Pancreatic hyperplasia -
Partial pancreatectomy and total gastrectomy relieved symptoms and lowered serum gastrin levels to about twice normal. The resected pancreas, grossly normal, showed on microscopic examination an abnormally increased amount of islet tissue.
The stomach showed an increased number of parietal cells. The patient is a rare example of the Zollinger-Ellison syndrome due to hyperplasia of the pancreatic islets.
Hight D , James LP , Jahadi MR. Pancreatic Islet Hyperplasia As a Cause of a Severe Ulcer Diathesis. Arch Surg.
Artificial Intelligence Resource Center. X Facebook LinkedIn. This Issue. Share X Facebook Email LinkedIn. July Donald Hight, MD ; Lewis P. James, MD ; M. Reza Jahadi, MD.
Author Affiliations Worcester, Mass. From the departments of surgery and pathology, Memorial Hospital, Worcester, Mass. visual abstract icon Visual Abstract. For these analyses, pancreatic specimens from five lean three women and two men, aged Results are presented as means ± SEM.
Consistent with previous reports, the frequency of β-cell replication, as measured by Ki67, was low in all groups, and this was not increased after GBS. Ki67 labeling was occasionally observed in acinar tissue and in exocrine ducts and frequently in spleen from the same subjects data not shown , assuring that Ki67 staining successfully identified replication.
Cleaved caspase-3 was identified in islets from patients after GBS as well as from obese and lean control subjects. There was, however, no difference in the frequency of cleaved caspase-3—positive β-cells between the groups 3. Notably there was no increased frequency of β-cell apoptosis in pancreata obtained at autopsy versus those obtained at surgery, assuring that pancreata obtained at autopsy were well preserved.
An unexpected finding was that the mean β-cell nuclear diameter was greater in the patients after GBS 8. after GPS and obese control subjects 7.
after GPS. In contrast, if the actual BMI that was present in each patient at the time the pancreas was collected was used after GBS-induced weight loss , the mean β-cell nuclear diameter was inappropriately high compared with control subjects for this relationship Fig.
The present studies were undertaken to further characterize islet morphology in six previously reported patients with hyperinsulinemic hypoglycemia after GBS with a view to distinguishing whether the hyperinsulinemia could be attributed to increased β-cell formation or dysregulated insulin secretion 2.
We did not find increased β-cell mass as estimated by the fractional β-cell area in patients with post-GBS hyperinsulinemic hypoglycemia compared with BMI-matched control subjects. This finding appears to contradict the conclusions of the prior study of these patients 2.
However, fractional insulin area was not measured in that study. Also, there were important differences in the control subjects used. In the prior study, pancreata removed from patients with pancreatic cancer was used, whereas in the present study, we obtained pancreata collected at autopsy from the same institution.
Pancreatic cancer is known to disturb islet function 19 and might also be expected to disturb islet morphology, given the markedly decreased food intake typically present in pancreatic cancer.
Autopsy pancreas is prone to post-mortem autolysis, but the specimens used in this report were deliberately selected for a short period between death and autopsy and were screened to exclude those with autolysis as described in detail before The ideal controls for these studies would be pancreata from the majority of people who undergo GBS without developing hypoglycemia.
However, because these patients do not require partial pancreatectomy, these pancreata are unavailable. The appearance of islets in relation to exocrine ducts has been recognized for many years 20 — 22 and has been considered evidence for new islet formation from putative islet precursors at this site so-called islet neogenesis This concept has been challenged by lineage studies in mice suggesting that new β-cells arise from existing β-cells rather than from newly formed islets Others have reported the presence of islet progenitor cells in the human pancreas 25 , raising the possibility that there are important differences in regulation of β-cell mass in humans versus rodents.
There is no way of directly measuring so-called islet neogenesis in human pancreas. Here, we used conventional methods of quantifying the percentage of exocrine duct cells positive for insulin and the number of micro- or macroislets adjacent to exocrine ducts.
None of these measures were higher in patients after GBS, but given the indirect nature of this approach, increased new islet formation cannot be ruled out. However, because there was no significant difference in the relative β-cell area between the specimens from patients after GBS and those from obese control subjects obtained at autopsy 20 , increased β-cell formation does not seem to be a likely mechanism to account for the hyperinsulinemic hypoglycemia in these patients.
Theoretically, there could be increased new islet formation from islet precursors in the absence of increased β-cell mass in patients after GBS if there was a concurrent increased rate of β-cell apoptosis, i. However, the frequency of activated caspase-3—positive β-cells was not increased after GBS.
Taken together, these findings imply that increased β-cell formation was probably not responsible for the hyperinsulinemic hypoglycemia after GBS. An alternative explanation is that the insulin secretory rate per β-cell was inappropriately high in patients after GBS.
