Iatrogenic, sulfonamide-induced hypothyroid crisis in a Labrador Retriever.

This case report describes a sulfonamide-induced hypothyroid crisis in a 4-year-old Labrador Retriever bitch. Empirical therapy with high-dose trimethoprim-sulfamethoxazole for 10 days produced signs of weakness, ataxia and mental depression and the clinicopathological results supported hypothyroid-induced central nervous system depression. Short-term levothyroxine sodium therapy led to complete resolution of all clinical signs and follow-up thyroid hormone assays ruled out underlying thyroid pathology. This case report is the first to highlight this potentially life-threatening manifestation of sulfonamide-induced hypothyroidism. Sulfonamide combinations are widely used antimicrobials in veterinary medicine and early recognition of this syndrome is critical.

Unusually rapid growth and adult stature in an American hairless terrier puppy.

A puppy was evaluated for rapid growth and large stature. Extensive diagnostic evaluation suggested a growth hormone independent disorder. As the sole detected abnormality was elevated leptin concentration, an obesity syndrome causing leptin resistance was speculated to explain the puppy's condition but was not confirmed. Except for large body size, the puppy remained clinically normal.

Cellular and molecular characterization of a feline insulinoma.

BACKGROUND: Insulinoma is an autonomous insulin-secreting islet cell neoplasm that is rarely diagnosed in cats. The clinical and pathological aspects of feline insulinoma have been described previously, but the molecular characteristics of these tumors have not been investigated. OBJECTIVES: The study objectives were to characterize peptide hormone production and determine expression of selected genes involved in glucose metabolism and insulin secretion in a feline insulinoma. METHODS: Immunohistochemistry and RT-PCR were used to examine hormone and gene expression, respectively, by insulinoma cells. RESULTS: Immunohistochemistry examination indicated that the tumor cells expressed insulin, chromogranin A, and somatostatin but not glucagon or pancreatic polypeptide. The tumor expressed several genes characteristic of pancreatic beta cells (beta cells) including insulin (INS), glucose transporter 2 (GLUT2), and glucokinase (GCK). The tumor also expressed hexokinase 1 (HK1), a glycolytic enzyme not normally expressed in beta cells. GCK expression was higher in the insulinoma than in normal pancreas from the same cat. The GCK : HK1 ratio was >20-fold higher in insulinoma tissue than in normal pancreas. CONCLUSIONS AND CLINICAL IMPORTANCE: The feline insulinoma produced several peptide hormones and expressed genes consistent with a beta-cell phenotype. The pattern of hexokinase gene expression in tumor cells differed from that of normal pancreas. These findings suggest insulinoma cells may have an increased sensitivity to glucose that could contribute to the abnormal insulin secretory response observed at low serum glucose concentrations.

Matrix metalloproteinase and tissue inhibitor of metalloproteinase in serum and synovial fluid of osteoarthritic dogs.

To better understand the mechanisms responsible for the pathological processes of osteoarthritis (OA) and to potentially identify a profile of changes that could be predictive of early OA, matrix metalloproteinase-1 (MMP-1) and tissue inhibitor of matrix metalloproteinase-2 (TIMP-2) in the synovial fluid and serum of normal and osteoarthritic dogs were examined. The concentration of MMP-1 in the synovial fluid of osteoarthritic dogs (0.62 +/- 0.16), as measured by densitometry, was significantly higher than that found in control dogs (0.42 +/- 0.19) (P = 0.03). The concentration of MMP-1 in the serum of osteoarthritic dogs (0.74 +/- 0.16) was significantly less than that found in control dogs (0.87 +/- 0.08) (P = 0.05). The concentration of TIMP-2 in the synovial fluid of osteoarthritic dogs (46.2 +/- 21.9 ng/ml) was significantly less than that of control dogs (122.0 +/- 66.5 ng/ml) (P = 0.009). The concentration of TIMP-2 in the serum of osteoarthritic dogs (116.2 +/- 43.1 ng/ml) was not significantly different than that of control dogs (95.1 +/- 94.4 ng/ml) (P = 0.554). In addition, a phospho-tyrosine immunoprecipitation and mass spectrometry were used to isolate and identify interferon-alpha in canine synovial fluid.

Serum-effusion albumin gradient in dogs with transudative abdominal effusion.

