Sporadic multiple parathyroid gland disease-a consensus report of the European Society of Endocrine Surgeons (ESES)

BACKGROUND: Sporadic multiglandular disease (MGD) has been reported in literature in 8–33 % of patients with primary hyperparathyroidism (pHPT). This paper aimed to review controversies in the pathogenesis and management of sporadic MGD. METHODS: A literature search and review was made to evaluate the level of evidence concerning diagnosis and management of sporadic MGD according to criteria proposed by Sackett, with recommendation grading by Heinrich et al. and Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system. Results were discussed at the 6th Workshop of the European Society of Endocrine Surgeons entitled ‘Hyperparathyroidism due to multiple gland disease: An evidence-based perspective’. RESULTS: Literature reports no prospective randomised studies; thus, a relatively low level of evidence was achieved. Appropriate surgical therapy of sporadic MGD should consist of a bilateral approach in most patients. Unilateral neck exploration guided by preoperative imaging should be reserved for selected patients, performed by an experienced endocrine surgeon and monitored by intraoperative parathormone assay (levels of evidence III–V, grade C recommendation). There is conflicting or equally weighted levels IV–V evidence supporting that cure rates can be similar or worse for sporadic MGD than for single adenomas (no recommendation). Best outcomes can be expected if surgery is performed by an experienced parathyroid surgeon working in a high-volume centre (grade C recommendation). Levels IV–V evidence supports that recurrent/persistence pHPT occurs more frequently in patients with double adenomas hence in situations where a double adenoma has been identified, the surgeon should have a high index of suspicion during surgery and postoperatively for the possibility of a four-gland disease (grade C recommendation). CONCLUSIONS: Identifying preoperatively patients at risk for MGD remains challenging, intraoperative decisions are important for achieving acceptable cure rates and long-term follow-up is mandatory in such patients

Inward and outward currents of native and cloned K(ATP) channels (Kir6.2/SUR1) share single-channel kinetic properties

BACKGROUND: The ATP-sensitive K(+) (K(ATP)) channel is found in a variety of tissues extending from the heart and vascular smooth muscles to the endocrine pancreas and brain. Common to all K(ATP) channels is the pore-forming subunit Kir6.x, a member of the family of small inwardly rectifying K(+) channels, and the regulatory subunit sulfonylurea receptor (SURx). In insulin secreting β-cells in the endocrine part of the pancreas, where the channel is best studied, the K(ATP) channel consists of Kir6.2 and SUR1. Under physiological conditions, the K(ATP) channel current flow is outward at membrane potentials more positive than the K(+) equilibrium potential around −80 mV. However, K(ATP) channel kinetics have been extensively investigated for inward currents and the single-channel kinetic model is based on this type of recording, whereas only a limited amount of work has focused on outward current kinetics. METHODS: We have estimated the kinetic properties of both native and cloned K(ATP) channels under varying ionic gradients and membrane potentials using the patch-clamp technique. RESULTS: Analyses of outward currents in K(ATP) and cloned Kir6.2ΔC26 channels, alone or co-expressed with SUR1, show openings that are not grouped in bursts as seen for inward currents. Burst duration for inward current corresponds well to open time for outward current. CONCLUSIONS: Outward K(ATP) channel currents are not grouped in bursts regardless of membrane potential, and channel open time for outward currents corresponds to burst duration for inward currents

Evidence for Presence and Functional Effects of Kv1.1 Channels in β-Cells: General Survey and Results from mceph/mceph Mice

BACKGROUND:Voltage-dependent K(+) channels (Kv) mediate repolarisation of β-cell action potentials, and thereby abrogate insulin secretion. The role of the Kv1.1 K(+) channel in this process is however unclear. We tested for presence of Kv1.1 in different species and tested for a functional role of Kv1.1 by assessing pancreatic islet function in BALB/cByJ (wild-type) and megencephaly (mceph/mceph) mice, the latter having a deletion in the Kv1.1 gene. METHODOLOGY/PRINCIPAL FINDINGS:Kv1.1 expression was detected in islets from wild-type mice, SD rats and humans, and expression of truncated Kv1.1 was detected in mceph/mceph islets. Full-length Kv1.1 protein was present in islets from wild-type mice, but, as expected, not in those from mceph/mceph mice. Kv1.1 expression was localized to the β-cell population and also to α- and δ-cells, with evidence of over-expression of truncated Kv1.1 in mceph/mceph islets. Blood glucose, insulin content, and islet morphology were normal in mceph/mceph mice, but glucose-induced insulin release from batch-incubated islets was (moderately) higher than that from wild-type islets. Reciprocal blocking of Kv1.1 by dendrotoxin-K increased insulin secretion from wild-type but not mceph/mceph islets. Glucose-induced action potential duration, as well as firing frequency, was increased in mceph/mceph mouse β-cells. This duration effect on action potential in β-cells from mceph/mceph mice was mimicked by dendrotoxin-K in β-cells from wild-type mice. Observations concerning the effects of both the mceph mutation, and of dendrotoxin-K, on glucose-induced insulin release were confirmed in pancreatic islets from Kv1.1 null mice. CONCLUSION/SIGNIFICANCE:Kv1.1 channels are expressed in the β-cells of several species, and these channels can influence glucose-stimulated insulin release

