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W Y Fujimoto

Publications and source records attributed to W Y Fujimoto.

At least 91 records · Page 5Linked to original sources
PubMed1987

Phasic effects of glucose, phospholipase A2, and lysophospholipids on insulin secretion.

Arachidonic acid and lysophospholipids generated by glucose stimulation of phospholipase A2 may be related to the biphasic pattern of insulin secretion. Therefore, we examined the effects of glucose, exogenous phospholipase A2, lysophospholipids, and pharmacological agents which perturb the reesterification or oxygenation of arachidonic acid in superfused monolayer cultures of neonatal rat islet cells. Nordihydroguaiaretic acid (20 microM), an inhibitor of islet lipoxygenase, significantly decreased phasic glucose-stimulated insulin secretion, especially during phase 1, suggesting that stimulatory lipoxygenase metabolites of arachidonic acid contribute to the effects of glucose stimulation. Treatment with exogenous phospholipase A2 (10 mU/ml) or melittin (1.0 or 2.0 micrograms/ml) to generate arachidonic acid and lysophospholipids de novo caused a monophasic release of insulin, followed by a gradual decline in insulin secretion despite the continued presence of these agonists. Conversely, p-hydroxymercuribenzoate (15, 30, and 50 microM), which blocks the reacylation of lysophospholipids with arachidonic acid, evoked a concentration-dependent biphasic stimulation of insulin secretion which was reversible. Lipoxygenase inhibition had no effect upon phase 1 secretion by p-hydroxymercuribenzoate, although it did partially reduce phase 2 secretion. However, lysophosphatidylcholine (50, 75, and 100 micrograms/ml) also caused a concentration-dependent biphasic stimulation of insulin secretion which resembled that seen with p-hydroxymercuribenzoate, suggesting that lysophospholipids were mediating the effects of p-hydroxymercuribenzoate. We speculate that during glucose stimulation of the islet, the following three phospholipase A2-initiated changes may be important: generation of lysophospholipid to stimulate directly insulin secretion, generation of arachidonic acid and lipoxygenase-mediated arachidonate metabolites, which positively modulate insulin secretion, and generation of cyclooxygenase-mediated arachidonate metabolites, which negatively modulate insulin secretion.

Animals↗
PubMed1987

Prevalence of diabetes mellitus and impaired glucose tolerance among second-generation Japanese-American men.

We describe the initial findings from a multidisciplinary, epidemiologic study of diabetes mellitus conducted in a population of second-generation Japanese-American (Nisei) men born between 1910 and 1939 who reside in King County, Washington (n = 1746). From this study population, 487 volunteered, and 229 were enrolled to comprise the study sample. A random sample of Nisei men was also drawn from the population to develop a reference sample of 189 men. All subjects participated in a 75-g oral glucose tolerance test; the National Diabetes Data Group (NDDG) and World Health Organization (WHO) diagnostic criteria as well as a modification of the WHO criteria were used to classify individuals with normal glucose tolerance, impaired glucose tolerance (IGT), or diabetes. Within the study sample, 79 men were found to have normal glucose tolerance, 72 had IGT, and 78 had type II diabetes. The mean age of the study sample was 61.4 yr. Based on comparison of the study sample to the reference sample, the study sample was ascertained to be representative of Nisei men in King County. Extrapolating from our observations in the reference sample and in the study sample, we have estimated that approximately 56% of Nisei men in the study population have abnormal glucose tolerance. Much of this is undiagnosed because only approximately 13% of the reference sample of Nisei men reported a prior diagnosis of diabetes. Of the men who enrolled in the study as nondiabetic subjects, 11.1% had diabetes and 39.2% had IGT; i.e., 50.3% had previously unknown abnormalities in glucose tolerance. We estimate that approximately 20% of Nisei men have diabetes (both previously diagnosed and undiagnosed) and approximately 36% have IGT.

Adult↗
PubMed1987

Prevalence of complications among second-generation Japanese-American men with diabetes, impaired glucose tolerance, or normal glucose tolerance.

