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G Pittenger

Publications and source records attributed to G Pittenger.

10 recordsLinked to original sources
PubMed1996

Induction of islet cell differentiation and new islet formation in the hamster--further support for a ductular origin.

Partial obstruction of the adult hamster pancreas leads to islet cell differentiation and new islet formation. From morphologic and morphometric observations, we have tentatively identified the source of the new islet tissue to be from cells in the ducts. In this study, in vivo labeling with a single pulse of tritiated thymidine after partial duct obstruction was used to ascertain whether newly formed islet cells were in fact derived from cells in the ductal epithelium. Supportive evidence for this formulation was also sought using immunocytochemistry for islet hormones and in situ hybridization for glucagon and insulin mRNA to probe areas of proliferating duct cells. Endocrine cell differentiation was observed as a migration of cells out from small ducts beginning at about 10 days after obstruction. Duct and islet cell labeling indices (LI;%) in control animals remained at a low level (0.25 +/- 0.01 and 0.26 +/- 0.03, respectively) throughout the experiment. In contrast, at 2 weeks after partial obstruction, the duct and islet cell LI were 4.2 +/- 0.7 and 0.80 +/- 0.1 (p < 0.05 vs. control). After 2 weeks, there was a rapid and significant 86% decline in the duct cell LI to a low of 0.6 +/- 0.2 at 8 weeks, which was accompanied by a comparable, but reciprocal, 113% increase in the islet cell LI to a high of 1.7 +/- 0.8 (p < 0.05). In situ hybridization demonstrated glucagon and insulin mRNA-positive cells within intralobular ducts as early as 6 and 8 days, respectively, after obstruction. Glucagon and insulin peptides appeared in these cells at approximately 8 and 10 days, respectively, as cells migrated out from the duct wall. This study provides additional evidence that further supports our concept that pancreatic endocrine cell differentiation in this model reiterates the normal ontogeny of beta cell differentiation from cells in the ductular epithelium.

Age Factors↗
PubMed1993

Factors controlling pancreatic islet neogenesis.

We have established a model in which cellophane wrapping induces reiteration of the normal ontogeny of beta-cell differentiation from ductal tissue. The secretion of insulin is physiologic and coordinated to the needs of the animal. Streptozotocin-induced diabetes in hamsters can be 'cured' at least half the time. There appears to be activation of growth factor(s) within the pancreas acting in an autocrine, paracrine or juxtacrine manner to induce ductal cell proliferation and differentiation into functioning beta-cells. Given the results of our studies to date, it does not seem premature to envisage new approaches to the treatment of diabetes mellitus. Identification of the factor(s) which regulates islet cell proliferation and differentiation in our model may permit proto-undifferentiated cells and islets to be grown in culture. This concept could be extended to induce endocrine cell differentiation in vitro as well. Furthermore, islet cell growth factors could be used to provide 'trophic support' to islet transplants as a means of maintaining graft viability. There may also be greater scope for gene therapy when the growth factor(s) has been isolated, purified, sequenced and cloned.

Animals↗
PubMed1984

A dual role of calcium in release of somatostatin from canine gastric antral mucosa.

We have examined the factors regulating the mucosal release of somatostatin-like immuno-reactivity (SRIF-LI) from 1-cm2 sheets of isolated canine gastric antral mucosa mounted in a Ussing chamber. SRIF-LI was released predominantly into the luminal perfusate, was maximal at pH 2.5, 1,987 +/- 319 pg X ml-1 X h-1, and reached a nadir at pH 6.0 of 89 +/- 24 pg X ml-1 X h-1. Increasing extracellular Ca2+ to 10 mM stimulated the release of SRIF-LI at both high and low pH. The Ca2+ ionophore A23187 had no apparent effect at either pH 2.5 or 7.0. LaCl3 stimulated the release of SRIF-LI at pH 7.0 but not at pH 2.5. Ouabain and TMB-8 had no significant effect on the release of SRIF-LI. At pH 7.0, trifluoperazine (TFP) stimulated release of SRIF-LI (80 +/- 10 pg X ml-1 X h-1). EGTA stimulated release of SRIF-LI at pH 2.5 (1,134 +/- 137 pg X ml-1 X h-1) and at pH 7.0 (300 +/- 57 pg X ml-1 X h-1), which was reversed by replacement of Ca2+ (22 +/- 6 pg X ml-1 X h-1). Thus Ca2+ appears to exert a dual effect on the release of SRIF-LI: both an increase and depletion of extracellular Ca2+ release SRIF-LI.

Animals↗
PubMed1983

Role of calcium in the stimulus-secretion coupling of antral gastrin release.