Prolactin Receptor in Primary Hyperparathyroidism – Expression, Functionality and Clinical Correlations

<div><h3>Background</h3><p>Primary hyperparathyroidism (PHPT) is an endocrine disorder most commonly affecting women, suggesting a role for female hormones and/or their receptors in parathyroid adenomas. We here investigated the prolactin receptor (PRLr) which is associated with tumours of the breast and other organs.</p> <h3>Methodology/Principal Findings</h3><p>PRLr expression was investigated in a panel of 37 patients with sporadic parathyroid tumours and its functionality in cultured parathyroid tumour cells. In comparison with other tissues and breast cancer cells, high levels of prolactin receptor gene (<em>PRLR</em>) transcripts were demonstrated in parathyroid tissues. PRLr products of 60/70 kDa were highly expressed in all parathyroid tumours. In addition varying levels of the 80 kDa PRLr isoform, with known proliferative activity, were demonstrated. In parathyroid tumours, PRLr immunoreactivity was observed in the cytoplasm (in all cases, n = 36), cytoplasmic granulae (n = 16), the plasma membrane (n = 12) or enlarged lysosomes (n = 4). In normal parathyroid rim (n = 28), PRLr was uniformly expressed in the cytoplasm and granulae. In <em>in vitro</em> studies of short-term cultured human parathyroid tumour cells, prolactin stimulation was associated with significant transcriptional changes in JAK/STAT, RIG-I like receptor and type II interferon signalling pathways as documented by gene expression profiling. Moreover, <em>PRLR</em> gene expression in parathyroid tumours was inversely correlated with the patients’ plasma calcium levels.</p> <h3>Conclusions</h3><p>We demonstrate that the prolactin receptor is highly abundant in human parathyroid tissues and that PRLr isoforms expression and PRLr subcellular localisation are altered in parathyroid tumours. Responsiveness of PRLr to physiological levels of prolactin was observed in the form of increased PTH secretion and altered gene transcription with significant increase of RIG-I like receptor, JAK-STAT and Type II interferon signalling pathways. These data suggest a role of the prolactin receptor in parathyroid adenomas.</p> </div

Metabolic signals and the ATP-sensitive potassium channel in the pancreatic [beta]-cell

ATP-sensitive K+ (KATP) channels are widely distributed in a variety of tissues and cell types. KATP channels are comprised of two subunits, a pore forming subunit (Kir6.x) and a regulatory sulfonylurea receptor (SURx). Both subunits are required for fully functional channels. In the present thesis the role of the pancreatic [beta]-cell KATP channel, with regard to oscillations in electrical activity and modulation of channel activity by various compounds as well as the functional organization of channel subunits, were investigated. In the [beta]-cell the KATP channel (comprised of Kir6.2 and SUR1) couples metabolic changes to electrical activity. Although electrophysiological studies during the last decade have provided clues to the complex control of the KATP channel by various nucleotides and pharmacological agents, the metabolic signals responsible for its physiological regulation remain to be clarified. The widely accepted model of glucose-induced insulin secretion involves a number of events. Following glucose metabolism, the ATP/ADP ratio increases, inducing closure of the KATP channel, depolarization of the [beta]-cell plasma membrane and thereby opening of voltage-gated Ca2+ channels. The rise in cytoplasmic free Ca2+ concentration ([Ca2+]i) triggers insulin release. Oscillations in some or all of these signals are thought to play an important role in the pulsatile nature of insulin release. The molecular mechanism underlying these oscillations is unknown but is an important issue since absence of normal oscillations in plasma insulin levels is observed in non-insulin dependent diabetes mellitus. In this thesis, it is shown that KATP channel activity is oscillating in intact [beta]-cells under stimulatory concentrations of glucose, thereby inducing fluctuations in electrical activity and [Ca2+]i. This effect is likely to reflect oscillations in metabolism, since blocking of glucose metabolism induced openings of the KATP channel that correlated with periods of hyperpolarization and lowering in [Ca2+]i. Glucose is metabolized through glycolysis in the cytosol and through the tricarboxylic acid cycle in the mitochondria. The relative role of mitochondrial metabolism has frequently been studied using [alpha]-ketoisocaproate as substrate. In contrast to previous findings, assuming that [alpha]-ketoisocaproate needs to be metabolized in order to close the KATP channel, it is shown that [alpha]-ketoisocaproate reversibly and in a dose-dependent manner inhibits the KATP channel directly. Besides glucose, free fatty acids (FFA) have been demonstrated to play a critical role in insulin secretion. It is shown that the metabolic active form of FFA, long-chain CoA (LC-CoA) esters, are accumulated intracellularly in response to prolonged exposure to elevated FFA, and are potent and chain-length specific activators of the KATP channel. Using a truncated version of Kir6.2 (Kir6.2[delta]C26), which generates channels in the absence of SUR1, it was shown that LC-CoA esters interact directly with Kir6.2. These findings verify that LC-CoA esters have a unique binding site on the KATP channel complex and may be of physiological importance. Finally, KATPchannels are organized as heterooctameric complexes assembled with a 4:4 stoichiometry of Kir6.2 and SUR1. It is shown that SUR1 plays a critical role in the functional organization of Kir6.2 by a mechanism distinct from the ability of SUR1 to recruit Kir6.2 to the membrane and the ability to convey sensitivity to sulfonylurea and MgADP

