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PubMedDate not supplied

ABCC8 (SUR1) and KCNJ11 (KIR6.2) mutations in persistent hyperinsulinemic hypoglycemia of infancy and evaluation of different therapeutic measures.

Persistent hyperinsulinemic hypoglycemia of infancy (PHHI) can occur as a result of mutations in the subunits that form the ATP-sensitive potassium channel (K+ATP) in pancreatic beta-cells which play a major role in modulating insulin secretion from the beta-cells. Mutations have been shown in the genes for these subunits, namely for the plasma membrane sulfonylurea receptor (SUR1), ABCC8, and its associated inwardly rectifying potassium channel (KIR6.2) KCNJ11. Drugs which act on K+ATP channels, such as diazoxide, seem to need intact ABCC8 to be able to show their effects. Thus, it would be desirable to know the exact locus of the abnormality in the beta-cell to be able to choose the right therapeutic agent or to perform early pancreatectomy. The aim of this study was to search for the correlation between the mutations of the K+ATP channel and the outcome of therapeutic measures in patients with PHHI followed for a duration of 4 months to 7.3 years. Thirteen patients (5 F, 8 M) with PHHI with a median age of 2.5 months (8 days-12.1 years) were included in the study. Therapy for PHHI was initiated either with diazoxide (n = 9) or with calcium channel blocker (n = 4) as the agent of first choice. Three patients unresponsive to drugs underwent 95% pancreatectomy. Mutation analysis was performed by polymerase chain reaction (PCR) and single strand conformation polymorphism (SSCP) in DNA samples extracted from patients' peripheral leukocytes. The PCR products were directly sequenced. Screening of ABCC8 and KCNJ11 for mutations revealed abnormalities in the ABCC8 gene in three patients out of 13: homozygosity for the 155del1 mutation, compound heterozygosity for T267-->G/A4612-2-->G, and compound heterozygosity for G4310-->A/ R1494Q. No mutations in the KCNJ11 gene were identified. Of the three patients who underwent pancreatectomy, two had identified mutations and one did not have any known mutation. In two patients in whom hyperinsulinism recurred after surgery and in the rest of the children, therapy with either diazoxide or calcium channel blocker proved to be effective in controlling hypoglycemia over the follow-up period. Thus it may be concluded that mutations in the ABCC8 gene were not predictive of the response to drugs. Unidentified mutations in the K+ATP channels other than those screened or other functional abnormalities in these channels may account for the different therapeutic responses.

ATP-Binding Cassette Transporters↗

PubMed1983

Functional and morphologic characterization of human insulinomas.

Circulating levels of insulin, proinsulin-like component, glucagon, growth hormone, and pancreatic polypeptide were measured in 12 patients with functioning insulinomas, and the suppressibility of serum insulin by somatostatin and diazoxide was assessed before surgical removal of the tumors. The hormone content of the tumors was evaluated by radioimmunoassay and by immunofluorescence and the structure of the tumor cells by electron microscopy. Based on these findings, we propose a new classification of insulinomas in two groups: group A is characterized morphologically by abundant well-granulated typical B-cells, trabecular arrangement of tumor cells, and uniform insulin immunofluorescence; functionally, these tumors are associated with a moderate elevation of proinsulin-like component and with an almost complete suppressibility of serum insulin by somatostatin and diazoxide. In contrast, tumors of group B are characterized by scarce well-granulated typical B-cells, a medullary-type histologic structure, and irregular insulin immunofluorescence; functionally these tumors show elevated circulating levels of proinsulin-like component and a marked resistance of insulin secretion to somatostatin and diazoxide inhibition. This way of separating human insulinomas in groups A and B represents a simplification of existing classifications and emphasizes the quantitative ultrastructure in relationship to suppressibility of insulin secretion. The proposed classification of human insulinomas in groups A and B, however, does not allow the assessment of the clinical or histopathologic malignancy of the tumors.

Adenoma, Islet Cell↗

PubMed1998

Glucose activates both K(ATP) channel-dependent and K(ATP) channel-independent signaling pathways in human islets.

