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Cold Spring Harbor Perspectives in... May 2017Type 2 diabetes (T2D) is a highly prevalent metabolic disease characterized by chronic insulin resistance and β-cell dysfunction and loss, leading to impaired insulin... (Review)
Review
Type 2 diabetes (T2D) is a highly prevalent metabolic disease characterized by chronic insulin resistance and β-cell dysfunction and loss, leading to impaired insulin release and hyperglycemia. Although the mechanism responsible for β-cell dysfunction and death is not completely understood, recent findings suggest that the accumulation of misfolded aggregates of the islet amyloid polypeptide (IAPP) in the islets of Langerhans may play an important role in pancreatic damage. Misfolding and aggregation of diverse proteins and their accumulation as amyloid in different organs is the hallmark feature in a group of chronic, degenerative diseases termed protein misfolding disorders (PMDs). PMDs include highly prevalent human illnesses such as Alzheimer's and Parkinson's disease, as well as more than 25 rarer disorders. Among them, prion diseases are unique because the pathology can be transmitted by a proteinaceous infectious agent, termed a prion, which induces disease by propagating protein misfolding and aggregation. This phenomenon has a striking resemblance to the process of protein misfolding and aggregation in all of the PMDs, suggesting that misfolded aggregates have an intrinsic potential to be transmissible. Indeed, recent studies have shown that the pathological hallmarks of various PMDs can be induced in vivo under experimental conditions by inoculating tissue extracts containing protein aggregates into animal models. In this review, we describe our current understanding of the molecular mechanism underlying the prion-like transmission of protein aggregates and its possible role in T2D.
Topics: Animals; Brain; Diabetes Mellitus, Type 2; Humans; Islet Amyloid Polypeptide; Pancreas; Prions; Protein Aggregates; Protein Folding; Proteostasis Deficiencies
PubMed: 28159831
DOI: 10.1101/cshperspect.a024315 -
Journal of Alzheimer's Disease : JAD 2018Type II diabetes (T2D) has been identified as a major risk factor for the development of Alzheimer's disease (AD). Interestingly, both AD and T2D have similar... (Review)
Review
Type II diabetes (T2D) has been identified as a major risk factor for the development of Alzheimer's disease (AD). Interestingly, both AD and T2D have similar characteristics including amyloid peptide aggregation, decreased metabolism, and increased oxidative stress and inflammation. Despite their prevalence, therapies for these diseases are limited. To date, most therapies for AD have targeted amyloid-β or tau. Unfortunately, most of these clinical trials have been largely unsuccessful, creating a crucial need for novel therapies. A number of studies have shown that metabolic hormone therapies are effective at ameliorating high blood glucose levels in diabetics as well as improving cognitive function in AD and mild cognitive impairment patients. Pramlintide, a synthetic analogue of the pancreatic hormone amylin, has been developed and used for years now as a treatment for both type I diabetes and T2D due to the loss of β-islet cells responsible for producing amylin. Importantly, recent data demonstrates its potential therapeutic role for AD as well. This review aims at addressing parallels between T2D and AD at a pathological and functional level, focusing on amylin signaling as a key, overlapping mediator in both diseases. The potential therapeutic use of this hormone to treat AD will also be explored from a mechanistic viewpoint.
Topics: Alzheimer Disease; Amino Acid Sequence; Cognition; Cognitive Dysfunction; Humans; Islet Amyloid Polypeptide; Neuroprotective Agents; Oxidative Stress; Treatment Outcome
PubMed: 30282360
DOI: 10.3233/JAD-180433 -
Frontiers in Endocrinology 2023Chronic kidney disease (CKD) is increasing worldwide and is associated with diabetic states (obesity, prediabetes and type-2 diabetes mellitus). The kidney is... (Review)
Review
Chronic kidney disease (CKD) is increasing worldwide and is associated with diabetic states (obesity, prediabetes and type-2 diabetes mellitus). The kidney is intrinsically susceptible to low oxygen (hypoxia) and renal hypoxia plays a vital role in the progression of CKD. Recent studies suggest an association between CKD and renal deposition of amyloid-forming amylin secreted from the pancreas. Renal accumulation of amyloid-forming amylin is associated with hypertension, mitochondrial dysfunction, increased production of reactive oxygen species (ROS) and activation of hypoxia signaling in the kidney. In this review we will discuss potential associations between renal amylin amyloid accumulation, hypertension, and mechanism of hypoxia-induced kidney dysfunction, including activation of hypoxia-inducible factors (HIFs) and mitochondrial dysfunction.
