scholarly journals Vaccination Against Amyloidogenic Aggregates in Pancreatic Islets Prevents Development of Type 2 Diabetes Mellitus

Vaccines ◽  
2020 ◽  
Vol 8 (1) ◽  
pp. 116 ◽  
Author(s):  
Elisa S. Roesti ◽  
Christina N. Boyle ◽  
Daniel T. Zeman ◽  
Marcos Sande-Melon ◽  
Federico Storni ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Pancreatic Islets ◽  
Hormone Secretion ◽  
Β Cell ◽  
Islet Amyloid ◽  
Disease Modifying

Type 2 diabetes mellitus (T2DM) is a chronic progressive disease characterized by insulin resistance and insufficient insulin secretion to maintain normoglycemia. The majority of T2DM patients bear amyloid deposits mainly composed of islet amyloid polypeptide (IAPP) in their pancreatic islets. These—originally β-cell secretory products—extracellular aggregates are cytotoxic for insulin-producing β-cells and are associated with β-cell loss and inflammation in T2DM advanced stages. Due to the absence of T2DM preventive medicaments and the presence of only symptomatic drugs acting towards increasing hormone secretion and action, we aimed at establishing a novel disease-modifying therapy targeting the cytotoxic IAPP deposits in order to prevent the development of T2DM. We generated a vaccine based on virus-like particles (VLPs), devoid of genomic material, coupled to IAPP peptides inducing specific antibodies against aggregated, but not monomeric IAPP. Using a mouse model of islet amyloidosis, we demonstrate in vivo that our vaccine induced a potent antibody response against aggregated, but not soluble IAPP, strikingly preventing IAPP depositions, delaying onset of hyperglycemia and the induction of the associated pro-inflammatory cytokine Interleukin 1β (IL-1β). We offer the first cost-effective and safe disease-modifying approach targeting islet dysfunction in T2DM, preventing pathogenic aggregates without disturbing physiological IAPP function.

scholarly journals Noninvasive Evaluation of GPR119 Agonist Effects on β-Cell Mass in Diabetic Male Mice Using 111In-Exendin-4 SPECT/CT

Endocrinology ◽  
2019 ◽  
Vol 160 (12) ◽  
pp. 2959-2968 ◽  
Author(s):  
Takaaki Murakami ◽  
Hiroyuki Fujimoto ◽  
Naotaka Fujita ◽  
Keita Hamamatsu ◽  
Koji Matsumoto ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Dietary Restriction ◽  
Single Photon ◽  
Cell Mass ◽  
Photon Emission ◽  
Β Cell

Abstract Longitudinal observation of pancreatic β-cell mass (BCM) remains challenging because noninvasive techniques for determining BCM in vivo have not been established. Such observations would be useful for the monitoring of type 2 diabetes mellitus, a progressive disease involving loss of pancreatic BCM and function. An indium 111 (111In)–labeled exendin-4 derivative ([Lys12(111In-BnDTPA-Ahx)]exendin-4) targeting the glucagon-like peptide-1 receptor has been developed recently as a promising probe for quantifying the BCM noninvasively. In the present study, we used the 111In-exendin-4 single-photon emission CT/CT (SPECT/CT) technique to investigate the efficacy of DS-8500a, a novel G protein–coupled receptor-119 agonist currently under investigation for type 2 diabetes mellitus treatment in prediabetic db/db mice under dietary restriction. During the 8-week study, the treatment of mice with DS-8500a delayed and attenuated the progression of glucose intolerance compared with mice under dietary restriction alone. 111In-exendin-4 SPECT/CT of db/db mice revealed continuously decreasing radioactive isotope (RI) intensity in the pancreas during the 8-week intervention. DS-8500a attenuated this decrease and preserved pancreatic RI accumulation compared with dietary restriction alone at the end of the observation period. This result was corroborated not only by ex vivo pancreatic analysis using the [Lys12(111In-BnDTPA-Ahx)]exendin-4 probe but also by conventional histological BCM analysis. These results indicate that DS-8500a attenuates the progression of BCM loss beyond that of dietary restriction alone in prediabetic db/db mice. These results have shown that 111In-exendin-4 SPECT/CT will be useful for noninvasive longitudinal investigation of BCM in vivo.