In a study sample of 229 second-generation Japanese-American (Nisei) men, 79 with normal glucose tolerance, 72 with impaired glucose tolerance (IGT), and 78 with non-insulin-dependent diabetes, we have determined prevalence rates for certain conditions (ischemic heart disease, peripheral vascular disease, hypertension, retinopathy, neuropathy, and nephropathy) associated with diabetes. All subjects participated in a 75-g oral glucose tolerance test. World Health Organization (WHO) diagnostic criteria and information from the subject's medical history and personal physician were used to classify the subjects. Retinopathy was observed only in diabetic men in the study sample (11.5% of diabetic men). Furthermore, it was observed only in men who were receiving drug treatment for diabetes--40.0% of insulin-treated and 17.2% of sulfonylurea-treated men. Electrophysiologic evidence of peripheral neuropathy was observed in 46.2% of diabetic men and in 4.0% of nondiabetic (normal and IGT) men. For diabetic men with fasting serum glucose greater than or equal to 140 mg/dl, 63.8% had peripheral neuropathy and 19.1% had retinopathy, whereas for diabetic men with fasting serum glucose less than 140 mg/dl, 19.4% had neuropathy and none had retinopathy. For diabetic men with a diabetes duration of greater than or equal to 10 yr, 72.7% had neuropathy and 31.8% had retinopathy; with a diabetes duration of 5-9 yr, 70.6% had neuropathy and 11.8% had retinopathy; and with a diabetes duration of less than 5 yr, 20.5% had neuropathy and none had retinopathy. Nephropathy was distinctly uncommon, and among the measurements of kidney function, only proteinuria was clearly abnormal with diabetes. Prevalence rates of hypertension, peripheral vascular disease, and ischemic heart disease were highest in Nisei men with diabetes, lowest in men with normal glucose tolerance, and intermediate in men with IGT.(ABSTRACT TRUNCATED AT 250 WORDS)

Coronary Disease↗
PubMed1986

Primary lipoprotein lipase deficiency.

The enzyme lipoprotein lipase plays a central role in the processing of energy in the form of calorically dense triglyceride. Classical LPL deficiency usually presents in childhood with the multiple manifestations related to chylomicronemia. Many patients with genetic variations have been noted who differ in one of many ways from the classical patients. With the development of techniques to measure enzyme mass and to study gene expression, the molecular defects in each of these families should become evident.

Adipose Tissue↗
PubMed1986

Abnormal body fat distribution detected by computed tomography in diabetic men.

Previous studies of body fat using tape measurement of body circumference and hand-held caliper skinfold measurements have suggested abnormal fat distribution in patients with diabetes mellitus. These methods, however, have high interobserver variability and cannot assess intra-abdominal fat independent of subcutaneous fat. We used computed tomography to evaluate body fat distribution in a group of 53 Japanese-American men of similar age and body mass index (weight divided by height squared). As determined by a 75-g oral glucose tolerance test, 29 subjects had type II diabetes and 24 were normal. Computed tomography cuts were obtained at three body levels to measure thorax, abdomen, and thigh subcutaneous fat area as well as intra-abdominal fat area. We found greater intra-abdominal fat in men with diabetes than in those without (123.74 vs. 95.54 cm2, P = 0.034) and a greater ratio of thorax to thigh subcutaneous fat (2.55 vs. 1.88, P = 0.016). These findings support the hypothesis that fat in different areas of the body differs metabolically. Computed tomography can be a useful tool for investigating whether abnormal body fat distribution is associated with the pathogenesis of abnormal glucose tolerance.

Adipose Tissue↗
PubMed1986

Responses of pancreatic b cells to alloxan and streptozotocin in the guinea pig.

Guinea pigs injected with streptozotocin were significantly hyperglycemic on day 1 after injection but only mildly so on day 14. However, serum insulin levels were significantly depressed on day 14; at this time the animals had lost 25% of their initial body weights and were severely glycosuric. The volume fraction of immunostainable B cells in the pancreas was reduced to one third of control values by day 1 after injection and remained at this level by day 14. Animals that received alloxan were slightly hyperglycemic on day 1 but not day 14. Both serum insulin and volume fraction of B cells in the pancreas were reduced by 70% on day 1 but had returned to control levels by day 14. Body weights for this group were equivalent to controls at both time points. These data indicate that: streptozotocin treatment of guinea pigs causes a diabetes-like condition characterized by insulin deficiency, pancreatic B cell loss, glycosuria, and weight loss, which are not reversed in the first 2 weeks after injection, whereas hyperglycemia is only transitory; alloxan also produces a diabetes-like condition early after injection, but all signs of diabetes disappear within 2 weeks, by which time serum insulin levels and the volume fraction of B cells in the pancreas have returned to normal. The experimental results suggest that regeneration of islet B cells following destruction by alloxan may be the primary cause of the recovery of alloxan-injected guinea pigs from the effects of the drug, whereas the persistence of insulin deficiency is consistent with an absence of islet B cell regeneration in the streptozotocin-treated animals.

Alloxan↗
PubMed1986

A culture method for the isolation of pancreatic islet cells from young rats.

Following digestion of a single pancreas from 30- to 50-day-old Sprague Dawley rats, many single cells and small cell clusters were obtained. Over a succeeding 5-day interval in tissue culture, many islet-like cell clusters were noted. They were smaller than isolated intact rat islets and appeared to develop from selective aggregation of islet cells. More than 1,000 of these islet-like clusters were obtained from a single pancreas. The physiologic characteristics of these cells indicated preservation of insulin secretory responses to glucose (30, 50, 100, 150, 200, and 300 mg/dl), theophylline (1.5 mM), and arginine (10 mM). This appears to be a useful method to follow when large quantities of islet cells are required, as for transplantation.