Insulin secretion by isolated islets of Langerhans from 19 human donors (9 women and 10 men) was studied in vitro to test the hypothesis that human islets contain both the K(ATP) channel-dependent and the K(ATP) channel-independent signaling pathways. The results demonstrated the presence of both of these major pathways of glucose signaling. Thus, insulin secretion was stimulated by high glucose concentrations, by the sulfonylurea tolbutamide, and by a depolarizing concentration of potassium chloride. Diazoxide, which activates the K(ATP) channel, completely blocked the stimulation of release by glucose. Stimulation of insulin release by tolbutamide, which inhibits the K(ATP) channel and depolarizes the beta-cell, and inhibition of glucose-stimulated release by diazoxide, which activates the channel and repolarizes the beta-cell, confirm the involvement of the K(ATP) channel-dependent pathway in glucose signaling. The participation of the K(ATP) channel-independent pathway in the stimulation of insulin release by glucose was demonstrated for the first time in human islets. This was done in two ways. The first method, in the presence of diazoxide, blocked the action of glucose on the K(ATP) channel in combination with a depolarizing concentration of KCl to raise [Ca2+]i. Under these conditions, glucose stimulated insulin release. A second method to demonstrate the involvement of the K(ATP) channel-independent pathway was to close the K(ATP) channels with tolbutamide. Again, with no possibility of further action on the K(ATP) channel, glucose stimulated insulin release. In a final series of experiments, glucose-stimulated insulin release was profoundly inhibited by somatostatin, clonidine, and prostaglandin E2, but not by galanin.

Adenosine Triphosphate↗

PubMed1997

[A study on the possible mechanism for the second control site of insulin secretion in islets].

Glucose stimulation of insulin release involves closure of ATP-sensitive K+ channels (K(+)-ATP channels) in beta cells. However, by using diazoxide to open K(+)-ATP channels, it has been reported that another mechanism exists, by which glucose can control insulin release independently from changes in K(+)-ATP channel activity. These data suggested that there is a second control site in islets when insulin is secreted. To probe the possible existence of this site, mouse islets were used to investigate the energy state of islets in insulin secretion when the activity of K(+)-ATP channels was eliminated by diazoxide. In the present study, isolated islets were cultured in PRMI 1640 medium for 18 hours. The islets were then divided into 6 groups randomly, with 10 islets per group, placed in 1 ml KREBS medium containing 30 mmol/L K(+) and 250 mmol/L diazoxide with 0, 3, 6, 10, 15, 20 mmol/L glucose respectively and incubated in 37 degrees C water for 60 minutes. A portion of the supernatant was withdrawn at the end of the incubation for insulin assay, the islets were treated with trichloracetic acid and diethyl ether for the measurements of ATP, ADP, GTP and UTP. The above findings demonstrated that insulin secretion increases with the rise of glucose concentration. In the same time, the level of ATP increaseded and the level of ADP decreased gradully. The ratio of ATP/ADP in islets correlated with the insulin secretion very well. The level of GTP and UTP also increased with the rise of glucose concentration. It is suggested that glucose can control insulin secretion independently from its action of K(+)-ATP channels and the existence of a second control site as an another mechanism for insulin release. The ratio of ATP/ADP is an important factor in this mechanism; GTP and UTP also participated in the control of insulin secretion.

Adenosine Diphosphate↗

PubMed1992

The binding properties of the solubilized sulfonylurea receptor from a pancreatic B-cell line are modulated by the Mg(++)-complex of ATP.

