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157 results on '"Verchere, C B"'

16. Islet macrophages shift to a reparative state following pancreatic beta-cell death and are a major source of islet IGF-1

Author

Nackiewicz, D., Dan, M., Speck, M., Chow, S. Z., Chen, Y.C., Pospisilik, J. A., Verchere, C. B., and Ehses, J. A.

Subjects
endocrine system, 0303 health sciences, medicine.medical_specialty, geography, geography.geographical_feature_category, endocrine system diseases, business.industry, 030209 endocrinology & metabolism, Type 2 diabetes, medicine.disease, Islet, Proinflammatory cytokine, 03 medical and health sciences, 0302 clinical medicine, Immune system, Endocrinology, Internal medicine, Diabetes mellitus, medicine, Glucose homeostasis, Beta cell, business, Tissue homeostasis, 030304 developmental biology
Abstract

SummaryMacrophages play a dynamic role in tissue repair following injury. Here we found that following streptozotocin (STZ)-induced beta-cell death, mouse islet macrophages expressed increasedIgf1, decreased proinflammatory cytokine expression, and transcriptome changes consistent with macrophages undergoing efferocytosis and having an enhanced state of metabolism. Macrophages were the major, if not sole, contributors to islet IGF-1 production. Adoptive transfer experiments showed that macrophages can maintain insulin secretionin vivofollowing beta-cell death with no effects on islet-cell turnover. IGF-1 neutralization during STZ-treatment decreased insulin secretion without affecting islet-cell apoptosis or proliferation. Interestingly, high fat diet (HFD) combined with STZ further skewed islet macrophages to a reparative state. Finally, islet macrophages fromdb/dbmice also expressed decreased proinflammatory cytokines and increasedIgf1mRNA. These data have important implications for islet biology and pathology and show that islet macrophages preserve their reparative state following beta-cell death even during HFD feeding and severe hyperglycemia.

Published
2018
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21. Increased dietary fat promotes islet amyloid formation and beta-cell secretory dysfunction

Author

Hull, R. L., Andrikopoulos, S., Verchere, C. B., Vidal, J., Wang, F., Cnop, Miriam, Prigeon, R. L., and Kahn, Steven E.

Subjects
Male, endocrine system, Islets of Langerhans -- physiopathology, endocrine system diseases, Blood Glucose -- metabolism, Somatostatin -- metabolism, Body Weight, Mice, Transgenic, Glucose Tolerance Test, Glucose Intolerance -- blood, Dietary Fats -- pharmacology, Glucose Intolerance -- physiopathology, Amyloid -- physiology, Glucagon -- metabolism, Mice, Islets of Langerhans -- drug effects, Islets of Langerhans -- secretion, Amyloid -- genetics, Animals, Humans, Médecine clinique [biologie clinique], Insulin -- analysis, Pancreatic Polypeptide -- metabolism
Abstract

Transgenic mice expressing the amyloidogenic human islet amyloid polypeptide (hIAPP) in their islet beta-cells are a model of islet amyloid formation as it occurs in type 2 diabetes. Our hIAPP transgenic mice developed islet amyloid when fed a breeder chow but not regular chow. Because the breeder chow contained increased amounts of fat, we hypothesized that increased dietary fat enhances islet amyloid formation. To test this hypothesis, we fed male hIAPP transgenic and nontransgenic control mice diets containing 15% (low fat), 30% (medium fat), or 45% (high fat) of calories derived from fat for 12 months, and we measured islet amyloid, islet endocrine cell composition, and beta-cell function. Increased dietary fat in hIAPP transgenic mice was associated with a dose-dependent increase in both the prevalence (percentage of islets containing amyloid deposits; 34 +/- 8, 45 +/- 8, and 58 +/- 10%, P < 0.05) and severity (percentage of islet area occupied by amyloid; 0.8 +/- 0.5, 1.0 +/- 0.5, and 4.6 +/- 2.5%, P = 0.05) of islet amyloid. In addition, in these hIAPP transgenic mice, there was a dose-dependent decrease in the proportion of islet area comprising beta-cells, with no significant change in islet size. In contrast, nontransgenic mice adapted to diet-induced obesity by increasing their islet size more than twofold. Increased dietary fat was associated with impaired insulin secretion in hIAPP transgenic (P = 0.05) but not nontransgenic mice. In summary, dietary fat enhances both the prevalence and severity of islet amyloid and leads to beta-cell loss and impaired insulin secretion. Because both morphologic and functional defects are present in hIAPP transgenic mice, this would suggest that the effect of dietary fat to enhance islet amyloid formation might play a role in the pathogenesis of the islet lesion of type 2 diabetes in humans., Comparative Study, Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S., info:eu-repo/semantics/published

