scholarly journals One year of sitagliptin treatment protects against islet amyloid-associated β-cell loss and does not induce pancreatitis or pancreatic neoplasia in mice

2013 ◽  
Vol 305 (4) ◽  
pp. E475-E484 ◽  
Author(s):  
Kathryn Aston-Mourney ◽  
Shoba L. Subramanian ◽  
Sakeneh Zraika ◽  
Thanya Samarasekera ◽  
Daniel T. Meier ◽  
...  
Keyword(s):  
Exocrine Pancreas ◽  
Cell Mass ◽  
Cell Loss ◽  
Amyloid Deposition ◽  
Amyloid Formation ◽  
Metformin Treatment ◽  
Cell Toxicity ◽  
Β Cell ◽  
Islet Amyloid

The dipeptidyl peptidase-4 (DPP-4) inhibitor sitagliptin is an attractive therapy for diabetes, as it increases insulin release and may preserve β-cell mass. However, sitagliptin also increases β-cell release of human islet amyloid polypeptide (hIAPP), the peptide component of islet amyloid, which is cosecreted with insulin. Thus, sitagliptin treatment may promote islet amyloid formation and its associated β-cell toxicity. Conversely, metformin treatment decreases islet amyloid formation by decreasing β-cell secretory demand and could therefore offset sitagliptin's potential proamyloidogenic effects. Sitagliptin treatment has also been reported to be detrimental to the exocrine pancreas. We investigated whether long-term sitagliptin treatment, alone or with metformin, increased islet amyloid deposition and β-cell toxicity and induced pancreatic ductal proliferation, pancreatitis, and/or pancreatic metaplasia/neoplasia. hIAPP transgenic and nontransgenic littermates were followed for 1 yr on no treatment, sitagliptin, metformin, or the combination. Islet amyloid deposition, β-cell mass, insulin release, and measures of exocrine pancreas pathology were determined. Relative to untreated mice, sitagliptin treatment did not increase amyloid deposition, despite increasing hIAPP release, and prevented amyloid-induced β-cell loss. Metformin treatment alone or with sitagliptin decreased islet amyloid deposition to a similar extent vs untreated mice. Ductal proliferation was not altered among treatment groups, and no evidence of pancreatitis, ductal metaplasia, or neoplasia were observed. Therefore, long-term sitagliptin treatment stimulates β-cell secretion without increasing amyloid formation and protects against amyloid-induced β-cell loss. This suggests a novel effect of sitagliptin to protect the β-cell in type 2 diabetes that appears to occur without adverse effects on the exocrine pancreas.

Genetic background determines the extent of islet amyloid formation in human islet amyloid polypeptide transgenic mice

2005 ◽  
Vol 289 (4) ◽  
pp. E703-E709 ◽  
Author(s):  
Rebecca L. Hull ◽  
Melissah R. Watts ◽  
Keiichi Kodama ◽  
Zhen-ping Shen ◽  
Kristina M. Utzschneider ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Genetic Background ◽  
Cell Mass ◽  
Islet Amyloid Polypeptide ◽  
Amyloid Deposition ◽  
Human Islet ◽  
Amyloid Formation ◽  
Β Cell ◽  
Islet Amyloid ◽  
Background Strain

Genetic background is important in determining susceptibility to metabolic abnormalities such as insulin resistance and β-cell dysfunction. Islet amyloid is associated with reduced β-cell mass and function and develops in the majority of our C57BL/6J × DBA/2J (F1) male human islet amyloid polypeptide (hIAPP) transgenic mice after 1 yr of increased fat feeding. To determine the relative contribution of each parental strain, C57BL/6J (BL6) and DBA/2J (DBA2), to islet amyloid formation, we studied male hIAPP mice on each background strain (BL6, n = 13; and DBA2 n = 11) and C57BL/6J × DBA/2J F1mice ( n = 17) on a 9% (wt/wt) fat diet for 1 yr. At the end of 12 mo, islet amyloid deposition was quantified from thioflavin S-stained pancreas sections. The majority of mice in all groups developed islet amyloid (BL6: 91%, F1: 76%, DBA2: 100%). However, the prevalence (%amyloid-positive islets; BL6: 14 ± 3%, F1: 44 ± 8%, DBA2: 49 ± 9%, P < 0.05) and severity (%islet area occupied by amyloid; BL6: 0.03 ± 0.01%, F1: 9.2 ± 2.9%, DBA2: 5.7 ± 2.3%, p ≤ 0.01) were significantly lower in BL6 than F1and DBA2 mice. Increased islet amyloid severity was negatively correlated with insulin-positive area per islet, in F1( r2= 0.75, P < 0.001) and DBA2 ( r2= 0.87, P < 0.001) mice but not BL6 mice ( r2= 0.07). In summary, the extent of islet amyloid formation in hIAPP transgenic mice is determined by background strain, with mice expressing DBA/2J genes (F1and DBA2 mice) being more susceptible to amyloid deposition that replaces β-cell mass. These findings underscore the importance of genetic and environmental factors in studying metabolic disease.