A prospective clinical study in dogs with transudative abdominal effusions examined the clinical usefulness of the serum albumin-effusion albumin (SA-EA) gradient. In humans, the SA-EA gradient facilitates classification of abdominal effusion, with a gradient > or = 1.1 indicating the presence of portal hypertension. Gradient values proved useful for predicting therapeutic response to sodium restriction and diuresis in humans. Of 49 dogs evaluated, 25 had hepatobiliary disease (group 1) and 24 had other nonhepatobiliary conditions (group 2). Portal hypertension was clinically suspected in 24 of 25 dogs in group 1 and in 15 of 24 dogs in group 2. A broad range of SA-EA gradients was found. A gradient > or = 1.1 was found in 22 of 25 (88.0%) dogs with liver disease and in 14 of 24 (58.3%) dogs with other disorders. The median SA-EA gradient was higher in group 1 than in group 2, with values of 1.4 (range, 0.7-3.1) and 1.1 (range, 0.3-2.6), respectively (P < .04). Considerable overlapping of SA-EA gradients occurred between groups and among dogs with diverse conditions such that gradient values could not distinguish dogs with hepatobiliary disease from dogs with other conditions. The overall diagnostic accuracy of the SA-EA gradient in predicting portal hypertension in dogs with and without hepatobiliary disease (69.4%) exceeded that of hypoalbuminemia (57.1%). These findings suggest that portal hypertension is a predominant force in formation of transudative abdominal effusion in dogs with hepatobiliary disease and in dogs with other disorders. Whether the SA-EA gradient can be used to guide therapeutic mobilization of effusion in dogs remains to be proved.

Monoclonal immunoglobulin G cryoglobulinemia and multiple myeloma in a domestic shorthair cat.

A 13-year-old castrated domestic shorthair cat was examined because of fever, anorexia, and dermatologic lesions. Crusting, erythema, and well-demarcated purple discoloration of the foot pads and the tips of the pinnae, nose, and tail were seen. A white flocculent precipitate was detected in cooled serum. This precipitate dissolved upon rewarming, consistent with a cryoglobulin. Hypercalcemia, high alanine and aspartate aminotransferase activities, thrombocytopenia, and a monoclonal IgG gammopathy were found. Numerous hepatic nodules were detected by means of abdominal ultrasonography. Cytologic evaluation of fine-needle aspirates of the liver and spleen revealed numerous plasma cells, and evaluation of a bone marrow aspirate revealed plasmacytosis. A diagnosis of multiple myeloma and monoclonal IgG cryoglobulinemia was made, and the cat was euthanatized.

Norepinephrine acts on the KATP channel and produces different effects on [Ca2+]i in oscillating and non-oscillating HIT-T15 cells.

Norepinephrine (NE) is an inhibitor of insulin secretion that acts, in part, by decreasing intracellular free calcium ([Ca2+]i). We examined the effects of NE on [Ca2+]i in individual HIT-T15 cells loaded with indo 1. Cells were categorized as oscillators or non-oscillators on the basis of the pattern of the calcium response to glucose and the effect of NE on [Ca2+]i was subsequently measured in each cell. NE caused a simple decrease in [Ca2+]i in nonoscillators. In oscillators, NE decreased the amplitude and frequency of the oscillations. Furthermore, the duration of the NE effect in oscillators was longer than in non-oscillators. NE did not affect the rise in [Ca2+]i elicited by depolarizing concentrations of 20 mM or 35 mM KCl alone, or in the presence of 20 mM KCl, 100 microM diazoxide, and 10 mM glucose. In other experiments, NE had no effect on [Ca2+]i when the KATP channels were fully clamped with diazoxide or tolbutamide. We conclude that the action of NE to decrease [Ca2+]i in both oscillators and non-oscillators is mediated via activation of the KATP channel. Despite this common mechanism, NE exerts different effects on oscillating and non-oscillating cells.

Calbindin-D(28k) controls [Ca(2+)](i) and insulin release. Evidence obtained from calbindin-d(28k) knockout mice and beta cell lines.