Published
2003

22. SPECIES-SPECIFIC SEQUENCE VARIATION OF PORCINE ISLET AMYLOID POLYPEPTIDE REDUCES ITS AMYLOIDOGENICITY AND MAY CONTRIBUTE TO IMPROVED FUNCTION AND SURVIVAL OF PIG ISLET XENOGRAFTS

Author

Potter, K, Abedini, A, Butterworth, S, Driscoll, M, Marek, P, Baker, R, Korbutt, G S, Fraser, P E, Raleigh, D P, Verchere, C B, Potter, K, Abedini, A, Butterworth, S, Driscoll, M, Marek, P, Baker, R, Korbutt, G S, Fraser, P E, Raleigh, D P, and Verchere, C B

Abstract

Introduction: Long-term success of human islet transplants has been limited. Beta cell mass and function in transplanted islets progressively decline over time, resembling the progressive loss of insulin secretion in type2 diabetes. Transplanted islets, like those in type 2 diabetes, are subject to apoptotic beta cell death and the formation of toxic aggregates of the betacell peptide islet amyloid polypeptide (IAPP). Interestingly, porcine islets consistently maintain long-term normoglycemia when transplanted into immune-deficient, diabetic mice. We hypothesized that transplanted pig islets may not be subject to amyloid formation and amyloid-induced cell death, and that this may contribute to the success of porcine islet grafts. Methods & Results: Sequencing of porcine IAPP (pIAPP) from neonatal pig islet (NPI)-extracted RNA confirmed notabledifferences from human IAPP (hIAPP), including a proline substitution within the known amyloidogenic region and a glutamine-for-lysine at the N-terminalcleavage site of porcine proIAPP. Fibril formation was assessed by electron miscroscopy (EM) and Thioflavin T fluorescence. While synthetic hIAPP fibrillized within minutes, pIAPP required 6 weeks to form fibrils detectableby EM. Small peptide fragments of pIAPP failed to aggregate. By Thioflavin T fluorescence assay, hIAPP (40 µM) had an average lag time of 1 h and a 1,000-fold increase in fluorescence by 2 h while pIAPP showed little increase in fluorescence after 20 h. Small peptide fragments of pIAPP also failed to aggregate. hIAPP was significantly more toxic to INS-1 cells than pIAPP (20-200 µM), asassessed by TUNEL (16 h) and Alamar blue (24 h). We also failed to detect amyloid in any (0/9) NPI transplanted into streptozotocin diabetic murine recipients, while human islets had extensive amyloid deposition by 8 weeks post-transplant, associated with graft failure. Conclusion: Porcine IAPP, unlike human IAPP, is only weakly amyloidogenic and cytotoxic. We speculate that dec

Published
2008

24. The effect of apolipoprotein E deficiency on islet amyloid deposition in human islet amyloid polypeptide transgenic mice

Author

Vidal, J., Verchere, C. B., Andrikopoulos, S., Wang, F., Hull, R. L., Cnop, Miriam, Olin, K. L., LeBoeuf, R. C., O'Brien, K. D., Chait, A., Kahn, Steven E., Vidal, J., Verchere, C. B., Andrikopoulos, S., Wang, F., Hull, R. L., Cnop, Miriam, Olin, K. L., LeBoeuf, R. C., O'Brien, K. D., Chait, A., and Kahn, Steven E.