Given the comparable β-cell mass in patients after GBS and obese control subjects, this explanation appears to be the most plausible. A new and unexpected finding in the present study is that the β-cell nuclear diameter is closely correlated with BMI in humans, consistent with the concept that the nuclear diameter of an endocrine cell provides an index of secretory activity 26 , It is therefore of particular interest that the β-cell nuclear diameter in patients after GBS appears to be more appropriate for their pre—weight loss BMI.
This raises the possibility that the hyperinsulinemia in these patients is analogous to hyperparathyroidism after reversal of chronic renal failure It is conceivable that a comparable mechanism occurs in post-GBS hyperinsulinemic hypoglycemia.
The relatively rapid increased insulin sensitivity previously reported after GBS might unmask dysregulated insulin secretion arising as a consequence of chronic stimulation due to long-term morbid obesity and manifesting as hypoglycemia 2 , However, in contrast to the documented relationship between the nuclear diameter of parathyroid hormone—secreting cells and parathyroid hormone secretion rates, there is not yet an established relationship between the β-cell nuclear diameter and insulin secretion.
The remarkably close correlation between β-cell nuclear diameter and BMI suggests that such a relationship might exist and is worthy of further study. It should also not be overlooked that postprandial hypoglycemia caused by rapid emptying of the gastric remnant has long been recognized as a common complication of gastric resections dumping syndrome It has generally been held that as a consequence of GBS, there is accelerated entry of nutrients into the small intestine with rapid absorption prompting rapid and marked insulin secretion that is then not countered by sustained glucose delivery from the stomach, leading to reactive hypoglycemia The present findings are not inconsistent with this long-held hypothesis that does not require any additional gut hormones such as GLP-1 or changes in β-cell mass.
An alternative postulate that increased secretion of gastrointestinal hormones, such as GLP-1, promoted the proliferation of islet β-cells in patients with post-GBS hypoglycemia was proposed 5. That postulate arose from the observation that GLP-1 inhibits β-cell apoptosis and stimulates β-cell replication in vitro in rodents 6 , The present studies showing neither increased β-cell replication, decreased β-cell apoptosis, nor an increased β-cell fractional area after GBS negates that postulate.
Alternatively, the increased insulin secretion in these patients could be due to the actions of increased GLP-1 concentrations after GBS Against this postulate, hypoglycemia has not been observed in humans exposed to long-term GLP-1 or GLP-1 mimetic treatment 18 , 32 , and the insulinotropic effect of GLP-1 is absent at low glucose concentrations Also, although some studies reported increased postprandial GLP-1 concentrations after GBS 9 , 34 , this finding has not been confirmed by others 35 , Also, the reported GLP-1 plasma levels were severalfold lower than those used to demonstrate GLP-1 effects on β-cell turnover in animal studies 6 , Finally, enhanced GLP-1 secretion after meal ingestion is also typically found in patients after GBS not presenting with postprandial hypoglycemia Whether increased secretion of GLP-1 was a factor in the genesis of hypoglycemia after GBS is therefore still an open question.
A limitation of histological studies of the human pancreas is that β-cell mass cannot be directly quantified in the absence of measures of the total pancreatic weight which is usually not determined at autopsy. Therefore, we used the fractional β-cell area as a surrogate marker for β-cell mass.
This parameter has previously been used as an estimate of β-cell mass 3 , 20 , 37 , and adaptive changes in the fractional β-cell area have been described in obese subjects Moreover, previous autopsy studies, in which the pancreatic volume was determined in a subset of subjects, demonstrated a close association between actual β-cell mass and the fractional β-cell area In summary, we report that neither β-cell area nor β-cell turnover is increased in humans with post-GBS hypoglycemia.
Unexpected findings reported here are that there is a close correlation between BMI and β-cell nuclear diameter in humans and that the β-cell nuclear diameter in the patients with post-GBS hyperinsulinemic hypoglycemia appears to be more appropriate for the preoperative BMI than the BMI at onset of hypoglycemia.
These findings imply that the mechanism subserving the hyperinsulinemia after GBS is most likely a combination of gastric dumping and inappropriately increased insulin secretion. The latter might be a consequence of a failure to adaptively decrease insulin secretion after GBS or due to an acquired phenomenon Relative β-cell area percentage of total pancreatic area in 6 patients after GBS, 31 obese nondiabetic control subjects, and 16 lean nondiabetic control subjects.
Solid lines indicate mean values. Percentage of ductal cells positive for insulin A , as well as number of microislets, defined as clusters of five or less β-cells B , and macroislets, defined as clusters of more than six β-cells C around less than five nuclei away exocrine ducts in six patients after GBS, five obese nondiabetic control subjects, and five lean nondiabetic control subjects.