Topics: Humans; Islet Amyloid Polypeptide; Amyloidogenic Proteins; Kidney; Renal Insufficiency, Chronic; Hypertension; Ischemia; Hypoxia; Peptide Hormones
PubMed: 36875454
DOI: 10.3389/fendo.2023.1104662 -
Physiology & Behavior Nov 2011Obesity develops despite a complex and seemingly well orchestrated network that controls eating, energy expenditure and ultimately body weight; many of the involved... (Review)
Review
Obesity develops despite a complex and seemingly well orchestrated network that controls eating, energy expenditure and ultimately body weight; many of the involved signals are derived from the gastrointestinal tract. It is assumed that this network as an entity aims at maintaining body weight and body adiposity at a relatively constant level, but the control mechanisms seem to fail at least if an individual is chronically exposed to an oversupply of food. This article summarizes recent findings about the role of amylin in the control of eating in lean and obese rodents. The article gives some short background information about the well investigated adiposity and satiating signals leptin and cholecystokinin, respectively; this will provide the framework to discuss aspects of amylin physiology and pathophysiology in the control of eating in leanness and obesity. This discussion also involves the mechanisms mediating amylin's eating inhibitory effect in the area postrema and the interactions between amylin and leptin. Further, we discuss the effect of high fat diets on amylin release and amylin action in lean and obese rats. The last part of this article raises the question whether amylin interacts with the reward system in the forebrain.
Topics: Animals; Diet, High-Fat; Eating; Hypothalamus; Islet Amyloid Polypeptide; Neurons; Obesity; Rats; Satiation
PubMed: 21324327
DOI: 10.1016/j.physbeh.2011.02.015 -
Biochimica Et Biophysica Acta.... May 2018Amylin is a pancreatic β-cell hormone co-secreted with insulin, plays a role in normal glucose homeostasis, and forms amyloid in the pancreatic islets of individuals...
Amylin is a pancreatic β-cell hormone co-secreted with insulin, plays a role in normal glucose homeostasis, and forms amyloid in the pancreatic islets of individuals with type-2 diabetes. Aggregated amylin is also found in blood and extra-pancreatic tissues, including myocardium. Myocardial amylin accumulation is associated with myocyte Ca dysregulation in diabetic rats expressing human amylin. Whether deposition of amylin in the heart is a consequence of or a contributor to diabetic cardiomyopathy remains unknown. We used amylin knockout (AKO) mice intravenously infused with either human amylin (i.e, the aggregated form) or non-amyloidogenic (i.e., monomeric) rodent amylin to test the hypothesis that aggregated amylin accumulates in the heart in the absence of diabetes. AKO mice infused with human amylin, but not rodent amylin, showed amylin deposits in the myocardium. Cardiac amylin level was larger in males compared to females. Sarcolemmal Ca leak and Ca transients were increased in myocytes isolated from males infused with human amylin while no significant changes occurred in either females injected with human amylin or in rat amylin-infused mice. In isolated cardiac myocytes, the amylin receptor antagonist AC-187 did not effectively block the interaction of amylin with the sarcolemma. In conclusion, circulating aggregated amylin accumulates preferentially in male vs. female hearts and its effects on myocyte Ca cycling do not require diabetic remodeling of the myocardium. This article is part of a Special issue entitled Cardiac adaptations to obesity, diabetes and insulin resistance, edited by Professors Jan F.C. Glatz, Jason R.B. Dyck and Christine Des Rosiers.
Topics: Animals; Calcium; Calcium Signaling; Diabetic Cardiomyopathies; Disease Models, Animal; Female; Inflammation Mediators; Infusions, Intravenous; Interleukin-1beta; Islet Amyloid Polypeptide; Male; Mice, Knockout; Myocytes, Cardiac; Protein Aggregates; Protein Aggregation, Pathological; Sarcolemma; Sex Factors; Ventricular Remodeling
PubMed: 29066284
DOI: 10.1016/j.bbadis.2017.10.024 -
Journal of Alzheimer's Disease : JAD 2019Recent studies demonstrate that peripheral amylin treatment reduces pathology in mouse models of Alzheimer's disease (AD). However, soluble and aggregated amylin are...