Animals↗
PubMed1986

Physiological and morphological changes in islet B cells following treatment of the guinea pig with alloxan.

Alloxan injections (200 mg/kg i.v.) into guinea pigs led to a significant decline of serum insulin levels and a marked inhibition of normal weight gain during the first 96 hr following treatment. Both of these parameters tended to normalize between 96 and 120 hr after treatment. However, neither hyperglycemia nor glycosuria occurred at any time. Volume densities of islet B cells (= volume density of islet cells immunostained for insulin per islet volume density) decreased and pyknotic nuclei appeared in the islets during the initial 48 hr after alloxan treatment. Islet B-cell volume density then returned to normal over the ensuing 24 hr, and remained normal up to 120 hr following administration of alloxan. In summary, after high doses of alloxan were given guinea pigs, serum insulin levels were reduced below control levels within 24 hr; this was associated with changes in body weight which paralleled changes in insulin levels more closely than did levels of blood or urine glucose; the volume density of immunostained B cells initially decreased and then returned to control levels by 72 hr following alloxan injection. The alloxan-treated guinea pig may represent a unique model for studying the restoration of insulinogenic capacity in insulinopenic diabetes.

Alloxan↗
PubMed1984

Immunocytochemical identification of cells containing insulin, glucagon, somatostatin, and pancreatic polypeptide in the islets of Langerhans of the guinea pig pancreas with light and electron microscopy.

Cell types containing insulin, glucagon, somatostatin, and pancreatic polypeptide were identified in guinea pig islets with light and electron microscopic immunoperoxidase staining. Cells containing immunostainable insulin (B cells) are located throughout the islets, including the islet periphery, and contain irregularly shaped granules (350-550 nm). Granule contents are of variable opacity and are often fragmented but not crystalloid. Cells containing immunoreactive glucagon (A cells) are found in the interior of islets and contain numerous spheroid electron-opaque granules (250-350 nm). Cells containing immunoreactive somatostatin (D cells) have elongate, axonlike processes that end adjacent to islet capillaries. D cells, which are very numerous and distributed uniformly throughout the islet parenchyma, contain small spheroid granules (150-25 nm) of pale electron opacity. Cells with immunoreactive pancreatic polypeptide (F cells) are rare in islets but numerous among the exocrine parenchyma. F cells contain pale spheroid granules (100-200 nm). Morphological criteria are reliable indicators for A cells and B cells, but D cells and F cells require immunostaining for positive identification.

Animals↗
PubMed1984

Oxygenation products of arachidonic acid: third messengers for insulin release.

Although an association between membrane phospholipid turnover and exocytotic hormone release has long been recognized, a causal relationship has not been firmly established. Recent studies suggest that glucose (and probably other insulin secretagogues) activates phospholipases and thereby releases membrane-bound arachidonic acid (AA). AA is then converted through islet 12-lipoxygenase to mediators or modulators of insulin release (tentatively identified as peroxides and epoxides of arachidonate). These products may be critical links in stimulus-secretion coupling, since blockade of either AA release or lipoxygenation abrogates insulin release induced by glucose and many other (but not all) stimuli. Cogeneration of prostaglandins from AA through the cyclooxygenase pathway may directly or indirectly modulate the formation and/or effect of lipoxygenase products. A critical role for lipoxygenase products (and possibly metabolites of AA synthesized by other pathways, such as P-450-dependent monooxygenases) may extend to many secretory cells in addition to pancreatic beta cells. The phasic release of AA described in many cells could explain the biphasic pattern of insulin release induced by glucose. Since some phospholipases and lipoxygenases are Ca++ activated, the release of AA in conjunction with its oxygenation appears to be a concerted system generating "third messengers" for hormone release.

12-Hydroxy-5,8,10,14-eicosatetraenoic Acid↗
PubMed1984

Rat islet cells have glucose-dependent periodic electrical activity.

In order to examine whether rat islet cells have a glucose-dependent plateau/silent phase pattern of electrical activity as seen in mouse islets, intracellular recordings were made in cultured whole rat islets. Rat islet cells responded to glucose stimulation with membrane potential alterations between a polarized silent phase and a depolarized plateau phase associated with spikes. Increasing or decreasing glucose stimulation prolonged or shortened the relative duration of plateau phase, respectively. Removal of glucose from the medium caused membrane hyperpolarization with disappearance of electrical activity while reintroduction of glucose caused membrane depolarization and biphasic onset of electrical activity. These results indicate that rat islet cells have a glucose dependent plateau/silent phase electrical mechanism nearly identical to that seen in mouse islets.