scholarly journals Apolipoprotein CIII links islet insulin resistance to β-cell failure in diabetes

2015 ◽  
Vol 112 (20) ◽  
pp. E2611-E2619 ◽  
Author(s):  
Karin Åvall ◽  
Yusuf Ali ◽  
Ingo B. Leibiger ◽  
Barbara Leibiger ◽  
Tilo Moede ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Molecular Mechanisms ◽  
Cell Function ◽  
Β Cell ◽  
Apolipoprotein Ciii

Insulin resistance and β-cell failure are the major defects in type 2 diabetes mellitus. However, the molecular mechanisms linking these two defects remain unknown. Elevated levels of apolipoprotein CIII (apoCIII) are associated not only with insulin resistance but also with cardiovascular disorders and inflammation. We now demonstrate that local apoCIII production is connected to pancreatic islet insulin resistance and β-cell failure. An increase in islet apoCIII causes promotion of a local inflammatory milieu, increased mitochondrial metabolism, deranged regulation of β-cell cytoplasmic free Ca2+ concentration ([Ca2+]i) and apoptosis. Decreasing apoCIII in vivo results in improved glucose tolerance, and pancreatic apoCIII knockout islets transplanted into diabetic mice, with high systemic levels of the apolipoprotein, demonstrate a normal [Ca2+]i response pattern and no hallmarks of inflammation. Hence, under conditions of islet insulin resistance, locally produced apoCIII is an important diabetogenic factor involved in impairment of β-cell function and may thus constitute a novel target for the treatment of type 2 diabetes mellitus.

Photodegradation of porphyrin-bound hIAPP(1–37) fibrils

2020 ◽  
Vol 44 (22) ◽  
pp. 9438-9443
Author(s):  
Yongxiu Song ◽  
Ping Li ◽  
Zhiming Zhang ◽  
Yin Wang ◽  
Zhefei Zhang ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Pancreatic Islets ◽  
Islet Amyloid Polypeptide ◽  
Human Islet ◽  
Preventive Strategy ◽  
Islet Amyloid ◽  
Amyloid Deposits

Amyloid deposits in pancreatic islets of type 2 diabetes mellitus (T2DM) are mainly comprised of human islet amyloid polypeptide (hIAPP), the degradation of hIAPP fibrils by photoactive porphyrin could be a preventive strategy against T2DM.

Pancreatic Vascular Pathologies and Islet Amyloid in Type 2 Diabetes Mellitus

2019 ◽  
Author(s):  
Wei Ling ◽  
Yi Huang ◽  
Yan-Mei Huang ◽  
Jian Shen ◽  
Shan-Huan Wang ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Islet Amyloid

Animal Research for Type 2 Diabetes Mellitus, Its Limited Translation for Clinical Benefit, and the Way Forward

2018 ◽  
Vol 46 (1) ◽  
pp. 13-22 ◽  
Author(s):  
Zeeshan Ali ◽  
P. Charukeshi Chandrasekera ◽  
John J. Pippin
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Animal Models ◽  
Animal Research ◽  
Therapeutic Options ◽  
Research Findings

Obesity and type 2 diabetes mellitus (T2DM) have reached pandemic proportions worldwide, and considerable research efforts have been dedicated to investigating disease pathology and therapeutic options. The two hallmark features of T2DM, insulin resistance and pancreatic dysfunction, have been studied extensively by using various animal models. Despite the knowledge acquired from such models, particularly mechanistic discoveries that sometimes mimic human T2DM mechanisms or pathways, many details of human T2DM pathogenesis remain unknown, therapeutic options remain limited, and a cure has eluded research. Emerging human data have raised concern regarding inter-species differences at many levels (e.g. in gene regulation, pancreatic cytoarchitecture, glucose transport, and insulin secretion regulation), and the subsequent impact of these differences on the clinical translation of animal research findings. Therefore, it is important to recognise and address the translational gap between basic animal-based research and the clinical advances needed to prevent and treat T2DM. The purpose of this report is to identify some limitations of T2DM animal research, and to propose how greater human relevance and applicability of hypothesis-driven basic T2DM research could be achieved through the use of human-based data acquisition at various biological levels. This report addresses how in vitro, in vivo and in silico technologies could be used to investigate particular aspects of human glucose regulation. We do not propose that T2DM animal research has been without value in the identification of mechanisms, pathways, or potential targets for therapies, nor do we claim that human-based methods can provide all the answers. We recognise that the ultimate goal of T2DM animal research is to identify ways to advance the prevention, recognition and treatment of T2DM in humans, but postulate that this is where the use of animal models falls short, despite decades of effort. The best way to achieve this goal is by prioritising human-centred research.