Abstract

AIMS/HYPOTHESIS: Islet amyloid deposits are present in over 85% of Type 2 diabetic patients and have been suggested to be pathogenic. The mechanism that converts islet amyloid polypeptide (IAPP), the unique component of these deposits, into amyloid fibrils in vivo is not known. The amino acid sequence of IAPP is critical but insufficient for beta-pleated sheet formation. As apolipoprotein E (apoE), another component of islet amyloid deposits, plays a critical role in amyloid formation in Alzheimer's disease, we hypothesised that apoE could play an important role in islet amyloid formation. METHODS: Transgenic mice expressing the human form of IAPP ( hIAPP (+/0)) were crossbred with apoE deficient ( apoE (-/-)) mice and followed for 12 months, at which time the prevalence and severity of islet amyloid, as well as plasma glucose, hIAPP, immunoreactive insulin (IRI) and lipid concentrations were measured. RESULTS: The prevalence and severity of islet amyloid after one year of follow up were comparable among hIAPP (+/0) mice that were apoE (+/+), apoE (+/-) or apoE (-/-). Differences in glucose tolerance, lipid abnormalities or changes in pancreatic content or plasma concentrations of hIAPP and/or IRI did not account for these findings. CONCLUSION/INTERPRETATION: Our data shows that, unlike in the localized amyloidosis in the brain characteristic of Alzheimer's disease, apoE is not critical for islet amyloid formation in a transgenic mouse model of Type 2 diabetes mellitus. These results indicate that the mechanisms of localised amyloid formation probably vary among different amyloid-associated disorders. Therefore, therapeutic strategies targeting apoE might not apply equally to patients with different amyloid associated diseases., Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S., info:eu-repo/semantics/published

Published
2003

45. Moderate exercise attenuates caspase-3 activity, oxidative stress, and inhibits progression of diabetic renal disease in db/db mice.

Author

Ghosh, S., M. Khazaei, Moien-Afshari, F., Ang, L. S., Granville, D. J., Verchere, C. B., Dunn, S. R., McCue, P., Mizisin, A., Sharma, K., and Laher, I.

Subjects
DIABETIC nephropathies, BODY weight, CHRONIC kidney failure, SUPEROXIDES, LABORATORY mice
Abstract

Moderate exercise attenuates caspase-3 activity, oxidative stress, and inhibits progression of diabetic renal disease in db/db mice. Am J Physiol Renal Physiol 296: F700-F708, 2009. First published January 14, 2009; doi: 10.11 52/ajprenal.90548.2008.-Diabetic nephropathy, the leading cause of end-stage renal disease, is characterized by a proapoptotic and prooxidative environment. The mechanisms by which lifestyle interventions, such as exercise, benefit diabetic nephropathy are unknown. We hypothesized that exercise inhibits early diabetic nephropathy via attenuation of the mitochondrial apoptotic pathway and oxidative damage. Type 2 diabetic db/db and normoglycemic wild-type mice were exercised for an hour everyday at a moderate intensity for 7 wk, following which renal function, morphology, apoptotic signaling, and oxidative stress were evaluated. Exercise reduced body weight, albuminuria, and pathological glomerular expansion in db/db mice independent of hyperglycemic status. Changes in renal morphology were also related to reduced caspase-3 (main effector caspase in renal apoptosis), caspase-8 (main initiator caspase of the "extrinsic" pathway) activities, and TNF-a expression. A role for the mitochondrial apoptotic pathway was unlikely as both caspase-9 activity (initiator caspase of this pathway) and expression of regulatory proteins such as Bax and Bcl-2 were unchanged. Kidneys from db/db mice also produced higher levels of superoxides and had greater oxidative damage concurrent with downregulation of superoxide dismutase (SOD) I and 3. Interestingly, although exercise also increased superoxides, there was also upregulation of multiple SODs that likely inhibited lipid (hydroperoxides) and protein (carbonyls and nitrotyrosine) oxidation in db/db kidneys. In conclusion, exercise can inhibit progression of early diabetic nephropathy independent of hyperglycemia. Reductions in caspase-3 and caspase-8 activities, with parallel improvements in SOD expression and reduced oxidative damage, could underlie the beneficial effects of exercise in diabetic kidney disease. [ABSTRACT FROM AUTHOR]

Published
2009
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46. The prohormone convertase enzyme 2 (PC2) is essential for processing pro-islet amyloid polypeptide at the NH2-terminal cleavage site.