The role of the calcium-binding protein, calbindin-D(28k) in potassium/depolarization-stimulated increases in the cytosolic free Ca(2+) concentration ([Ca(2+)](i)) and insulin release was investigated in pancreatic islets from calbindin-D(28k) nullmutant mice (knockouts; KO) or wild type mice and beta cell lines stably transfected and overexpressing calbindin. Using single islets from KO mice and stimulation with 45 mM KCl, the peak of [Ca(2+)](i) was 3.5-fold greater in islets from KO mice compared with wild type islets (p < 0.01) and [Ca(2+)](i) remained higher during the plateau phase. In addition to the increase in [Ca(2+)](i) in response to KCl there was also a significant increase in insulin release in islets isolated from KO mice. Evidence for modulation by calbindin of [Ca(2+)](i) and insulin release was also noted using beta cell lines. Rat calbindin was stably expressed in betaTC-3 and betaHC-13 cells. In response to depolarizing concentrations of K(+), insulin release was decreased by 45-47% in calbindin expressing betaTC cells and was decreased by 70-80% in calbindin expressing betaHC cells compared with insulin release from vector transfected betaTC or betaHC cells (p < 0.01). In addition, the K(+)-stimulated intracellular calcium peak was markedly inhibited in calbindin expressing betaHC cells compared with vector transfected cells (225 nM versus 1,100 nM, respectively). Buffering of the depolarization-induced rise in [Ca(2+)](i) was also observed in calbindin expressing betaTC cells. In summary, our findings, using both isolated islets from calbindin-D(28k) KO mice and beta cell lines, establish a role for calbindin in the modulation of depolarization-stimulated insulin release and suggest that calbindin can control the rate of insulin release via regulation of [Ca(2+)](i).

cAMP enhances insulin secretion by an action on the ATP-sensitive K+ channel-independent pathway of glucose signaling in rat pancreatic islets.

Cyclic AMP potentiates glucose-stimulated insulin release by actions predominantly at a site, or sites, distal to the elevation of the cytosolic free Ca2+ concentration ([Ca2+]i). Glucose also acts at a site, or sites, distal to the elevation of [Ca2+]i via the ATP-sensitive K+ channel (K+ATP channel)-independent signaling pathway. Accordingly, using rat pancreatic islets, we studied the location of the action of cAMP and its interaction with the glucose pathway. Forskolin, an activator of adenylyl cyclase, raised intracellular cAMP levels and enhanced KCl-induced (Ca2+ -stimulated) insulin release in the presence, but not in the absence, of glucose. Thus, cAMP has no direct effect on Ca2+ -stimulated insulin release. The interaction between cAMP and glucose occurs at a step distal to the elevation of [Ca2+]i because forskolin enhancement of KCl-induced insulin release, in the presence of glucose, was demonstrated in the islets treated with diazoxide, a K+ATP channel opener. The enhancement of insulin release was not associated with any increase in [Ca2+]i. Furthermore, the interaction between cAMP and glucose was unequivocally observed even under stringent Ca2+ -free conditions, indicating the Ca2+ -independent action of cAMP. This action of cAMP is physiologically relevant, because not only forskolin but also glucagon-like peptide 1, glucose-dependent insulinotropic polypeptide, and pituitary adenylyl cyclase activating polypeptide exerted similar actions. In conclusion, the cAMP/protein kinase A pathway has no direct effect on Ca2+ -stimulated insulin exocytosis. Rather, it strongly potentiates insulin release by increasing the effectiveness of the K+ATP channel-independent action of glucose.

Cullen's sign and haemoglobinuria as presenting signs of retroperitoneal haemorrhage in a dog.

Haemoglobinuria and periumbilical discoloration (also known as Cullen's sign) are clinical signs uncommonly reported in veterinary patients. This report describes a case of retroperitoneal haemorrhage in a dog, associated with haemoglobinuria and Cullen's sign. To the authors' knowledge, these clinical signs have not previously been reported singularly or in combination with retroperitoneal haemorrhage in dogs. A neutered male Shetland sheepdog, which was presented for haematuria, also had an abdominal mass, abdominal pain and a large area of periumbilical discoloration. Laboratory studies determined that haemoglobinuria was the cause of the red-coloured urine. Abdominal radiographs suggested a splenic mass and a coeliotomy was performed. During the induction and throughout the anaesthetic period the dog was hypertensive and a large haematoma originating from the right retroperitoneal space was identified at surgery. The cause of the haemorrhage was uncertain but a ruptured phaeochromocytoma was thought possible on the basis of the persistent hypertension and the location of the haemorrhage.

Naturally acquired leptospirosis in 36 dogs: serological and clinicopathological features.