Previous studies demonstrated that the Mg complex of ATP decreases glyburide- and increases diazoxide-binding to membranes from pancreatic islets. To examine further the mechanism of these effects, the sulfonylurea receptors in microsomes of the hamster B-cell line HIT-T15 were solubilized with detergents. Maximum recovery of receptors (40%) was obtained with Triton X-100. Specific binding of [3H]glyburide to the solubilized receptors (Kd = 0.35 nM, maximum number of binding sites = 170 fmol/mg of protein) corresponded well to specific binding to microsomes. In Triton X-100 extracts, MgATP (300 microM) reduced the number of high-affinity sites for [3H]glyburide by 50% and increased the dissociation constant for [3H]glyburide by 4-fold; MgATP was half-maximally effective at 20 microM. Development of MgATP-induced inhibition of [3H]glyburide binding to solubilized binding sites was not slower than dissociation of [3H]glyburide binding. Alkaline phosphatase accelerated the reversal of MgATP-induced inhibition of [3H]glyburide binding. In the presence of Mg++, not only ATP but also ADP, GTP and GDP inhibited [3H]glyburide binding to the solubilized receptor. However, MgADP did not inhibit [3H]glyburide binding when the MgATP concentration was kept low by the hexokinase reaction. MgATP significantly enhanced diazoxide-induced displacement of [3H]glyburide from the solubilized receptor. The MgATP-induced inhibition of binding was weakened by millimolar concentrations of free ATP. It is concluded that the binding sites for MgATP, glyburide and diazoxide are located at a single protein or at closely associated proteins which may include a protein kinase.

ATP-Binding Cassette Transporters↗

PubMed1991

Characterization of sulfonylurea receptors and the action of potassium channel openers on cholinergic neurotransmission in guinea pig isolated small intestine.

Specific binding sites for [3H]glibenclamide, a potent ATP-sensitive K+ channel blocker, have been characterized in the isolated guinea pig longitudinal muscle-myenteric plexus preparation. The Scatchard plot of the saturation isotherm was curvilinear and revealed two binding sites, one of high affinity (Kd = 0.42 nM; maximum binding site = 156 fmol/mg of protein), the other of low affinity (Kd = 83 nM; maximum binding site = 3100 fmol/mg of protein). Displacement experiments in the presence of various sulfonylureas showed the same order of potency for the two binding sites (glibenclamide greater than gliquidone greater than glipizide glibornuride greater than chlorpropamide greater than tolbutamide). The K+ channel opener RP 49356 (but not diazoxide or cromakalim) displaced the [3H] glibenclamide with an IC50 of 4.8 microM. The effects of the K+ channel openers diazoxide, RP 49356, cromakalim and its two optical isomers BRL 38226 and BRL 38227 were also studied on the electrically induced contractions of isolated guinea pig small intestine. These compounds produce an inhibition of neurally evoked twitch height with pD2 values of 4.5 to 6.2 (BRL 38227 greater than cromakalim greater than RP 49356 greater than diazoxide, whereas BRL 38226 was practically ineffective). The effects of cromakalim and RP 49356 were antagonized competitively by glibenclamide (pA2 = 7.2) and other sulfonylureas, suggesting they act on ATP-sensitive K+ channels. Affinities of the sulfonylureas obtained from concentration-response curves to cromakalim on electrically induced contractions are better correlated with the IC50 value corresponding to the low affinity binding site than to the high affinity.(ABSTRACT TRUNCATED AT 250 WORDS)

ATP-Binding Cassette Transporters↗

PubMed1986

Insulin-secreting tumor: diagnosis and medical and surgical management in 55 dogs.

Insulin-secreting tumor of the pancreas was diagnosed in 55 dogs. Diagnosis was based mainly on the increase of serum insulin concentrations in the presence of hypoglycemia. The use of the amended insulin/glucose ratio to diagnose the tumor, although providing less false-negative results than did increased serum insulin concentrations alone, appeared less specific and gave false-positive results in dogs without insulin-secreting tumors. Management of the disease included surgical intervention alone (26 dogs), surgery plus medical management with diazoxide (14 dogs), and medical management with diazoxide alone (4 dogs). Eleven dogs were euthanatized at the time of diagnosis. Diazoxide therapy controlled hypoglycemia in about 70% of the dogs.

Adenoma, Islet Cell↗

PubMedDate not supplied

[New activators of potassium channels: design, pharmacology and therapeutic perspectives].

Potassium channels (K+ channels) constitute the most diverse group of ionic channels. One of them, the ATP-sensitive K+ channel (KATP channel), was identified in numerous tissues (smooth muscle, pancreatic B-cells, central nervous system,...). This channel is of particular interest for us since we have developed various pharmacological models for the study of new potassium channel openers. Among those, diazoxide (a benzothiadiazine dioxide) is an interesting reference compound since its biological activity was observed with comparable intensity on the vascular tissue (smooth muscle) as well as on the pancreatic tissue (endocrine tissue). One of our aims was the preparation of original pyridinic analogues of diazoxide (pyridothiadiazinedioxides) and their evaluation as potassium channel openers in order to show a tissue selectivity different from that of diazoxide. Indeed, therapeutic perspectives of potassium channel openers will depend upon the discovery of new classes of compounds exhibiting an effective tissue selectivity.