scholarly journals Inhibition of glycosaminoglycan synthesis and protein glycosylation with WAS-406 and azaserine result in reduced islet amyloid formation in vitro

2007 ◽  
Vol 293 (5) ◽  
pp. C1586-C1593 ◽  
Author(s):  
Rebecca L. Hull ◽  
Sakeneh Zraika ◽  
Jayalakshmi Udayasankar ◽  
Robert Kisilevsky ◽  
Walter A. Szarek ◽  
...  
Keyword(s):  
Heparan Sulfate ◽  
Cell Mass ◽  
Amyloid Deposition ◽  
Protein Glycosylation ◽  
Amyloid Formation ◽  
Β Cell ◽  
Islet Amyloid ◽  
Glycosaminoglycan Synthesis ◽  
Amyloid A

Deposition of islet amyloid polypeptide (IAPP) as amyloid in the pancreatic islet occurs in ∼90% of individuals with Type 2 diabetes and is associated with decreased islet β-cell mass and function. Human IAPP (hIAPP), but not rodent IAPP, is amyloidogenic and toxic to islet β-cells. In addition to IAPP, islet amyloid deposits contain other components, including heparan sulfate proteoglycans (HSPGs). The small molecule 2-acetamido-1,3,6-tri- O-acetyl-2,4-dideoxy-α-d- xylo-hexopyranose (WAS-406) inhibits HSPG synthesis in hepatocytes and blocks systemic amyloid A deposition in vivo. To determine whether WAS-406 inhibits localized amyloid formation in the islet, we incubated hIAPP transgenic mouse islets for up to 7 days in 16.7 mM glucose (conditions that result in amyloid deposition) plus increasing concentrations of the inhibitor. WAS-406 at doses of 0, 10, 100, and 1,000 μM resulted in a dose-dependent decrease in amyloid deposition (% islet area occupied by amyloid: 0.66 ± 0.14%, 0.10 ± 0.06%, 0.09 ± 0.07%, and 0.004 ± 0.003%, P < 0.001) and an increase in β-cell area in hIAPP transgenic islets (55.0 ± 2.6 vs. 60.6 ± 2.2% islet area for 0 vs. 100 μM inhibitor, P = 0.05). Glycosaminoglycan, including heparan sulfate, synthesis was inhibited in both hIAPP transgenic and nontransgenic islets (the latter is a control that does not develop amyloid), while O-linked protein glycosylation was also decreased, and WAS-406 treatment tended to decrease islet viability in nontransgenic islets. Azaserine, an inhibitor of the rate-limiting step of the hexosamine biosynthesis pathway, replicated the effects of WAS-406, resulting in reduction of O-linked protein glycosylation and glycosaminoglycan synthesis and inhibition of islet amyloid formation. In summary, interventions that decrease both glycosaminoglycan synthesis and O-linked protein glycosylation are effective in reducing islet amyloid formation, but their utility as pharmacological agents may be limited due to adverse effects on the islet.

scholarly journals β-Cell Loss and β-Cell Apoptosis in Human Type 2 Diabetes Are Related to Islet Amyloid Deposition

2011 ◽  
Vol 178 (6) ◽  
pp. 2632-2640 ◽  
Author(s):  
Catherine A. Jurgens ◽  
Mirna N. Toukatly ◽  
Corinne L. Fligner ◽  
Jayalakshmi Udayasankar ◽  
Shoba L. Subramanian ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Cell Apoptosis ◽  
Cell Loss ◽  
Amyloid Deposition ◽  
Β Cell ◽  
Islet Amyloid ◽  
Human Type

scholarly journals CHOP Contributes to, But Is Not the Only Mediator of, IAPP Induced β-Cell Apoptosis

2016 ◽  
Vol 30 (4) ◽  
pp. 446-454 ◽  
Author(s):  
T. Gurlo ◽  
J. F. Rivera ◽  
A. E. Butler ◽  
M. Cory ◽  
J. Hoang ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Er Stress ◽  
Cell Apoptosis ◽  
Protein Misfolding ◽  
Nuclear Translocation ◽  
Cell Mass ◽  
Cell Loss ◽  
Β Cell ◽  
Islet Amyloid