Case records of 36 dogs with confirmed leptospirosis diagnosed at the New York State College of Veterinary Medicine from 1980 to 1995 were reviewed retrospectively, and clinical, serological and pathological findings were recorded to characterise the epidemiology of this disease in upstate New York. Titres were directed predominantly against serovars grippotyphosa and/or pomona in 31 of 34 dogs. Convalescent titres were measured for 53 per cent of dogs. The most common clinical presentation was acute renal failure. Increased liver enzyme activity was documented in 22 of 36 dogs. It is clear from this study that Leptospira pomona and grippotyphosa are important pathogens capable of causing severe renal and hepatic injury in dogs.

Augmentation of insulin release by glucose in the absence of extracellular Ca2+: new insights into stimulus-secretion coupling.

Glucose stimulates insulin secretion in the pancreatic beta-cell by means of a synergistic interaction between at least two signaling pathways. One, the K(ATP) channel-dependent pathway, increases the entry of Ca2+ through voltage-gated channels by closure of the K(ATP) channels and depolarization of the beta-cell membrane. The resulting increase in [Ca2+]i stimulates insulin exocytosis. The other, a K(ATP) channel-independent pathway, requires that [Ca2+]i be elevated and augments the Ca2+-stimulated release. These mechanisms are in accord with the belief that glucose-stimulated insulin secretion has an essential requirement for extracellular Ca2+ and increased [Ca2+]i. However, when protein kinases A and C are activated simultaneously, a large effect of glucose to augment insulin release can be seen in the absence of extracellular Ca2+, under conditions in which [Ca2+]i is not increased, and even when [Ca2+]i is decreased to low levels by intracellular chelation with BAPTA. In the presence or absence of Ca2+, there are similarities in the characteristics of augmentation of insulin release that suggest that only one augmentation mechanism may be involved. These similarities include time course, glucose dose-responses, augmentation by nutrients other than glucose such as alpha-ketoisocaproate (alpha-KIC), and augmentation by the fatty acids palmitate and myristate. However, augmentation in the presence and absence of Ca2+ is distinctly different in GTP dependency. Therefore, exocytosis under these two conditions appears to be triggered differently-one by Ca2+ and the other by GTP or a GTP-dependent mechanism. The augmentation pathways are likely responsible for time-dependent potentiation of secretion and for the second phase of glucose-stimulated insulin release.

Suspected microscopic hepatic arteriovenous fistulae in a young dog.

Portal hypertension can develop from any disorder that obstructs portal blood flow and may cause ascites in young dogs. Anomalous hepatic arteriovenous (AV) connections are rare but should be suspected in any young dog with portal hypertension or ascites. All previous reports of dogs with hepatic AV fistulae have documented macroscopic connections between the arterial and venous systems. Identical clinical signs and histopathologic findings can develop in dogs in which a macroscopic hepatic AV connection cannot be detected. Microscopic AV connections may be responsible for clinical signs in these dogs.

Clinicopathologic variables predictive of residual dysplasia after cervical conization.

OBJECTIVE: To evaluate the clinicopathologic variables that are important for predicting residual dysplasia after cervical conization or the loop electroexcisional procedure. STUDY DESIGN: A retrospective review of 80 cases was performed on patients with squamous dysplasia in the conization specimen, endocervical curettage (ECC) performed immediately after resection, margin status reported by the pathologist and adequate postprocedure follow-up. RESULTS: Twelve patients had residual dysplasia. No case progressed to invasive carcinoma. A multivariate analysis was performed with presence or absence of residual dysplasia as the dependent variable and patient age, type of procedure (cold knife conization or loop excision), grade of dysplasia, margin status and ECC status as independent variables. Margin status was the strongest predictor of residual disease, followed by ECC status. Patient age had a minimal association with persistence. Of the 12 patients with residual dysplasia, 11 had a positive margin, and 8 had a positive ECC. Only 38% of patients with a positive margin had residual disease, but 67% with a positive margin and ECC had residual dysplasia. CONCLUSION: Margin status and ECC are useful in predicting residual dysplasia after conization.

Two signaling pathways, from the upper glycolytic flux and from the mitochondria, converge to potentiate insulin release.