Animals↗

PubMed1998

Persistent hyperinsulinemic hypoglycemia of infancy.

OBJECTIVE: To study the nature and clinical course of persistent hyperinsulinemic hypoglycemia of infancy (PHHI) due to nesidioblastosis. DESIGN: Clinical, laboratory and therapeutic evaluation of infants with this disorder and study the outcome. SETTING: Hospital born neonates and infants referred from other hospitals. SUBJECTS: Thirteen infants from 9 families inclusive of four pairs of siblings referred within few hours of birth to 3 months of age, for seizures. Mean birth weight was 3.68 +/- 0.45 kg. Consanguinity documented in one sporadic and one familial case. METHODS: Clinical and laboratory evaluation by standard biochemical and radioimmunoassay techniques. RESULTS: The mean serum insulin level of 24.2 +/- 12.5 mIU/ml was in the normal range but inappropriately high for the corresponding hypoglycemic blood sugar (23.1 +/- 9.1 mg/dl) value, with an I/G ratio of 1.36 +/- 0.97; as in hyperinsulinemia (normal < 0.4). Investigations excluded other causes of persistent hypoglycemia. A trial of i.v./oral glucose, frequent carbohydrate rich feeds in all, oral diazoxide (10 to 20 mg/kg) in 9/13 cases along with subcutaneous octreotide (20 micrograms/kg QID) in one helped, but pancreatic resection (85 to 90%) was opted for in two (1 familial, 1 sporadic). Six infants including one with pancreatic resection succumbed to hypoglycemia (n = 1) or fulminating infection (n = 3) or brain damage. Of the seven survivors, one familial case with pancreatic resection is brain damaged, and of the six on diazoxide therapy, one is slightly subnormal while one sporadic and three familial cases have done well. One infant was lost to follow up. Diazoxide could be withdrawn in two subjects (1 familial, 1 sporadic) by 8 years of age signifying maturation of islet cell function. CONCLUSION: PHHI appropriately known as 'Islet cell dysmaturation syndrome' is a complex disorder posing problems in diagnosis and therapy. The high familial incidence (77%), with intrafamilial variation in the severity, insulin levels in the normal range but in appropriately high for the blood glucose levels, normal C-peptide levels, with normal I/G ratio (< 0.4) in 4/13 are some of the notable features of this study. Severe recurrent infections in nearly 30%, is an unusual feature in this series and needs an indepth study. The mortality (46%) and morbidity (43%) in survivors is high and calls for greater awareness, early diagnosis and genetic counselling, as this disorder may be familial.

Birth Weight↗

PubMed1980

Nesidioblastosis in children.

Three cases in which seizure disorder was first noticed were examined in the last seven years; low fasting glucose and high serum insulin levels then led to the diagnosis of severe hypoglycemia secondary to nesidioblastosis. Hypoglycemic episodes were uncontrolled by frequent oral feedings and intravenous administration of dextrose, glucagon, and diazoxide. Within three weeks after diagnosis, all three patients underwent subtotal pancreatectomy; all three survived and have been followed-up for two to seven years. Two remain euglycemic and have no evidence of CNS damage. The third has occasional fasting hypoglycemia that is treated with diazoxide; he continues to have a seizure disorder and is mentally retarded. Neonatal hypoglycemia secondary to hyperinsulinism requires prompt recognition and aggressive treatment to avoid irreversible CNS damage. Subtotal pancreatectomy safely and effectively restores the euglycemic state.

Adenoma, Islet Cell↗

PubMed1996

Crosstalk between the cAMP and inositol trisphosphate-signalling pathways in pancreatic beta-cells.

