106 research outputs found
Supplementary Information for "Top-down proteomics of mouse islets with beta cell CPE deletion reveals molecular details in prohormone processing"; Figures S1-S9, Tables S1-S4
No full textSupplementary information (figures and tables) for "Top-down proteomics of mouse islets with beta cell CPE deletion reveals molecular details in prohormone processing" by James M. Fulcher, Adam C. Swensen, Yi-Chun Chen, C. Bruce Verchere, Vladislav A. Petyuk, Wei-Jun Qian</p
The activity and biosynthesis of beta-cell peptide hormones : implications in diabetes, obesity, and pancreatic cancer
No full textType 1 and type 2 diabetes are characterized by hyperglycemia and loss of beta-cell mass, function, and peptide hormones. Beyond hyperglycemia, diabetes is also associated with obesity and increased risk of cancer, particularly pancreatic cancer. Islet amyloid polypeptide (IAPP) is the second most abundant beta-cell hormone, co-secreted with insulin, and reduced in diabetes. Paracrine actions of endogenous IAPP have been proposed in glycemic regulation and tumour growth suppression, but remain incompletely understood. To further characterize the effects of IAPP loss, we used an IAPP-knockout mouse fed a high-fat or control diet and assessed glycemia and adiposity. We also generated a genetic mouse model of pancreatic ductal adenocarcinoma in IAPP-knockout mice to investigate IAPP loss as a potential mechanism for the association of diabetes and pancreatic cancer. Trends in IAPP-knockout mice suggest elevated adiposity and glycemia in the absence of IAPP. We observed no effect of IAPP on pancreatic ductal adenocarcinoma survival in mice, or cancer cell proliferation, death, or glycolysis.
A reduction in the processing efficiency of beta-cell peptide prohormones is also observed in diabetes. Pcsk1 and Pcsk2 are the two major prohormone endoproteases within insulin granules, and are responsible for multiple steps in the proIAPP and proinsulin processing pathways. To determine whether impaired processing functions as a biomarker or driver of beta-cell dysfunction, we generated mouse models of beta-cell specific (Ins1cre-driven) Pcsk1 and Pcsk2 deficiency using Cre-lox recombination. Loss of Pcsk1 in beta cells caused severe proinsulin processing impairments and increased diabetes susceptibility in male mice, while female mice remained euglycemic. In contrast, male and female beta-cell Pcsk2-deficient mice were euglycemic with minimally impaired proinsulin processing, but severely impaired proIAPP processing. Deletion of both Pcsk1 and Pcsk2 in beta cells blocked proinsulin processing, drove hyperglycemia, increased beta-cell glucose responsiveness and mass, and reduced beta-cell maturity and proliferative capacity. In a mouse model expressing amyloidogenic human IAPP in beta cells, Pcsk1 deficiency significantly increased amyloid deposition. Collectively, these findings show that loss of beta-cell prohormone processing alters beta-cell function and drives hyperglycemia, and that endogenous IAPP does not act as a pancreatic tumour suppressor but may alter glycemia and adiposity.Medicine, Faculty ofPathology and Laboratory Medicine, Department ofGraduat
Islet macrophages response to beta cell stresses
No full textThe full abstract for this thesis is available in the body of the thesis, and will be available when the embargo expires.Medicine, Faculty ofPathology and Laboratory Medicine, Department ofGraduat
Peptide Therapeutics for Weight Loss: Preventing Plasma Pancreatic Polypeptide Proteolysis
No full textAdvances and Challenges in Islet Transplantation: Islet Procurement Rates and Lessons Learned from Suboptimal Islet Transplantation
No full textThe initial step in successful islet transplantation is procurement of healthy donor islets. Given the limited number of donor pancreata selected for islet isolation and that islets from multiple donors are typically required to obtain insulin independence, it is critical to improve pancreas procurement rates and yield of islets for transplantation. Islets are delicate microorgans that are susceptible to apoptosis, hypoxia, and ischemia during isolation, culture, and the peritransplant period. Once the islets are engrafted, both prompt revascularization and protection from beta-cell death and graft rejection are key to secure long-term survival and function. To facilitate the engraftment of more robust islets suitable for combating the challenging isolation period and proinflammatory transplantation milieu, numerous approaches have been employed to prevent beta-cell dysfunction and death including immune modulation, prevention of apoptosis and hypoxia, as well as stimulation of growth factors, angiogenesis, and reinnervation. In addition to briefly discussing islet isolation procedures, procurement rates, and islet transplantation, the relevant literature pertaining to successful suboptimal islet transplantation is reviewed to provide insight into potential approaches to balance the limited supply of available donor islets