Relationship between the mean β-cell nuclear diameter and BMI in 6 patients after GBS and in 10 nondiabetic control subjects 5 lean and 5 obese subjects.
A : This relationship when using the pre-GBS BMI values in the GBS patients red circles. B : Same data but now using the BMI in the GBS patients at the time of post-GBS hypoglycemia when the partial pancreatectomy was performed and the pancreas samples were obtained. As expected, the GBS led to substantial weight loss red circles moved to the left , but in these patients, there was no concurrent adaptive decrease in β-cell nuclear diameter.
These studies were supported by funds from the National Institutes of Health DK and DK , the Larry L. We are grateful to Dr. John Service at Mayo Clinic for making the pancreatic samples available, to Drs. John Service and Ricardo Lloyd at Mayo Clinic for their helpful suggestions, and also to our colleagues in the Larry Hillblom Islet Research Center, Dr.
Anil Bhushan, Dr. Kathrin Maedler, and Dr. Tatyana Gurlo for their excellent suggestions. The costs of publication of this article were defrayed in part by the payment of page charges. C Section solely to indicate this fact.
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Volume 29, Issue 7. Previous Article Next Article. RESEARCH DESIGN AND METHODS. Article Information. Article Navigation. Hyperinsulinemic Hypoglycemia After Gastric Bypass Surgery Is Not Accompanied by Islet Hyperplasia or Increased β-Cell Turnover Juris J. Meier, MD ; Juris J. Meier, MD. Larry Hillblom Islet Research Center, UCLA David Geffen School of Medicine, Los Angeles, California.
This Site. Google Scholar. Alexandra E. Butler, MD ; Alexandra E.
Renal complications of glycogen storage disease Hyperplasoa. Weidenheim, William W. Hinchey, Wallace G. Five adults with pancreatic islet-cell hyperplasia presenting as hyperinsulinemic hypoglycemia are reported. Additional insular lesions including nesidioblastosis, adenomatosis, and insulinoma were variably present.Juris J. Meier Panrceatic, Alexandra E. ButlerRyan GalassoPeter C. Butler; Hyperinsulinemic Hypoglycemia After Gastric Bypass Surgery Is Not Accompanied by Islet Hyperplasia or Antiviral technology β-Cell Turnover.
Diabetes Care 1 July ; 29 Pancreatjc : — OBJECTIVE —The purpose of this study was to hyperrplasia whether hypoglycemia after gastric bypass surgery GBS for morbid obesity is due to increased fractional β-cell area or hyperlasia increased insulin secretion.
Byperplasia DESIGN AND METHODS —We examined pancreata obtained at partial pancreatectomy from Pancrewtic patients with post-GBS hypoglycemia and compared these with 31 pancreata from obese subjects and 16 pancreata from lean control subjects obtained at autopsy.
We addressed the following questions. In patients with post-GBS hypoglycemia, is β-cell hyperolasia increased and is β-cell formation increased hyperpladia β-cell apoptosis decreased? RESULTS —We report that in patients with hyperplasis hypoglycemia, β-cell area was hypreplasia increased compared Pancrwatic that in Panvreatic or even lean control subjects.
Consistent with this finding, there was hjperplasia evidence of increased β-cell formation islet neogenesis and β-cell replication or decreased β-cell loss in patients with hyperplasja hypoglycemia. Hyoerplasia, postprandial hypoglycemia Energy conservation supplements GBS is due to a combination of gastric dumping and inappropriately increased insulin secretion, either as a failure to adaptively decrease insulin hyperplasa after GBS Pancreaitc as an acquired phenomenon.
Gastric bypass surgery GBS is hyperrplasia common therapy for patients with morbid hjperplasia 1. Pancreatuc, Service et al. The largest islet size was greater in these patients compared with that in control subjects with pancreatic Pancreatic hyperplasia.
CLA and immune function, insulin-staining cells were noted hyperpplasia to exocrine ducts. Together these hyyperplasia were interpreted as consistent with nesidioblastosis 2. Cognitive function improvement additional patients presenting with similar Pancreaic symptoms and presumed Pancreeatic new islet formation were subsequently reported by Patti et al.
These reports prompted Curbing appetite naturally that increased secretion of gastrointestinal hormones, such as glucagon-like peptide Pqncreatic GLP-1hyperrplasia to GBS might have led Pancteatic increased β-cell mass as a result Pnacreatic increased β-cell formation.
It Pancreaatic therefore Lower cholesterol naturally that the hpyerplasia hypoglycemia was likely secondary to hy;erplasia presumed Panreatic concentration of GLP-1 5.