Glucose was found to induce large amplitude oscillations of cytoplasmic Sr2+ and Ca2+ in individual pancreatic beta-cells exposed to the respective cation. Subsequent addition of 20 nM glucagon or other agents raising cAMP triggered pronounced transients superimposed upon the large amplitude oscillations. Hyperpolarization with diazoxide prevented both the large amplitude oscillations and the superimposed transients. After short exposure to carbachol or ATP there was a temporary, and after addition of the Ca2+-ATPase inhibitor thapsigargin a permanent, disappearance of the transients with persistence of the glucose-induced large amplitude oscillations. The Ca2+ channel blocker methoxyverapamil exhibited opposite specificity in preventing the large amplitude oscillations under conditions when the transients often remained. In the presence of methoxyverapamil the transients disappeared during diazoxide hyperpolarization and were restored by subsequent K+ depolarization, which also elevated the content of inositol 1,4,5-trisphosphate (IP3) by 45%. The glucagon-induced transients were obliterated by 12-O-tetradecanoylphorbol 13-acetate, insensitive to ryanodine and paradoxically inhibited by high concentrations of caffeine. The IP3-mediated intracellular ion mobilization induced by carbachol was amplified by glucagon. The results indicate that depolarization-dependent formation of IP3 causes intracellular Ca2+ mobilization in individual beta-cells when the IP3 receptors are sensitized by cAMP. This mechanism may be an important determinant for the electrophysiological burst activity in intact pancreatic islets due to the presence of endogenous glucagon.

Animals↗

PubMed1998

Necessity of endogenous GTP derived from glucose-6-phosphate for insulin secretion augmented by glucose under protein kinase A activation.

To investigate the possible involvement of some intracellular metabolic signaling other than the ATP derived from glucose metabolism under protein kinase A (PKA) activation, we measured the insulin secretory capacity stimulated by glucose and other fuel secretagogues using diazoxide-treated pancreatic islets. Under these conditions, we found a signal from a site proximal to glyceraldehyde-3-phosphate (GA-3-P) in the glycolysis to be necessary for glucose-induced insulin secretion. By using several different glycolytic enzyme inhibitors, we found that this proximal signal is derived from glucose-6-phosphate (G-6-P), and that metabolic signaling distal to GA-3-P also is necessary. Mycophenolic acid completely inhibited the augmented glucose-induced insulin secretion, which guanosine could reverse, indicating that the proximal signaling is coupling with endogenous GTP production. In this novel system of metabolic signaling, endogenous GTP derived from G-6-P in the glycolysis elicits the augmentation of glucose-induced insulin secretion under PKA activation in diazoxide-treated pancreatic islets.

Animals↗

PubMed1992

BAY K 8644 stimulates glucose-dependent rise of cytoplasmic Ca2+ in hyperpolarized pancreatic beta-cells.

The effect of BAY K 8644 on the cytoplasmic Ca2+ concentration ([Ca2+]i) was studied in pancreatic beta-cells hyperpolarized by the K+ channel-activating agent diazoxide. After 50-60 min preexposure to 0-20 mM glucose in the presence of 400 microM diazoxide [Ca2+]i was close to the level in unstimulated beta-cells. The addition of 5 microM BAY K 8644 then triggered a rise of [Ca2+]i dependent on Ca2+ influx. The magnitude of the BAY K 8644 effect increased with the glucose concentration and was almost 10-fold higher in 20 mM than in the absence of the sugar. It is concluded that glucose can modulate Ca2+ entry through the voltage-dependent channels by a mechanism additional to depolarization. This action may help to explain why previous exposure to the sugar results in an augmented insulin response to a second challenge.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗

PubMed1991

Phosphate and thiophosphate group donating adenine and guanine nucleotides inhibit glibenclamide binding to membranes from pancreatic islets.