Direct Inhibition of the Pancreatic β-Cell ATP-regulated Potassium Channel by α-Ketoisocaproate

The ATP-regulated potassium (KATP) channel plays an essential role in the control of insulin release from the pancreatic β-cell. In the present study we have used the patch-clamp technique to study the direct effects of α-ketoisocaproate on the KATPchannel in isolated patches and intact pancreatic β-cells. In excised inside-out patches, the activity of the KATPchannel was dose-dependently inhibited by α-ketoisocaproate, half-maximal concentration being approximately 8 mm. The blocking effect of α-ketoisocaproate was fully reversible. Stimulation of channel activity by the addition of ATP/ADP (ratio 1) did not counteract the inhibitory effect of α-ketoisocaproate. In the presence of the metabolic inhibitor sodium azide, α-ketoisocaproate was still able to inhibit single channel activity in excised patches and to block whole cell KATP currents in intact cells. No effect of α-ketoisocaproate could be obtained on either the large or the small conductance Ca2+-regulated K+ channel. Enzymatic treatment of the patches with trypsin prevented the inhibitory effect of α-ketoisocaproate. Based on these observations, it is unlikely that the blocking effect of α-ketoisocaproate is due to an unspecific effect on K+ channel pores. Leucine, the precursor of α-ketoisocaproate, did not affectKATP channel activity in excised patches. Our findings are compatible with the view that α-ketoisocaproate not only affects the β-cell stimulus secretion coupling by generation of ATP but also by direct inhibition of the KATPchannel

Mediation of irregular spiking activity by multiple neurokinin-receptors in the small intestine of the rat

1. We have studied the small intestinal myoelectric response to the natural tachykinins substance P (SP), neurokinin A (NKA), neurokinin B (NKB), and the neurokinin-receptor selective agonists substance P methyl esther (SPME), [β-Ala(8)]neurokinin A 4-10, and senktide in conscious rats. 2. The effects of the agonists were studied before and after administration of the selective neurokinin (2) (NK(2))-receptor antagonist MEN 10,627. 3. Under basal conditions SP, NKA, NKB, as well as the selective NK(1)-receptor agonist SPME, the NK(2)-receptor agonist [β-Ala(8)]NKA 4–10, and the NK(3)-receptor agonist senktide, disrupted the interdigestive rhythm with regularly recycling migrating myoelectric complexes and induced a phase II-like irregular spiking activity. 4. MEN 10,627 given alone did not affect the interdigestive rhythm. 5. MEN 10,627 inhibited the response to [β-Ala(8)]NKA 4–10 but not to SP, SPME, NKA, NKB or senktide. 6. It is concluded that not only NK(2) receptors, but also other receptors, such as NK(1) and NK(3) receptors, may mediate the motility-stimulating action of different tachykinins in vivo. 7. It is further concluded that MEN 10,627 exerts a selective NK(2)-receptor antagonism, and may be a valuable tool for assessing the functional role of NK(2)-receptors in gastrointestinal physiology

3H-serotonin as a marker of oscillatory insulin secretion in clonal β-cells (INS-1)

Serotonin release from preloaded pancreatic β-cells has been used as a marker for insulin release in studying exocytosis from single cells using the amperometric technique. We found that single pancreatic β-cells exhibited oscillations in exocytosis with a period of 1–1.5 min as measured amperometrically by serotonin release. We also show that 3H-serotonin can be used to monitor exocytosis from intact and streptolysin-O permeabilized clonal insulin-secreting cells preloaded with labeled serotonin and that serotonin release correlated with insulin secretion in the same cells. The use of 3H-serotonin provides a real-time indicator of exocytosis from populations of clonal insulin-secreting cells