IAPP and type 1 diabetes: implications for immunity, metabolism and islet transplants
No full textIslet amyloid polypeptide (IAPP), the main component of islet amyloid in type 2 diabetes and islet transplants, is now recognized as a contributor to beta cell dysfunction. Increasingly, evidence warrants its investigation in type 1 diabetes owing to both its immunomodulatory and metabolic actions. Autoreactive T cells to IAPP-derived epitopes have been described in humans, suggesting that IAPP is an islet autoantigen in type 1 diabetes. In addition, although aggregates of IAPP have not been implicated in type 1 diabetes, they are potent pro-inflammatory stimuli to innate immune cells, and thus, could influence autoimmunity. IAPP aggregates also occur rapidly in transplanted islets and likely contribute to islet transplant failure in type 1 diabetes through sterile inflammation. In addition, since type 1 diabetes is a disease of both insulin and IAPP deficiency, clinical trials have examined the potential benefits of IAPP replacement in type 1 diabetes with the injectable IAPP analogue, pramlintide. Pramlintide limits postprandial hyperglycemia by delaying gastric emptying and suppressing hyperglucagonemia, underlining the possible role of IAPP in postprandial glucose metabolism. Here, we review IAPP in the context of type 1 diabetes: from its potential involvement in type 1 diabetes pathogenesis, through its role in glucose metabolism and use of IAPP analogues as therapeutics, to its potential role in clinical islet transplant failure and considerations in this regard for future beta cell replacement strategies.</jats:p
Quantification of proliferating endocrine cells in NOD and Balb/c mice with and without STZ-induced diabetes.
No full text<p>Number of proliferating alpha, beta and delta-cells were quantified in relation to total respective endocrine cell number in 4-wk old diabetes-prone (black bars), 12-wk old insulitic (hatched bars) and 18–24 wk old diabetic (white bars) female NOD mice (A). Number of proliferating endocrine cells was quantified similarly in age-matched female Balb/c mice (B), and in 12 wk old Balb/c mice without (black bars) or with (white bars) STZ-induced diabetes (C). Significant changes among groups are indicated as: *<i>p<0.01</i>, **<i>p<0.001</i> and ***<i>p<0.0001</i>.</p
Improving glycaemic control in type 2 diabetes: Stimulate insulin secretion or provide beta-cell rest?
No full textType 2 diabetes (T2D) is characterized by a gradual decline in pancreatic beta cell function that determines the progressive course of the disease. While beta-cell failure is an important contributor to hyperglycaemia, chronic hyperglycaemia itself is also detrimental for beta-cell function, probably by inducing prolonged secretory stress on the beta cell as well as through direct glucotoxic mechanisms that have not been fully defined. For years, research has been carried out in search of therapies targeting hyperglycaemia that preserve long-term beta-cell function in T2D, a quest that is still ongoing. Current strategies aim to improve glycaemic control, either by promoting endogenous insulin secretion, such as sulfonylureas, or by mechanisms that may impact the beta cell indirectly, for example, providing beta-cell rest through insulin treatment. Although overall long-term success is limited with currently available interventions, in this review we argue that strategies that induce beta-cell rest have considerable potential to preserve long-term beta-cell function. This is based on laboratory-based studies involving human islets as well as clinical studies employing intensive insulin therapy, thiazolidinediones, bariatric surgery, short-acting glucagon-like peptide (GLP)-1 receptor agonists and a promising new class of diabetes drugs, sodium-glucose-linked transporter (SGLT)-2 inhibitors. Nevertheless, a lack of long-term clinical studies that focus on beta-cell function for the newer glucose-lowering agents, as well as commonly used combination therapies, preclude a straightforward conclusion; this gap in our knowledge should be a focus of future studies
Proliferation of endocrine cells and leukocytes in NOD and Balb/c mouse islets.
No full text<p>Co-immunostaining for the nuclear proliferation marker BrdU (green) and islet hormones (red) in 4, 12 and 20 wk old female NOD (A) and age-matched Balb/c mice (B). Sections are counterstained with DAPI to visualize nuclei (and infiltrating immune cells). White arrows indicate double-positive cells, and white arrowheads indicate single BrdU-positive cells within the islet mantel. Scale bar = 10 µm.</p
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