In microsomes obtained from mouse pancreatic islets, the Mg complex of adenosine 5'-triphosphate (MgATP) increased the dissociation constant (KD) for binding of [3H]glibenclamide by sixfold. In the presence of Mg2+, not only ATP but also adenosine 5'-0-(3-thiotriphosphate) (ATP gamma S), adenosine 5'-diphosphate (ADP), guanosine 5'-triphosphate (GTP), guanosine 5'-diphosphate (GDP), guanosine 5'-0-(3-thiotriphosphate) (GTP gamma S) and guanosine 5'-0-(2-thiodiphosphate) (GDP beta S) inhibited binding of [3H]glibenclamide. These effects were not observed in the absence of Mg2+. Half maximally effective concentrations of the Mg complexes of ATP, ADP, ATP gamma S and GDP were 11.6, 19.0, 62.3 and 90.1 mumol/l, respectively. The non-hydrolyzable analogues adenosine 5'-(beta,gamma-imidotriphosphate) (AMP-PNP) and guanosine 5'-(beta,gamma-imidotriphosphate) (GMP-PNP) did not alter [3H]glibenclamide binding in the presence of Mg2+, MgADP acted much more slowly than MgATP and both MgADP and MgGDP did not inhibit [3H]glibenclamide binding when the concentrations of MgATP and MgGTP were kept low by the hexokinase reaction. Development of MgATP-induced inhibition of [3H]glibenclamide binding and dissociation of [3H]glibenclamide binding occurred at similar rates. However, the reversal of MgATP-induced inhibition of [3H]glibenclamide binding was slower than the association of [3H]glibenclamide with its binding site. Exogenous alkaline phosphatase accelerated the reversal of MgATP-induced inhibition of [3H]glibenclamide binding. MgATP enhanced displacement of [3H]glibenclamide binding by diazoxide. The data suggest that sulfonylureas and diazoxide exert their effects by interaction with the same binding site at the sulfonylurea receptor and that protein phosphorylation modulates the affinity of the receptor.

Adenine Nucleotides↗

PubMed1985

Mechanism of the stimulation of insulin release in vitro by HB 699, a benzoic acid derivative similar to the non-sulphonylurea moiety of glibenclamide.

HB 699 is a benzoic acid derivative similar to the non-sulphonylurea moiety of glibenclamide. The mechanisms whereby it affects B-cell function have been studied in vitro with mouse islets. In the presence of 3 mmol/l glucose, HB 699 decreased 86Rb+ efflux and accelerated 45Ca2+ efflux from islet cells, depolarized the B-cell membrane and induced an electrical activity similar to that triggered by stimulatory concentrations of glucose, and increased insulin release. The changes in 45Ca2+ efflux and insulin release, but not the inhibition of 86Rb+ efflux, were abolished in the absence of Ca2+. In the presence of 10 mmol/l glucose, HB 699 increased 86Rb+ and 45Ca2+ efflux from the islets, caused a persistent depolarization of the B-cell membrane with continuous electrical activity and markedly potentiated insulin release. All these changes were suppressed by omission of extracellular Ca2+. In the presence of 15 mmol/l glucose, diazoxide increased 86Rb+ efflux, hyperpolarized the B-cell membrane, suppressed electrical activity and inhibited insulin release. HB 699 reversed these effects of diazoxide. It is suggested that HB 699 decreases K+ permeability of the B-cell membrane, thereby causing a depolarization which leads to activation of voltage-dependent Ca channels and Ca2+ influx, and eventually increases insulin release. A sulphonylurea group is thus not a prerequisite to trigger the sequence of events that is also thought to underlie the releasing effects of tolbutamide and glibenclamide.

Animals↗

PubMed1992

Identification of an ATP-sensitive K+ channel in rat cultured cortical neurons.

To determine whether membranes of mammalian central neurons contain an ATP-sensitive K+ (KATP) channel similar to that present in pancreatic beta cells, the patch-clamp technique was applied to cultured neurons prepared from the neonatal rat cerebral cortex and hippocampus. In whole-cell experiments with hippocampal neurons, extracellular application of 0.5 mM diazoxide (a KATP channel activator) elicited a hyperpolarization concomitant with an increase in membrane conductance, whereas application of 0.5 mM tolbutamide (a KATP channel blocker) induced a depolarization with a decrease in conductance. Similar results were obtained with cortical neurons. In outside-out patch experiments with cortical neurons, a K+ channel sensitive to these drugs was found. The channel was completely blocked by 0.5 mM tolbutamide and activated by 0.5 mM diazoxide. The single-channel conductance was 65 pS under symmetrical 145 mM K+ conditions and 24 pS in a physiological K+ gradient. In inside-out patch experiments, this channel was demonstrated to be inhibited by an application of 0.2-1 mM ATP to the cytoplasmic surface of the patch membrane. These results indicate that the membranes of rat cortical neurons contain a KATP channel that is quite similar to that found in pancreatic beta cells. It is also suggested that the same or a similar K+ channel may exist in membranes of hippocampal neurons.