In the rat pancreatic beta cell, low concentrations of glucose potentiate D-glyceraldehyde (GA)-induced insulin release without any potentiation of the triose-induced elevation of cytosolic free Ca2+ concentration. Namely, 2-3 mM glucose strongly potentiates 5 mM GA-induced insulin release, and the combination of stimulatory concentration of glucose (10 mM) and 5 mM GA elicits far more than additive insulin release: this glucose action is independent of ATP-sensitive K+ channel closure because it can be seen in the presence of diazoxide, an opener of the K+ channel. The triose-induced elevation of cytosolic free Ca2+ concentration was not potentiated by the presence of 3 mM glucose, and oxidation of labeled GA by the islet cells was not enhanced by the presence of glucose. The glucose action can be mimicked by mannose, but not by galactose, and was suppressed by inhibition of glucose phosphorylation with mannoheptulose or 2-deoxyglucose. Glucose also potentiates 2-ketoisocaproate-induced insulin release. In contrast, a combination of GA and 2-ketoisocaproate elicits only additive insulin release. Strikingly, 3 mM glucose does not potentiate insulin release in response to a depolarizing concentration of K+. Therefore, at least two signal pathways, one from upper glycolytic flux and one from mitochondrial metabolism, must converge to provide the potentiation of insulin release. We conclude that the upper glycolytic flux, acting at a site unrelated to the elevation of cytosolic free Ca2+, potentiates insulin release triggered by triose and mitochondrial fuels.

Intraoperative end-tidal carbon dioxide levels and derived calculations correlated with outcome in trauma patients.

BACKGROUND: To determine the relationship between the prognosis of seriously injured patients requiring emergency surgery and intraoperative end-tidal CO2 variables and "excess Pco2." METHOD: Retrospective chart review of 100 seriously injured patients admitted to Detroit Receiving Hospital and requiring major surgery (mortality rate of 40%). Standard intraoperative monitoring, including continuous capnography, plus arterial blood analyses every 15 to 30 minutes during surgery. RESULTS: After resuscitation for 45 to 90 minutes, 11 patients had a systolic blood pressure < 100 mm Hg and, of these patients, 10 (91%) died. Of the remaining 89 patients, mortality rates were 53% (16/30), with an end-tidal CO2 of 22 mm Hg or less, versus 24% (14/59) with an end-tidal CO2 of 23 mm Hg or more (p = 0.011). An arterial to end-tidal Pco2 difference of 13 mm Hg or more after resuscitation was associated with an increased mortality rate (50% (20/34 vs. 18% (20/55)) (p < 0.005). The mortality rate was particularly high, with a final arterial to end-tidal Pco2 difference of 12 mm Hg or more (73% (30/41) versus 17% (10/59) (p < 0.001). A final Paco2 excess (i.e., the amount by which the Paco2 was higher than expected from the bicarbonate) > 1.0 mm Hg was also associated with an increased mortality rate ((62% (33/53) vs. 15% (7/47)) (p < 0.001). CONCLUSION: Values derived from the end-tidal CO2 and the excess Pco2 should be monitored intraoperatively in critically injured patients. Efforts should be made to improve cardiac output and adjust ventilation to maintain an end-tidal Pco2 of 25 mm Hg or more, an arterial to end-tidal CO2 difference of 12 mm Hg or less, and an excess Paco2 of 1.0 mm Hg or less.

Pituitary adenylate cyclase-activating peptide, carbachol, and glucose stimulate insulin release in the absence of an increase in intracellular Ca2+.

Insulin secretion from the pancreatic beta cell line HIT-T15 was examined under conditions in which the elevation of intracellular free Ca2+ concentration ([Ca2+]i) was inhibited by nitrendipine or diazoxide or by severe Ca2+ deprivation. Glucose-induced insulin release was completely abolished under these conditions. However, in the presence of 12-O-tetradecanoyl-phorbol-13-acetate or forskolin, 10 mM glucose significantly enhanced insulin release, even in the presence of 5 microM nitrendipine or 150 microM diazoxide. The [Ca2+]i was not increased under these conditions. Even under Ca(2+)-deprived conditions, achieved by 60-min preincubation in Ca(2+)-free buffer containing 1 mM ethylene glycol bis-(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA), glucose in the complete absence of extracellular Ca2+ significantly enhanced insulin release when the cells were treated also with 12-O-tetradecanoylphorbol-13-acetate and forskolin. Because of these findings, additional studies were performed with pituitary adenylate cyclase-activating peptide (PACAP) and carbachol to see whether physiological stimulation via receptor activation could stimulate insulin release in the absence of a rise in [Ca2+]i. Under normal Ca(2+)-containing conditions, PACAP and carbachol stimulated insulin release and markedly potentiated glucose-stimulated release. In the presence of nitrendipine and thapsigargin, glucose failed to stimulate insulin release. Also, neither glucose in combination with PACAP nor glucose with carbachol was able to stimulate release. However, under the same conditions, the combination of glucose, PACAP, and carbachol did stimulate release while being unable to elevate [Ca2+]i. Thus, simultaneous activation of the beta cell by PACAP, carbachol, and glucose can stimulate insulin release even when [Ca2+]i is not elevated.