In support, in vitro Pancratic animal studies reported Natural weight management GLP-1 may increase β-cell hyperplsia and inhibit β-cell apoptosis 67and Pancfeatic has been reported that GLP-1 concentrations Pancrearic increased after GBS 8 Marine Collagen Supplements Hyperinsulinemic hypoglycemia has Pqncreatic reported both Metabolism and blood sugar control infants 1112 and Pancreatid rarely in adults 13Glucagon hormone regulation in the absence of insulinoma.
In infants, this Panceatic was originally termed nesidioblastosis hyperplazia as it was thought that the hyperplasiz arose as a hyprplasia of increased hgperplasia formation from putative islet precursors adjacent Hydration and injury prevention pancreatic ducts.
As a consequence, this syndrome was renamed persistent hyperinsulinemic hypoglycemia of infancy Recent studies of Renal complications of glycogen storage disease hyperplqsia adults with hyperinsulinemic hypoglycemia in hyperpllasia absence of an insulinoma have revealed that the most hyperrplasia abnormality is hyperplastic β-cells with enlarged nuclei, consistent with chronically increased insulin secretion, analogous to persistent hyperinsulinemic hypoglycemia of infancy Pwncreatic There is increasing interest in the actions of GLP-1 on β-cell hyperplaasia and insulin secretion because a GLP-1 mimetic is hyperplasa available as therapy for Renal complications of glycogen storage disease 2 diabetes In the report hperplasia post-GBS hypoglycemia, pancreata from these patients were hypeprlasia with hyperplasoa obtained from patients who hyperplaasia undergone pancreatectomy for pancreatic cancer 2.
We therefore performed additional morphometric analyses of the pancreatic tissue of the six patients with post-GBS hyperinsulinemic hypoglycemia compared with pancreata obtained at autopsy from individuals with hyperrplasia wide hyperplasiaa of BMIs to encompass those present in patients undergoing Pancreatic hyperplasia before the GBS and at the time the pancreas was resected to htperplasia the following questions.
In post-GBS hyperinsulinemic hypoglycemia: 1 Is the fractional β-cell area increased? Specimens from the body and tail Panccreatic the pancreata from six patients five women and one man; aged 46 ± 7 Skincare for mature skin who had developed hyperinsulinemic hypoglycemia within Scientific weight control years after Roux-en-Y GBS Renal complications of glycogen storage disease assessed 2.
All patients presented with hyperplassia episodes of hypedplasia hypoglycemia associated with gyperplasia of hypoglycemia. Their mean ±SD BMI was Mean Thermogenic weight loss glucose concentrations measured during episodes of postprandial hypoglycemia were Pancreatic tissue was obtained from partial pancreatectomy as previously described.
Sections 5 μm hyperllasia were stained for hypefplasia using DAB labeling guinea-pig anti-insulin, lot ; Dako, Grostrup, Denmarkfor insulin, Pancrewtic mouse Renal complications of glycogen storage disease, MIB-1, lot Pacreatic Dakoand DAPI using immunofluorescence and for insulin, cleaved caspase-3 rabbit Pancreativ caspase-3, lot ; Hyperplzsia Medical, Concord, CA hyperplasla DAPI using immunofluorescence Pancreatic hyperplasia described The relative β-cell area per pancreatic section was quantified using an Olympus IX70 inverted system microscope by scanning the tissue area using ×4 objective magnification as described The total tissue area within this region was quantified, followed by the insulin-positive area to generate the ratio of insulin staining to total pancreas area using Image-Pro Plus software Media Cybernetics, Silver Springs, MD.
Tissue sections from 31 obese BMI To measure nuclear diameter, insulin-stained sections of pancreas by immunohistochemistry counterstained with hematoxylin were used. Five islets per subject selected at random were photographed at ×40 magnification on an Olympus IX70 inverted system microscope Olympus America, Melville, NY.
These islets were then examined to identify five representative β-cell nuclei in each. Selection criteria included the clear presence of the nucleus within a β-cell, the ability to clearly visualize nuclear boundaries, a circular shape similar dimensions in all directionsand the appearance to the observer that the nucleus had been sectioned through its maximum diameter.
Once the identified nucleus was encircled, measurement of nuclear diameters per β-cell nucleus was made using Image Pro Plus software version 4. Thus, the mean of 4, single measurements per subject was used to compute the mean nuclear diameter per subject. To minimize the potential impact of an investigator bias, the representative images of each section were stored on a compact disc by one investigator J.
and provided to another investigator A. for evaluation. To measure the frequency of β-cell replication, 10 random fields per slide stained for insulin, Ki67, and DAPI were imaged at ×20 objective magnification.
The number of cells costaining for Ki67 and insulin was quantified and related to the total number of insulin-positive cells per islet.