Author

Wang, Jing, Xu, Jun, Finnerty, Jennifer, Furuta, Machi, Steiner, Donald F., Verchere, C. Bruce, Wang, J, Xu, J, Finnerty, J, Furuta, M, Steiner, D F, and Verchere, C B

Subjects
PROINSULIN, PEPTIDE hormones, AMYLOID, PANCREATIC beta cells, PROTEIN metabolism, ANIMAL experimentation, COMPARATIVE studies, FLUORESCENT antibody technique, ISLANDS of Langerhans, RESEARCH methodology, MEDICAL cooperation, MICE, PROTEINS, PROTEOLYTIC enzymes, REFERENCE values, RESEARCH, WESTERN immunoblotting, EVALUATION research, IN vitro studies
Abstract

Impaired processing of pro-islet amyloid polypeptide (proIAPP), the precursor of the beta-cell peptide islet amyloid polypeptide (IAPP) (amylin), has been implicated in islet amyloid formation in type 2 diabetes. The prohormone convertase enzymes PC3 (also known as PC1) and PC2 are localized to beta-cell secretory granules with proIAPP and proinsulin and are responsible for proinsulin processing. To determine whether PC2 might be essential for proIAPP processing, we performed Western blot analysis of freshly isolated islets from normal mice and mice lacking active PC2. As expected, the primary species of IAPP immunoreactivity in islets from wild-type mice was fully processed (4-kDa) IAPP, with only small amounts of the 8-kDa precursor (unprocessed proIAPP) present. Islets from heterozygous PC2 null mice were identical to wild-type animals, suggesting that half the normal complement of PC2 is sufficient for normal proIAPP processing. By contrast, in islets from homozygous PC2 null mice, the predominant IAPP-immunoreactive form was of intermediate size (approximately 6 kDa), with no detectable mature IAPP and slightly elevated amounts of the 8-kDa precursor form present. Thus, in the absence of PC2, proIAPP processing appears to be blocked at the level of a proIAPP conversion intermediate. Immunofluorescence of pancreas sections and immunoblotting using antisera raised to the NH2- and COOH-terminal flanking regions of mouse proIAPP demonstrated that the 6-kDa intermediate form was an NH2-terminally extended proIAPP conversion intermediate (processed only at the COOH-terminus). These data indicate that PC2 is essential for processing of proIAPP at the NH2-terminal cleavage site in vivo and that PC3 is likely only capable of processing proIAPP at the COOH-terminal cleavage site. [ABSTRACT FROM AUTHOR]

Published
2001
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50. Des-(27-31)C-peptide. A novel secretory product of the rat pancreatic beta cell produced by truncation of proinsulin connecting peptide in secretory granules.

Author

Verchere, C B, Paoletta, M, Neerman-Arbez, M, Rose, K, Irminger, J C, Gingerich, R L, Kahn, S E, and Halban, P A

Abstract

Insulin and connecting peptide (C-peptide) are produced in equimolar amounts during proinsulin conversion in the pancreatic beta cell secretory granule. To determine whether insulin and C-peptide are equally stable in beta cell granules (and thus secreted in equimolar amounts), neonatal and adult rat beta cells were pulse-chased, and radiolabeled insulin and C-peptide analyzed by high performance liquid chromatography. A novel truncated C-peptide was identified and shown by mass spectrometry to be des-(27-31)C-peptide (loss of 5 C-terminal amino acids). Des-(27-31)C-peptide is a major beta cell secretory product, accounting for 37.4 +/- 1.6% (neonatal) and 8.5 +/- 0.6% (adult) of total labeled C-peptide in secretory granules after 10 h of chase. Des-(27-31)C-peptide is also secreted in a glucose-sensitive manner from the perfused adult rat pancreas, accounting for approximately 10% of total C-peptide immunoreactivity secreted. Human C-peptide is also a substrate for truncation in granules. Thus, when human proinsulin was expressed (infection with recombinant adenovirus) in transformed (INS) rat beta cells, human des-(27-31)C-peptide was secreted along with the intact human peptide and both intact and truncated rat C-peptide. In addition to truncation, 33.1 +/- 1.2% of C-peptide in neonatal but not adult rat beta cell granules was further degraded. Such degradation was completely inhibited by ammonium chloride (known to neutralize intra-granular pH), whereas truncation was only partially inhibited by approximately 50%. In conclusion, a novel beta cell secretory product, des-(27-31)C-peptide, has been identified and should be considered as a potential bioactive peptide. Both truncation and degradation of C-peptide are responsible for non-equimolar secretion of insulin and C-peptide in rat beta cells.

Published
1996

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