scholarly journals An Immediate and Long-Term Complication of COVID-19 May Be Type 2 Diabetes Mellitus: The Central Role of β-Cell Dysfunction, Apoptosis and Exploration of Possible Mechanisms

Cells ◽  
2020 ◽  
Vol 9 (11) ◽  
pp. 2475
Author(s):  
Melvin R. Hayden
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Cell Injury ◽  
Light And Electron Microscopy ◽  
Β Cell ◽  
Cell Dysfunction

The novel coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) was declared a pandemic by the WHO on 19 March 2020. This pandemic is associated with markedly elevated blood glucose levels and a remarkable degree of insulin resistance, which suggests pancreatic islet β-cell dysfunction or apoptosis and insulin’s inability to dispose of glucose into cellular tissues. Diabetes is known to be one of the top pre-existing co-morbidities associated with the severity of COVID-19 along with hypertension, cardiocerebrovascular disease, advanced age, male gender, and recently obesity. This review focuses on how COVID-19 may be responsible for the accelerated development of type 2 diabetes mellitus (T2DM) as one of its acute and suspected long-term complications. These observations implicate an active role of metabolic syndrome, systemic and tissue islet renin–angiotensin–aldosterone system, redox stress, inflammation, islet fibrosis, amyloid deposition along with β-cell dysfunction and apoptosis in those who develop T2DM. Utilizing light and electron microscopy in preclinical rodent models and human islets may help to better understand how COVID-19 accelerates islet and β-cell injury and remodeling to result in the long-term complications of T2DM.

scholarly journals Ameliorative Effect and Mechanism of the Purified Anthraquinone-Glycoside Preparation from Rheum Palmatum L. on Type 2 Diabetes Mellitus

Molecules ◽  
2019 ◽  
Vol 24 (8) ◽  
pp. 1454 ◽  
Author(s):  
Fang-Rong Cheng ◽  
Hong-Xin Cui ◽  
Ji-Li Fang ◽  
Ke Yuan ◽  
Ying Guo
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Blood Glucose ◽  
Cell Apoptosis ◽  
Fasting Blood Glucose ◽  
Β Cell ◽  
Diabetes Mellitus Group ◽  
Rheum Palmatum

Rheum palmatum L. is a traditional Chinese medicine with various pharmacological properties, including anti-inflammatory, antibacterial, and detoxification effects. In this study, the mechanism of the hypoglycemic effect of purified anthraquinone-Glycoside from Rheum palmatum L. (PAGR) in streptozotocin (STZ) and high-fat diet induced type 2 diabetes mellitus (T2DM) in rats was investigated. The rats were randomly divided into normal (NC), T2DM, metformin (Met), low, middle (Mid), and high (Hig) does of PAGR groups. After six weeks of continuous administration of PAGR, the serum indices and tissue protein expression were determined, and the pathological changes in liver, kidney, and pancreas tissues were observed. The results showed that compared with the type 2 diabetes mellitus group, the fasting blood glucose (FBG), total cholesterol (TC), and triglyceride (TG) levels in the serum of rats in the PAGR treatment groups were significantly decreased, while superoxide dismutase (SOD) and glutathione peroxidase (GSH-PX) levels were noticeably increased. The expression of Fas ligand (FasL), cytochrome C (Cyt-c), and caspase-3 in pancreatic tissue was obviously decreased, and the pathological damage to the liver, kidney, and pancreas was improved. These indicate that PAGR can reduce oxidative stress in rats with diabetes mellitus by improving blood lipid metabolism and enhancing their antioxidant capacity, thereby regulating the mitochondrial apoptotic pathway to inhibitβ-cell apoptosis and improve β-cell function. Furthermore, it can regulate Fas/FasL-mediated apoptosis signaling pathway to inhibit β-cell apoptosis, thereby lowering blood glucose levels and improving T2DM.

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