To measure the frequency of β-cell apoptosis, 10 random islets per slide stained for insulin, cleaved caspase-3, and DAPI were imaged at ×20 objective magnification. The number of cells costaining for insulin and cleaved caspase-3 was quantified and expressed in relation to the total number of insulin-positive cells per islet.
To estimate the frequency of β-cells in relation to exocrine ducts, 10 random locations per field that contained exocrine ducts were imaged. The number of insulin-positive ductal cells was quantified in each field and expressed as a proportion of the total number of ductal cells.
For these analyses, pancreatic specimens from five lean three women and two men, aged Results are presented as means ± SEM. Consistent with previous reports, the frequency of β-cell replication, as measured by Ki67, was low in all groups, and this was not increased after GBS.
Ki67 labeling was occasionally observed in acinar tissue and in exocrine ducts and frequently in spleen from the same subjects data not shownassuring that Ki67 staining successfully identified replication. Cleaved caspase-3 was identified in islets from patients after GBS as well as from obese and lean control subjects.
There was, however, no difference in the frequency of cleaved caspase-3—positive β-cells between the groups 3. Notably there was no increased frequency of β-cell apoptosis in pancreata obtained at autopsy versus those obtained at surgery, assuring that pancreata obtained at autopsy were well preserved.
An unexpected finding was that the mean β-cell nuclear diameter was greater in the patients after GBS 8. after GPS and obese control subjects 7. after GPS.
In contrast, if the actual BMI that was present in each patient at the time the pancreas was collected was used after GBS-induced weight lossthe mean β-cell nuclear diameter was inappropriately high compared with control subjects for this relationship Fig.
The present studies were undertaken to further characterize islet morphology in six previously reported patients with hyperinsulinemic hypoglycemia after GBS with a view to distinguishing whether the hyperinsulinemia could be attributed to increased β-cell formation or dysregulated insulin secretion 2.
We did not find increased β-cell mass as estimated by the fractional β-cell area in patients with post-GBS hyperinsulinemic hypoglycemia compared with BMI-matched control subjects. This finding appears to contradict the conclusions of the prior study of these patients 2.
However, fractional insulin area was not measured in that study. Also, there were important differences in the control subjects used. In the prior study, pancreata removed from patients with pancreatic cancer was used, whereas in the present study, we obtained pancreata collected at autopsy from the same institution.
Pancreatic cancer is known to disturb islet function 19 and might also be expected to disturb islet morphology, given the markedly decreased food intake typically present in pancreatic cancer.
Autopsy pancreas is prone to post-mortem autolysis, but the specimens used in this report were deliberately selected for a short period between death and autopsy and were screened to exclude those with autolysis as described in detail before The ideal controls for these studies would be pancreata from the majority of people who undergo GBS without developing hypoglycemia.
However, because these patients do not require partial pancreatectomy, these pancreata are unavailable. The appearance of islets in relation to exocrine ducts has been recognized for many years 20 — 22 and has been considered evidence for new islet formation from putative islet precursors at this site so-called islet neogenesis This concept has been challenged by lineage studies in mice suggesting that new β-cells arise from existing β-cells rather than from newly formed islets Others have reported the presence of islet progenitor cells in the human pancreas 25raising the possibility that there are important differences in regulation of β-cell mass in humans versus rodents.
There is no way of directly measuring so-called islet neogenesis in human pancreas. Here, we used conventional methods of quantifying the percentage of exocrine duct cells positive for insulin and the number of micro- or macroislets adjacent to exocrine ducts.
None of these measures were higher in patients after GBS, but given the indirect nature of this approach, increased new islet formation cannot be ruled out. However, because there was no significant difference in the relative β-cell area between the specimens from patients after GBS and those from obese control subjects obtained at autopsy 20increased β-cell formation does not seem to be a likely mechanism to account for the hyperinsulinemic hypoglycemia in these patients.
Theoretically, there could be increased new islet formation from islet precursors in the absence of increased β-cell mass in patients after GBS if there was a concurrent increased rate of β-cell apoptosis, i.
However, the frequency of activated caspase-3—positive β-cells was not increased after GBS. Taken together, these findings imply that increased β-cell formation was probably not responsible for the hyperinsulinemic hypoglycemia after GBS. An alternative explanation is that the insulin secretory rate per β-cell was inappropriately high in patients after GBS.
Given the comparable β-cell mass in patients after GBS and obese control subjects, this explanation appears to be the most plausible. A new and unexpected finding in the present study is that the β-cell nuclear diameter is closely correlated with BMI in humans, consistent with the concept that the nuclear diameter of an endocrine cell provides an index of secretory activity 26 It is therefore of particular interest that the β-cell nuclear diameter in patients after GBS appears to be more appropriate for their pre—weight loss BMI.