Characterization of hepatoportal microvascular dysplasia in a kindred of cairn terriers.

Hepatoportal microvascular dysplasia (MVD), a congenital disorder of the hepatic vasculature, is described in a kindred of Cairn Terrier dogs. Cairn Terrier dogs (n = 165) were evaluated using the serum bile acid test. Affected dogs, identified by abnormal fasting or postprandial serum bile acid concentrations, were divided into 2 groups. Group 1 dogs (n = 147) were used for pedigree analysis. Group 2 dogs (n = 18) were characterized on the basis of history, physical examination, clinicopathologic studies, diagnostic imaging of the liver and portal circulation, and hepatic histopathology. Group 2 contained control dogs (n = 2), dogs with hepatoportal MVD (n = 11), and dogs with macroscopic portosystemic vascular anomalies (PVSA) (n = 5). With the exception of high serum bile acid concentrations, dogs with hepatoportal MVD were indistinguishable from control dogs on the basis of history, physical examination, clinicopathologic findings, survey abdominal radiography, abdominal ultrasound, or transcolonic scintigraphy. Contrast portography in dogs with MVD revealed abnormalities of terminal twigs of the portal vasculature with out large intrahepatic or extrahepatic shunting vessels. Histopathologic abnormalities in dogs with hepatoportal MVD were similar to those reported for dogs with PSVA. Pedigree analysis suggested an autosomal inheritance for MVD. Dogs with MVD had high serum bile acid concentrations, abnormal indocyanine green clearance, and hepatic pathology suggestive of PSVA, but they lacked characteristic clinical findings of PSVA. The clinical significance of MVD is unclear. Dogs with MVD were clinically normal when evaluated but long-term follow-up is not yet available. Dogs with hepatoportal MVD should be identified at an early age to avoid confusion in future diagnostic evaluations.

Glucose stimulation of insulin release in the absence of extracellular Ca2+ and in the absence of any increase in intracellular Ca2+ in rat pancreatic islets.

Insulin secretion has been studied in isolated rat pancreatic islets under stringent Ca(2+)-depleted, Ca(2+)-free conditions. Under these conditions, the effect of 16.7 mM glucose to stimulate insulin release was abolished. Forskolin, which activates adenylyl cyclase, also failed to stimulate release in the presence of either low or high glucose concentrations. A phorbol ester (phorbol 12-myristate 13-acetate; PMA) increased the release rate slightly and this was further increased by 16.7 mM glucose. Remarkably, in the presence of both forskolin and PMA, 16.7 mM glucose strongly augmented insulin release. The augmentation was concentration dependent and monophasic and had a temporal profile similar to the "second phase" of glucose-stimulated insulin release, which is seen under normal conditions when Ca2+ is present. Metabolism is required for the effect because mannoheptulose abolished the glucose response. Other nutrient secretagogues, alpha-ketoisocaproate, and the combination of leucine and glutamine augmented release under the same conditions. Norepinephrine, a physiological inhibitor of insulin secretion, totally blocked the stimulation of release by forskolin and PMA and the augmentation of release by glucose. Thus, under the stringent Ca(2+)-free conditions imposed, the stimulation of insulin release by forskolin and PMA, as well as the augmentation of release by glucose, is under normal physiological control. As no increase in intracellular [Ca2+] was observed, the results demonstrate that glucose can increase the rate of exocytosis and insulin release by pancreatic islets in a Ca(2+)-independent manner. This interesting pathway of stimulus-secretion coupling for glucose appears to exert its effect at a site beyond the usual elevation of intracellular [Ca2+] and is not due to an activation by glucose of protein kinase A or C.