The islet in type 2 diabetes is characterized by β-cell loss, increased β-cell apoptosis, and islet amyloid derived from islet amyloid polypeptide (IAPP). When protein misfolding protective mechanisms are overcome, human IAPP (h-IAPP) forms membrane permeant toxic oligomers that induce β-cell dysfunction and apoptosis. In humans with type 2 diabetes (T2D) and mice transgenic for h-IAPP, endoplasmic reticulum (ER) stress has been inferred from nuclear translocation of CCAAT/enhancer-binding protein homologous protein (CHOP), an established mediator of ER stress. To establish whether h-IAPP toxicity is mediated by ER stress, we evaluated diabetes onset and β-cell mass in h-IAPP transgenic (h-TG) mice with and without deletion of CHOP in comparison with wild-type controls. Diabetes was delayed in h-TG CHOP−/− mice, with relatively preserved β-cell mass and decreased β-cell apoptosis. Deletion of CHOP attenuates dysfunction of the autophagy/lysosomal pathway in β-cells of h-TG mice, uncovering a role for CHOP in mediating h-IAPP-induced dysfunction of autophagy. As deletion of CHOP delayed but did not prevent h-IAPP-induced β-cell loss and diabetes, we examined CHOP-independent stress pathways. JNK, a target of the IRE-1pTRAF2 complex, and the Bcl-2 family proapoptotic mediator BIM, a target of ATF4, were comparably activated by h-IAPP expression in the presence and absence of CHOP. Therefore, although these studies affirm that CHOP is a mediator of h-IAPP-induced ER stress, it is not the only one. Therefore, suppression of CHOP alone is unlikely to be a durable therapeutic strategy to protect against h-IAPP toxicity because multiple stress pathways are activated.

scholarly journals β-Cell Death in Diabetes: Past Discoveries, Present Understanding, and Potential Future Advances

Metabolites ◽  
2021 ◽  
Vol 11 (11) ◽  
pp. 796
Author(s):  
Noyonika Mukherjee ◽  
Li Lin ◽  
Christopher J. Contreras ◽  
Andrew T. Templin
Keyword(s):  
Cell Death ◽  
Molecular Mechanisms ◽  
Cell Loss ◽  
Pathological Process ◽  
Amyloid Formation ◽  
Β Cell ◽  
Islet Amyloid ◽  
Regulated Necrosis ◽  
Islet Inflammation ◽  
Stress Oxidative

β-cell death is regarded as a major event driving loss of insulin secretion and hyperglycemia in both type 1 and type 2 diabetes mellitus. In this review, we explore past, present, and potential future advances in our understanding of the mechanisms that promote β-cell death in diabetes, with a focus on the primary literature. We first review discoveries of insulin insufficiency, β-cell loss, and β-cell death in human diabetes. We discuss findings in humans and mouse models of diabetes related to autoimmune-associated β-cell loss and the roles of autoreactive T cells, B cells, and the β cell itself in this process. We review discoveries of the molecular mechanisms that underlie β-cell death-inducing stimuli, including proinflammatory cytokines, islet amyloid formation, ER stress, oxidative stress, glucotoxicity, and lipotoxicity. Finally, we explore recent perspectives on β-cell death in diabetes, including: (1) the role of the β cell in its own demise, (2) methods and terminology for identifying diverse mechanisms of β-cell death, and (3) whether non-canonical forms of β-cell death, such as regulated necrosis, contribute to islet inflammation and β-cell loss in diabetes. We believe new perspectives on the mechanisms of β-cell death in diabetes will provide a better understanding of this pathological process and may lead to new therapeutic strategies to protect β cells in the setting of diabetes.

scholarly journals Islet Amyloid in Type 2 Diabetes, and the Toxic Oligomer Hypothesis

2008 ◽  
Vol 29 (3) ◽  
pp. 303-316 ◽  
Author(s):  
Leena Haataja ◽  
Tatyana Gurlo ◽  
Chang J. Huang ◽  
Peter C. Butler
Keyword(s):  
Type 2 Diabetes ◽  
Neurodegenerative Diseases ◽  
Cell Mass ◽  
Cell Loss ◽  
Β Cell ◽  
Islet Amyloid ◽  
Amyloidogenic Proteins ◽  
Toxic Oligomer