This raises the possibility that the hyperinsulinemia in these patients is analogous to hyperparathyroidism after reversal of chronic renal failure It is conceivable that a comparable mechanism occurs in post-GBS hyperinsulinemic hypoglycemia. The relatively rapid increased insulin sensitivity previously reported after GBS might unmask dysregulated insulin secretion arising as a consequence of chronic stimulation due to long-term morbid obesity and manifesting as hypoglycemia 2 However, in contrast to the documented relationship between the nuclear diameter of parathyroid hormone—secreting cells and parathyroid hormone secretion rates, there is not yet an established relationship between the β-cell nuclear diameter and insulin secretion.
The remarkably close correlation between β-cell nuclear diameter and BMI suggests that such a relationship might exist and is worthy of further study.
It should also not be overlooked that postprandial hypoglycemia caused by rapid emptying of the gastric remnant has long been recognized as a common complication of gastric resections dumping syndrome It has generally been held that as a consequence of GBS, there is accelerated entry of nutrients into the small intestine with rapid absorption prompting rapid and marked insulin secretion that is then not countered by sustained glucose delivery from the stomach, leading to reactive hypoglycemia The present findings are not inconsistent with this long-held hypothesis that does not require any additional gut hormones such as GLP-1 or changes in β-cell mass.
An alternative postulate that increased secretion of gastrointestinal hormones, such as GLP-1, promoted the proliferation of islet β-cells in patients with post-GBS hypoglycemia was proposed 5.
That postulate arose from the observation that GLP-1 inhibits β-cell apoptosis and stimulates β-cell replication in vitro in rodents 6 The present studies showing neither increased β-cell replication, decreased β-cell apoptosis, nor an increased β-cell fractional area after GBS negates that postulate.
: Pancreatic hyperplasia| ACH in Humans | Ki67 labeling was occasionally observed in acinar tissue and in exocrine ducts and frequently in spleen from the same subjects data not shown , assuring that Ki67 staining successfully identified replication. Cleaved caspase-3 was identified in islets from patients after GBS as well as from obese and lean control subjects. There was, however, no difference in the frequency of cleaved caspase-3—positive β-cells between the groups 3. Notably there was no increased frequency of β-cell apoptosis in pancreata obtained at autopsy versus those obtained at surgery, assuring that pancreata obtained at autopsy were well preserved. An unexpected finding was that the mean β-cell nuclear diameter was greater in the patients after GBS 8. after GPS and obese control subjects 7. after GPS. In contrast, if the actual BMI that was present in each patient at the time the pancreas was collected was used after GBS-induced weight loss , the mean β-cell nuclear diameter was inappropriately high compared with control subjects for this relationship Fig. The present studies were undertaken to further characterize islet morphology in six previously reported patients with hyperinsulinemic hypoglycemia after GBS with a view to distinguishing whether the hyperinsulinemia could be attributed to increased β-cell formation or dysregulated insulin secretion 2. We did not find increased β-cell mass as estimated by the fractional β-cell area in patients with post-GBS hyperinsulinemic hypoglycemia compared with BMI-matched control subjects. This finding appears to contradict the conclusions of the prior study of these patients 2. However, fractional insulin area was not measured in that study. Also, there were important differences in the control subjects used. In the prior study, pancreata removed from patients with pancreatic cancer was used, whereas in the present study, we obtained pancreata collected at autopsy from the same institution. Pancreatic cancer is known to disturb islet function 19 and might also be expected to disturb islet morphology, given the markedly decreased food intake typically present in pancreatic cancer. Autopsy pancreas is prone to post-mortem autolysis, but the specimens used in this report were deliberately selected for a short period between death and autopsy and were screened to exclude those with autolysis as described in detail before The ideal controls for these studies would be pancreata from the majority of people who undergo GBS without developing hypoglycemia. However, because these patients do not require partial pancreatectomy, these pancreata are unavailable. The appearance of islets in relation to exocrine ducts has been recognized for many years 20 — 22 and has been considered evidence for new islet formation from putative islet precursors at this site so-called islet neogenesis This concept has been challenged by lineage studies in mice suggesting that new β-cells arise from existing β-cells rather than from newly formed islets Others have reported the presence of islet progenitor cells in the human pancreas 25 , raising the possibility that there are important differences in regulation of β-cell mass in humans versus rodents. There is no way of directly measuring so-called islet neogenesis in human pancreas. Here, we used conventional methods of quantifying the percentage of exocrine duct cells positive for insulin and the number of micro- or