal until liver failure developed. A hypersomatostatinemia was induced by combined injection of calcium and pentagastrin, which was not the case in normal volunteers or in patients with disseminated pancreatic adenocarcinoma. This test was also positive in a case of generalized pancreatic somatostatinoma 4 yr after streptozotocin treatment. It was concluded that the calcium-pentagastrin test might be useful in the diagnosis of somatostatinomas.

The present experiments were designed to assess the extent to which the β-cell microtu-bular-microfilamentous system contributes to the release of insulin evoked by glucose or sulfonylurea in the isolated perfused rat pancreas. Deuterium oxide (100%, v/v), which is thought to interfere with micro-tubular-microfilamentous function, was found to suppress insulin release during both the early and late phases of the secretory process. The inhibitory effect of D2O was reversible. When the pancreases) were first exposed to cytochalasin B (10 µg/ml) and, thereafter, (to both cytochalasin B and D2O, an escape)phenomenon from the D2O-induced inhibition was) invariably observed in response to either glucose or sulfonylurea. This escape phenomenon supports the view that the inhibitory effect of D2O on insulin)release is mainly due to a functional sideration of the microtubular-microfilamentous system. The present data suggest, therefore, that such a system is actively, involved in both phases of insulin release. (En...

The stimulus-secretion coupling of 2-keto acid-induced insulin release was investigated using 2-ketoisocaproate (4-methyl-2-oxopentanoate) as the principal model secretagogue. 2-Ketoisocaproate and 2-ketocaproate (2-oxo-, hexanoate) provoked changes in B cell electrical behavior characterized by an initial depolarization of the membrane potential, followed by rapid spike activity, which appeared either in a bursting pattern or as continuous activity. The onset of spike activity induced by 2-ketoisocaproate (5 mM) was biphasic in nature. The dynamic pattern of 2-ketoisocaproate-induced insulin release was also biphasic. 2-[U-14C]Ketoisocaproate (10 mM) was oxidized in islet tissue at a rate equivalent to that of [U-14C]glucose (17 mM) and a t a higher rate than 2-ketoisovalerate (3-methyl-2-oxobutyrate) and 2-keto-3-methyl-valerate, which were poor secretagogues. Like glucose, 2-ketoisocaproate provoked characteristic changes in 86Rb and 45Ca efflux from prelabeled islets and stimulated 45Ca net uptake. Proinsulin synthesis was stimulated by 2-ketoisocaproate through both a general effect on protein synthesis and a specific effect on hormonal biosynthesis. 2-Ketoisocaproate and 2-ketocaproate reproduced the effect of glucose on the islet content of ATP, ADP, AMP, NAD+, NADH, NADP+, and NADPH. These findings together with a series of observations on the effects upon the above parameters of site-specific inhibitors, e.g. respiratory inhibitors, suloctidil, theophylline, and epinephrine, suggested that the stimulus-secretion-coupling mechanisms for 2-ketoisocaproate- and glucose-induced release are similar. It is postulated that glucose- and 2-keto acid-induced insulin release may be initiated by a common signal.

In order to document the participation of microtubules in the dynamics of insulin release, the secretory response of the isolated perfused rat pancreas was measured after various times of exposure to vincristine (2.10−5M). After a short exposure time (25 min), both phases of glucose-induced insulin release were increased. After longer pretreatment (60 min), this facilitating effect disappeared and a slight, insignificant reduction of both phases of the secretory response to glucose was observed. A still longer exposure time (120 min) provoked a more marked and significant inhibition of the early and late phases of insulin release. The same enhancing effect after short pretreatment with vincristine was noticed when gliclazide was used as the insulinotropic agent. The ultrastructural studies indicated a progressive disappearance of microtubules concomitantly with an increase in number and size of vincristine-induced paracrystalline deposits. These findings suggest that microtubules indeed participate in the dynamics of insulin release, a reduction of both phases of insulin secretion being caused by an extended disruption of the microtubular apparatus, whereas a more limited disturbance of the microtubular system appears to be associated with facilitated insulin release in response to either glucose or sulfonylurea.