Abstract Type 2 diabetes (T2DM) is characterized by insulin resistance, defective insulin secretion, loss of β-cell mass with increased β-cell apoptosis and islet amyloid. The islet amyloid is derived from islet amyloid polypeptide (IAPP, amylin), a protein coexpressed and cosecreted with insulin by pancreatic β-cells. In common with other amyloidogenic proteins, IAPP has the propensity to form membrane permeant toxic oligomers. Accumulating evidence suggests that these toxic oligomers, rather than the extracellular amyloid form of these proteins, are responsible for loss of neurons in neurodegenerative diseases. In this review we discuss emerging evidence to suggest that formation of intracellular IAPP oligomers may contribute to β-cell loss in T2DM. The accumulated evidence permits the amyloid hypothesis originally developed for neurodegenerative diseases to be reformulated as the toxic oligomer hypothesis. However, as in neurodegenerative diseases, it remains unclear exactly why amyloidogenic proteins form oligomers in vivo, what their exact structure is, and to what extent these oligomers play a primary or secondary role in the cytotoxicity in what are now often called unfolded protein diseases.

scholarly journals Inhibition of Insulin-Degrading Enzyme Does Not Increase Islet Amyloid Deposition in Vitro

Endocrinology ◽  
2016 ◽  
Vol 157 (9) ◽  
pp. 3462-3468 ◽  
Author(s):  
Meghan F. Hogan ◽  
Daniel T. Meier ◽  
Sakeneh Zraika ◽  
Andrew T. Templin ◽  
Mahnaz Mellati ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Glucose Metabolism ◽  
Cell Loss ◽  
Amyloid Deposition ◽  
Insulin Degrading Enzyme ◽  
Β Cell ◽  
Islet Amyloid ◽  
Degrading Enzyme ◽  
Human Type

Islet amyloid deposition in human type 2 diabetes results in β-cell loss. These amyloid deposits contain the unique amyloidogenic peptide human islet amyloid polypeptide (hIAPP), which is also a known substrate of the protease insulin-degrading enzyme (IDE). Whereas IDE inhibition has recently been demonstrated to improve glucose metabolism in mice, inhibiting it has also been shown to increase cell death when synthetic hIAPP is applied exogenously to a β-cell line. Thus, we wanted to determine whether a similar deleterious effect is observed when hIAPP is endogenously produced and secreted from islets. To address this issue, we cultured hIAPP transgenic mouse islets that have the propensity to form amyloid for 48 and 144 hours in 16.7 mM glucose in the presence and absence of the IDE inhibitor 1. At neither time interval did IDE inhibition increase amyloid formation or β-cell loss. Thus, the inhibition of IDE may represent an approach to improve glucose metabolism in human type 2 diabetes, without inducing amyloid deposition and its deleterious effects.

Dual role of interleukin-1β in islet amyloid formation and its β-cell toxicity: Implications for type 2 diabetes and islet transplantation

2017 ◽  
Vol 19 (5) ◽  
pp. 682-694 ◽  
Author(s):  
Yoo Jin Park ◽  
Garth L. Warnock ◽  
Ziliang Ao ◽  
Nooshin Safikhan ◽  
Mark Meloche ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Islet Transplantation ◽  
Dual Role ◽  
Interleukin 1Β ◽  
Amyloid Formation ◽  
Cell Toxicity ◽  
Β Cell ◽  
Islet Amyloid

Harnessing immune cells to enhance β-cell mass in type 1 diabetes

2016 ◽  
Vol 64 (1) ◽  
pp. 14-20 ◽  
Author(s):  
Ercument Dirice ◽  
Rohit N Kulkarni
Keyword(s):  
Type 1 Diabetes ◽  
Mononuclear Cells ◽  
Islet Cells ◽  
Cell Mass ◽  
Cell Loss ◽  
Cell Types ◽  
Β Cells ◽  
Β Cell ◽  
Autoimmune Attack

Type 1 diabetes is characterized by early β-cell loss leading to insulin dependence in virtually all patients with the disease in order to maintain glucose homeostasis. Most studies over the past few decades have focused on limiting the autoimmune attack on the β cells. However, emerging data from patients with long-standing diabetes who continue to harbor functional insulin-producing cells in their diseased pancreas have prompted scientists to examine whether proliferation of existing β cells can be enhanced to promote better glycemic control. In support of this concept, several studies indicate that mononuclear cells that infiltrate the islets have the capacity to trigger proliferation of islet cells including β cells. These observations indicate the exciting possibility of identifying those mononuclear cell types and their soluble factors and harnessing their ability to promote β-cell growth concomitant with autoimmune therapy to prevent the onset and/or halt the progression of the disease.

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