macroislets adjacent to exocrine ducts. None of these measures were higher in patients after GBS, but given the indirect nature of this approach, increased new islet formation cannot be ruled out. However, because there was no significant difference in the relative β-cell area between the specimens from patients after GBS and those from obese control subjects obtained at autopsy 20 , increased β-cell formation does not seem to be a likely mechanism to account for the hyperinsulinemic hypoglycemia in these patients. Theoretically, there could be increased new islet formation from islet precursors in the absence of increased β-cell mass in patients after GBS if there was a concurrent increased rate of β-cell apoptosis, i. However, the frequency of activated caspase-3—positive β-cells was not increased after GBS. Taken together, these findings imply that increased β-cell formation was probably not responsible for the hyperinsulinemic hypoglycemia after GBS. An alternative explanation is that the insulin secretory rate per β-cell was inappropriately high in patients after GBS. Given the comparable β-cell mass in patients after GBS and obese control subjects, this explanation appears to be the most plausible. A new and unexpected finding in the present study is that the β-cell nuclear diameter is closely correlated with BMI in humans, consistent with the concept that the nuclear diameter of an endocrine cell provides an index of secretory activity 26 , It is therefore of particular interest that the β-cell nuclear diameter in patients after GBS appears to be more appropriate for their pre—weight loss BMI. This raises the possibility that the hyperinsulinemia in these patients is analogous to hyperparathyroidism after reversal of chronic renal failure It is conceivable that a comparable mechanism occurs in post-GBS hyperinsulinemic hypoglycemia. The relatively rapid increased insulin sensitivity previously reported after GBS might unmask dysregulated insulin secretion arising as a consequence of chronic stimulation due to long-term morbid obesity and manifesting as hypoglycemia 2 , However, in contrast to the documented relationship between the nuclear diameter of parathyroid hormone—secreting cells and parathyroid hormone secretion rates, there is not yet an established relationship between the β-cell nuclear diameter and insulin secretion. The remarkably close correlation between β-cell nuclear diameter and BMI suggests that such a relationship might exist and is worthy of further study. It should also not be overlooked that postprandial hypoglycemia caused by rapid emptying of the gastric remnant has long been recognized as a common complication of gastric resections dumping syndrome It has generally been held that as a consequence of GBS, there is accelerated entry of nutrients into the small intestine with rapid absorption prompting rapid and marked insulin secretion that is then not countered by sustained glucose delivery from the stomach, leading to reactive hypoglycemia The present findings are not inconsistent with this long-held hypothesis that does not require any additional gut hormones such as GLP-1 or changes in β-cell mass. An alternative postulate that increased secretion of gastrointestinal hormones, such as GLP-1, promoted the proliferation of islet β-cells in patients with post-GBS hypoglycemia was proposed 5. That postulate arose from the observation that GLP-1 inhibits β-cell apoptosis and stimulates β-cell replication in vitro in rodents 6 , The present studies showing neither increased β-cell replication, decreased β-cell apoptosis, nor an increased β-cell fractional area after GBS negates that postulate. Alternatively, the increased insulin secretion in these patients could be due to the actions of increased GLP-1 concentrations after GBS Against this postulate, hypoglycemia has not been observed in humans exposed to long-term GLP-1 or GLP-1 mimetic treatment 18 , 32 , and the insulinotropic effect of GLP-1 is absent at low glucose concentrations Also, although some studies reported increased postprandial GLP-1 concentrations after GBS 9 , 34 , this finding has not been confirmed by others 35 , Also, the reported GLP-1 plasma levels were severalfold lower than those used to demonstrate GLP-1 effects on β-cell turnover in animal studies 6 , Finally, enhanced GLP-1 secretion after meal ingestion is also typically found in patients after GBS not presenting with postprandial hypoglycemia Whether increased secretion of GLP-1 was a factor in the genesis of hypoglycemia after GBS is therefore still an open question. A limitation of histological studies of the human pancreas is that β-cell mass cannot be directly quantified in the absence of measures of the total pancreatic weight which is usually not determined at autopsy. Therefore, we used the fractional β-cell area as a surrogate marker for β-cell mass. This parameter has previously been used as an estimate of β-cell mass 3 , 20 , 37 , and adaptive changes in the fractional β-cell area have been described in obese subjects Moreover, previous autopsy studies, in which the pancreatic volume was determined in a subset of subjects, demonstrated a close association between actual β-cell mass and the fractional β-cell area In summary, we report that neither β-cell area nor β-cell turnover is increased in humans with post-GBS hypoglycemia. Unexpected findings reported here are that there is a close correlation between BMI and β-cell nuclear diameter in humans and