The role of calcium in the stimulus-secretion coupling of antral gastrin release was examined in isolated sheets of canine antral mucosa. Mucosa was obtained from 137 dogs and mounted in Ussing chambers to separate the luminal from nutrient surfaces. The influence of verapamil, LaCl3, A23187, and EGTA on the release of gastrin by luminal calcium and ethyl alcohol was examined and the release of immunoreactive gastrin (IG) was measured in luminal perfusates. Release of IG by luminal calcium was dose-related, unsaturable, and impaired by verapamil and by LaCl3. Release of IG by alcohol was prevented by leaching the mucosa of calcium and restored by repletion of the calcium. IG release induced by alcohol was prevented by topical, but not by nutrient, application of LaCl3. Molecular sieve and affinity chromatography of the endogenous IG released in the absence of luminal calcium, and of the exogenous gastrin added, indicated that antral gastrin was released as heptadecapeptide gastrin, and that which was released in the presence of CaCl2 degraded rapidly into a C-terminal fragment. The data indicate that calcium may participate in the stimulus-secretion coupling of canine antral gastrin release in vitro.

Animals↗
PubMed1983

Predictive value of intramural pH and other risk factors for massive bleeding from stress ulceration.

We have devised and validated an indirect method for measuring the intramural pH in the stomachs of patients in the intensive care unit and have assessed its value in predicting the occurrence of massive hemorrhage from stress ulceration. The 103 patients, studied on an average of 3.8 +/- 0.6 consecutive days, were assigned to one of five groups: no bleeding, weakly positive guaiac, strongly positive guaiac, massive bleeding from an extragastric site, and massive bleeding from stress ulceration. The pH in gastric juice, arterial blood, and the wall of the stomach, PCO2 and PO2 in gastric juice and arterial blood, and [HCO3-] in arterial blood were recorded, together with history of treatment with antacids, cimetidine, and heparin and the number of risk factors known to be associated with bleeding from stress ulceration. Massive bleeding from stress ulceration occurred in 7 patients, all of whom were receiving antacids. Six of these patients died. A logistic analysis of the data obtained showed that the occurrence of bleeding from stress ulceration was best predicted by consideration of the combination of the number of risk factors and intramural pH (p less than 0.0001). Prediction by these variables was not improved by inclusion of any of the other variables recorded. Bleeding from stress ulceration was only seen in patients whose intramural pH had fallen below the lower limit of normality. The data indicate that intensive care unit patients would be better monitored if the intramural pH were measured, and that the occurrence of massive bleeding from stress ulceration would be better averted by maintaining the intramural pH at normal levels.

Adolescent↗
PubMed1980

Effect of luminal somatostatin on acid secretion and gastrin release.

The mechanisms by which somatostatin inhibits acid secretion when infused into the lumen of the stomach have been examined in 20 healthy subjects. The acid secretory response to distension with 500 ml of neutral water was examined in nine successive 10-min test periods in each subject. Samples of serum and boiled neutral gastric juice were collected and frozen for later immunoassay for gastrin. Somatostatin was added to the distending fluid in a concentration of 600 pg/ml in the middle 3 test periods in 10 test subjects, and placebo added in the same 3 test periods in 10 control subjects. The addition of somatostatin inhibited the rate of acid secretion as compared with placebo alone in the control subjects (p < 0.025) without altering the concentration of immunoreactive gastrin in the serum but reducing the concentration of immunoreactive gastrin in gastric juice (p < 0.02). The data are consistent with the suggestions that the intraluminal administration of somatostatin inhibits antral gastrin release in a paracrinic manner and inhibits acid secretion indirectly by inhibiting lumina gastrin-mediated acid secretory activity.

Gastric Juice↗
PubMedDate not supplied

Factors controlling pancreatic islet neogenesis.

We have established a model in which cellophane wrapping induces reiteration of the normal ontogeny of beta-cell differentiation from ductal tissue. The secretion of insulin is physiologic and coordinated to the needs of the animal. Streptozotocin-induced diabetes in hamsters can be "cured" at least half the time. There appears to be activation of growth factor(s) within the pancreas, acting in an autocrine, paracrine, or juxtacrine manner to induce ductal cell proliferation and differentiation into functioning beta cells. Given the results of our studies to date, it does not seem premature to envisage new approaches to the treatment of diabetes mellitus. Identification of the factor(s) regulating islet-cell proliferation and differentiation in our model may permit islets to be grown in culture. This concept could be extended to induce endocrine cell differentiation in vitro as well. Furthermore, islet-cell growth factors could be used to provide "trophic support" to islet transplants as a means of maintaining graft viability. There may also be greater scope for gene therapy when the growth factor(s) have been isolated, purified, sequenced, and cloned.

Animals↗