Adenosine Triphosphate↗

PubMed1996

Sulphonylurea stimulates glucose uptake in rats through an ATP-sensitive K+ channel dependent mechanism.

We studied the effect of gliclazide, a second-generation sulphonylurea, on rat skeletal muscle glucose uptake using perfused hindquarter muscle preparations. Gliclazide at concentrations of 10 to 1000 microgram/ml increased (p < 0.05) the basal glucose uptake. The effect of gliclazide on glucose uptake was immediate and dose-dependent, reaching a plateau at a concentration of 300 micrograms/ml; the half-maximal effect was obtained between 25 and 50 micrograms/ml. The glucose uptake stimulated by gliclazide (300-1000 micrograms/ml) did not differ from that achieved by 10(-9) mol/l insulin, and was lower (p < 0.05) than that obtained with 10(-7) mol/l insulin. The combination of gliclazide (300 micrograms/ml) and 10(-9) mol/l insulin produced an increase in glucose uptake (7.7 +/- 0.6 mumol.g-1.h-1, n = 8, mean +/- SEM) which was higher (p < 0.05) than that achieved with 10(-9) mol/l insulin (5.6 +/- 0.7 mumol.g-1.h-1, n = 11) and not different from that obtained with 10(-7) mol/l insulin (9.8 +/- 1.0 mumol.g-1.h-1, n = 11). Diazoxide (100 mumol/l), an ATP-sensitive K+ channel opener, reversed the stimulatory effect of gliclazide (100 microgram/ml) on muscle glucose uptake from 3.1 +/- 0.4 to 0.5 +/- 0.2 mumol.g-1.h-1, (n = 7, p < 0.001). The addition of diazoxide prior to gliclazide into the perfusion medium blocked the gliclazide-induced glucose uptake by the hindquarter muscle preparations. In conclusion, gliclazide alone has an immediate stimulatory effect on glucose uptake by skeletal muscle and together with insulin has an additive effect on muscle glucose uptake. The effect of gliclazide on muscle glucose uptake seems to be due to the inhibition of ATP-sensitive K+ channels.

Adenosine Triphosphate↗

PubMed1992

Expression of the 64 kDa/glutamic acid decarboxylase rat islet cell autoantigen is influenced by the rate of insulin secretion.

This study examined the relationship between insulin secretion and expression of the 64 kDa/glutamic acid decarboxylase autoantigen in pancreatic islets. Islets isolated from Wistar rats were cultured for 3 days under different conditions: in 5.5 mmol/l glucose with or without alpha-ketoisocaproic acid or glipizide and in 28 mmol/l glucose with or without diazoxide. The 64 kDa/glutamic acid decarboxylase autoantigen was precipitated from lysates of [35S]-methionine-labelled islets with sera from patients with Type 1 (insulin-dependent) diabetes mellitus and identified by sodium dodecyl sulphate-polyacrylamide gel electrophoresis and fluorography. In parallel, insulin contents of the islets and the media were determined as well as the rates of glucose-stimulated (pro)insulin biosynthesis. alpha-Ketoisocaproic acid and glipizide were found to stimulate the expression of the 64 kDa/glutamic acid decarboxylase autoantigen and also the rate of insulin secretion. Diazoxide on the other hand reduced the rate of the 64 kDa/glutamic acid decarboxylase autoantigen synthesis in parallel with an inhibition of glucose-stimulated insulin release. Under most of the conditions employed, (pro)insulin biosynthesis was not affected. The correlation found between the rate of insulin release and expression of the 64 kDa/glutamic acid decarboxylase autoantigen might provide an explanation for the earlier observed relationship between the functional demands on the Beta cells and their rate of destruction which may result in diabetes.

Animals↗