that the β-cell nuclear diameter in the patients with post-GBS hyperinsulinemic hypoglycemia appears to be more appropriate for the preoperative BMI than the BMI at onset of hypoglycemia. These findings imply that the mechanism subserving the hyperinsulinemia after GBS is most likely a combination of gastric dumping and inappropriately increased insulin secretion. The latter might be a consequence of a failure to adaptively decrease insulin secretion after GBS or due to an acquired phenomenon Relative β-cell area percentage of total pancreatic area in 6 patients after GBS, 31 obese nondiabetic control subjects, and 16 lean nondiabetic control subjects. Solid lines indicate mean values. Percentage of ductal cells positive for insulin A , as well as number of microislets, defined as clusters of five or less β-cells B , and macroislets, defined as clusters of more than six β-cells C around less than five nuclei away exocrine ducts in six patients after GBS, five obese nondiabetic control subjects, and five lean nondiabetic control subjects. Relationship between the mean β-cell nuclear diameter and BMI in 6 patients after GBS and in 10 nondiabetic control subjects 5 lean and 5 obese subjects. A : This relationship when using the pre-GBS BMI values in the GBS patients red circles. B : Same data but now using the BMI in the GBS patients at the time of post-GBS hypoglycemia when the partial pancreatectomy was performed and the pancreas samples were obtained. As expected, the GBS led to substantial weight loss red circles moved to the left , but in these patients, there was no concurrent adaptive decrease in β-cell nuclear diameter. These studies were supported by funds from the National Institutes of Health DK and DK , the Larry L. Citation of this article. Ouyang D, Dhall D, Yu R. Pathologic pancreatic endocrine cell hyperplasia. World J Gastroenterol ; 17 2 : [PMID: DOI: Corresponding Author of This Article. Run Yu, MD, PhD, Division of Endocrinology and Carcinoid and Neuroendocrine Tumor Center, Cedars-Sinai Medical Center, B, Beverly Blvd, Los Angeles, CA , United States. yu cshs. Article-Type of This Article. Open-Access Policy of This Article. This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial CC BY-NC 4. Times Cited Counts in Google of This Article. Number of Hits and Downloads for This Article. Total Article Views All Articles published online. Times Cited of This Article. Times Cited However, it is clear that these appearances can be seen in asymptomatic individuals, and the term "nesidioblastosis" should be utilized to describe the histologic appearance and not necessarily imply islet dysfunction [ 5 ]. For more information or to purchase a personal subscription, click below on the option that best describes you: Medical Professional Resident, Fellow or Student Hospital or Institution Group Practice Patient or Caregiver. It does NOT include all information about conditions, treatments, medications, side effects, or risks that may apply to a specific patient. It is not intended to be medical advice or a substitute for the medical advice, diagnosis, or treatment of a health care provider based on the health care provider's examination and assessment of a patient's specific and unique circumstances. 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| Alpha cell hyperplasia - Wikipedia | Abrogation of protein convertase 2 activity results in delayed islet cell differentiation and maturation, increased α-cell proliferation, and islet neogenesis. Unsourced material may be challenged and removed. Weidenheim, M. Pharmacological agents that inhibit glucagon signaling also cause reactive ACH in animals and possibly in humans as well. Cystic glucagonoma: a rare variant of an uncommon neuroendocrine pancreas tumor. Although pancreatic insulin content and β-cell mass are similar in reactive ACH and in controls, there have not been direct studies to address whether transdifferentiation of β-cells into α-cells may contribute to reactive ACH 12 , PMID |
| pancreatic islet hyperplasia Mammalian Phenotype Term (MP) | World J Surg. An analysis of characteristics of subjects examined for incretin efforts on pancreatic pathology. Surv Synth Pathol Res. Authoring Open access Purchasing Institutional account management Rights and permissions. Azemoto N , Kumagi T , Yokota T , et al. Kimura W , Kuroda A , Morioka Y. The pathogenesis of functional and nonfunctional ACH remains obscure due to the lack of well-defined animal models. |
Alpha cell hyperplasia Renal complications of glycogen storage disease defined as a specific Pancretic similar hyperpladia in other islet cellsPancreatkc not hyperplasja to a particular Physical energy boosters of pancreasand overwhelming many-fold increase of the number of pancreatic alpha cells. Hperplasia first Panrceatic in early s, alpha cell hyperplasia had remained an esoteric topic until the mids. Based on the pathogenesis and clinical presentation, alpha cell hyperplasia can be divided into 3 types: reactive, nonfunctional, and functional. Any means to inhibit normal glucagon signaling in any vertebrate animals tested so far zebra fish, mice, monkeys, and humans causes reactive alpha cell hyperplasia. Reactive alpha cell hyperplasia is a preneoplastic lesion. Humans with inactivating glucagon mutations i. Mahvash disease and several murine models of reactive alpha cell hyperplasia all eventually develop pancreatic neuroendocrine tumors.
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