Animals↗
PubMed1984

Phasic glucose-stimulated insulin secretion by neonatal rat pancreatic islet cells. Enhancement by sodium salicylate.

UNLABELLED: Monolayer cultures of neonatal rat pancreatic islets were superfused to examine phasic insulin secretion. When stimulated with a constant glucose concentration of 300 mg/dl, insulin secretion promptly rose to a peak more than eightfold higher than the basal levels observed with glucose 30 mg/dl. This first-phase peak was followed by a quick decline in insulin to a level about four- to fivefold higher than basal, representing second-phase insulin secretion. Addition of sodium salicylate 20 mg/dl enhanced glucose-stimulated insulin secretion. Addition of salicylate concurrently with glucose greatly enhanced second-phase insulin secretion, but did not affect the first-phase peak, thereby converting the biphasic pattern to one that appeared to be monophasic. However, when cultures were superfused with salicylate both before and concurrent with stimulation by glucose, both the first-phase peak and the second phase of insulin secretion were increased, resulting in not only preservation but enhancement of the biphasic pattern. Salicylate had no effect on basal insulin secretion at glucose 30 mg/dl. During the transition from glucose 300 mg/dl to 30 mg/dl, immediately as glucose concentration began to fall in the superfusate, insulin secretion showed a transient increase ("off response"). CONCLUSIONS: (1) Cultures of neonatal rat pancreatic islet cells respond with a biphasic pattern of insulin secretion when exposed to a continuous and constant glucose stimulus. (2) When endogenous prostaglandin synthesis is inhibited by sodium salicylate, the biphasic pattern not only remains but is enhanced, indicating that endogenous prostaglandin synthesis exerts a tonic restraint throughout the entire period of glucose-stimulated phasic insulin release.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1983

In vitro paracrine regulation of islet B-cell function by A and D cells.

In monolayer cultures of islet cells from neonatal rats, incubation of cells for 1 hour with either anti-somatostatin serum or anti-glucagon serum enhanced insulin release. The former appears to be due to neutralization of endogenously secreted somatostatin. The latter may be due to removal of a stimulatory effect of endogenously released glucagon upon somatostatin secretion. Thus, although exogenously added glucagon stimulates insulin secretion, the effect of endogenously released glucagon upon islet B cells is a restraining one which may be mediated through an effect upon D cells and their release of endogenous somatostatin.

Animals↗
PubMed1983

A role for the lipoxygenase pathway of arachidonic acid metabolism in glucose- and glucagon-induced insulin secretion.

Although the cyclo-oxygenase pathway of arachidonic acid (AA) metabolism inhibits glucose-stimulated insulin release through synthesis of prostaglandins, very little attention has been given to the effects of lipoxygenase pathway products on beta cell function. We have examined the effects of two structurally-dissimilar lipoxygenase inhibitors on insulin release from monolayer-cultured rat islet cells. Both nordihydroguaiaretic acid (NDGA, 20-50 microM) and BW755c (100-250 microM) caused a dose-responsive inhibition of glucose-induced insulin release. This inhibitory effect occurred despite concomitant inhibition of prostaglandin E synthesis. Lipoxygenase inhibitors also impeded cyclic AMP accumulation. Insulin and cyclic AMP release induced by glucagon were also blunted. These studies suggest the hypothesis that AA released in or near the beta cell is metabolized to lipoxygenase product(s) which have feed-forward properties important to glucose- and glucagon-stimulated cyclic nucleotide accumulation and insulin release.

4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyraz↗
PubMed1983

Cytotoxic effects of alloxan treatment in vitro on monolayer cultures of neonatal rat pancreas.

Monolayer cultures of neonatal rat pancreas were exposed briefly (5 min) to alloxan and were then maintained for several days (up to 14 days) to examine the long-term effects of alloxan exposure on B cells. Alloxan (0-10 mM) caused a dose-dependent reduction in rates of insulin release during the first 24 h after treatment. This reduction persisted throughout the period of observation. Rates of glucagon release were unaltered by all concentrations of alloxan tested. Spontaneously decomposed alloxan had little or no effect on rates of insulin release. The simultaneous presence of high concentrations of glucose during exposure of cells to alloxan exerted a rapid protective effect against alloxan toxicity that was both glucose and alloxan dose dependent. Alloxan treatment of pancreatic monolayer cultures may allow for a comparison of those actions of alloxan that are directly on and specific for islet B cells. Furthermore, alloxan-treated cultures may represent a unique in vitro system for studying the physiology and biochemistry of other islet cell types in cultures in which B cells and insulin are reduced, as well as for studying glucose interactions with the B cell.

Alloxan↗