Recent studies demonstrate that peripheral amylin treatment reduces pathology in mouse models of Alzheimer's disease (AD). However, soluble and aggregated amylin are distinct species; while amylin is a physiological neuropeptide, amylin aggregation is a pathological factor for diabetes. We thus hypothesized that because of their similarity in secondary structures, amylin antagonizes amyloid-β peptide (Aβ)-induced AD pathology in neurons with a dose-dependent pattern. To test the hypothesis, we conducted both in vitro and in vivo experiments with different doses of amylin and with its analog, pramlintide. Here we report that a high concentration of either Aβ or amylin alone induced tau phosphorylation (pTau) in primary neurons. Interestingly, with a low concentration, amylin had direct effects to reverse the Aβ-induced pTau, as well as damaged neuronal synapses and neurite disorganization. However, when the concentration was high (10.24 μM), amylin lost the effects against the Aβ-induced cellular AD pathology and, together with Aβ, worsened tauopathy in neurons. In the 5XFAD AD mouse model, daily peripheral amylin treatment with a low dose (200 μg/kg) more effectively reduced amyloid burden, and increased synapse, but with a high dose (800 μg/kg), it more effectively reduced tauopathy. Correspondingly, amylin treatment improved learning and memory in these mice. It demonstrates that amylin has a dose-dependent U-shape effect against AD pathogenesis. Within a physiological range, amylin is a neuroprotective hormone against AD in neurons; but when both Aβ and amylin concentrations are elevated, imbalance of Aβ and amylin may contribute to brain AD pathogenesis.
Topics: Amino Acid Sequence; Amyloid beta-Peptides; Animals; Animals, Newborn; Cells, Cultured; Dose-Response Relationship, Drug; Female; Humans; Islet Amyloid Polypeptide; Mice; Mice, Transgenic; Neurons; Peptide Fragments; Pregnancy; Rats; Rats, Wistar; Synapses; Tauopathies
PubMed: 31306122
DOI: 10.3233/JAD-190161 -
Journal of Diabetes Research 2016The hormone islet amyloid polypeptide (IAPP, or amylin) plays a role in glucose homeostasis but aggregates to form islet amyloid in type-2 diabetes. Islet amyloid... (Review)
Review
The hormone islet amyloid polypeptide (IAPP, or amylin) plays a role in glucose homeostasis but aggregates to form islet amyloid in type-2 diabetes. Islet amyloid formation contributes to β-cell dysfunction and death in the disease and to the failure of islet transplants. Recent work suggests a role for IAPP aggregation in cardiovascular complications of type-2 diabetes and hints at a possible role in type-1 diabetes. The mechanisms of IAPP amyloid formation in vivo or in vitro are not understood and the mechanisms of IAPP induced β-cell death are not fully defined. Activation of the inflammasome, defects in autophagy, ER stress, generation of reactive oxygen species, membrane disruption, and receptor mediated mechanisms have all been proposed to play a role. Open questions in the field include the relative importance of the various mechanisms of β-cell death, the relevance of reductionist biophysical studies to the situation in vivo, the molecular mechanism of amyloid formation in vitro and in vivo, the factors which trigger amyloid formation in type-2 diabetes, the potential role of IAPP in type-1 diabetes, the development of clinically relevant inhibitors of islet amyloidosis toxicity, and the design of soluble, bioactive variants of IAPP for use as adjuncts to insulin therapy.
Topics: Diabetes Mellitus, Type 2; Humans; Insulin-Secreting Cells; Islet Amyloid Polypeptide; Islets of Langerhans; Structure-Activity Relationship
PubMed: 26649319
DOI: 10.1155/2016/2798269 -
Journal of Cerebral Blood Flow and... Apr 2017Amylin, a pancreatic β-cell-derived peptide hormone, forms inclusions in brain microvessels of patients with dementia who have been diagnosed with type 2 diabetes and...
Amylin, a pancreatic β-cell-derived peptide hormone, forms inclusions in brain microvessels of patients with dementia who have been diagnosed with type 2 diabetes and Alzheimer's disease. The cellular localization of these inclusions and the consequences thereof are not yet known. Using immunohistochemical staining of hippocampus and parahippocampal cortex from patients with Alzheimer's disease and non-demented controls, we show that amylin cell inclusions are found in pericytes. The number of amylin cell inclusions did not differ between patients with Alzheimer's disease and controls, but amylin-containing pericytes displayed nuclear changes associated with cell death and reduced expression of the pericyte marker neuron-glial antigen 2. The impact of amylin on pericyte viability was further demonstrated in in vitro studies, which showed that pericyte death increased in presence of fibril- and oligomer amylin. Furthermore, oligomer amylin increased caspase 3/7 activity, reduced lysate neuron-glial antigen 2 levels and impaired autophagy. Our findings contribute to increased understanding of how aggregated amylin affects brain vasculature and highlight amylin as a potential factor involved in microvascular pathology in dementia progression.
Topics: Aged; Aged, 80 and over; Alzheimer Disease; Antigens; Autophagy; Case-Control Studies; Cell Culture Techniques; Cell Survival; Cells, Cultured; Female; Hippocampus; Humans; Immunohistochemistry; Islet Amyloid Polypeptide; Male; Microvessels; Middle Aged; Pericytes; Proteoglycans
PubMed: 27354094
DOI: 10.1177/0271678X16657093 -
Biomedicine & Pharmacotherapy =... Dec 2022Cagrilintide is a novel long-acting amylin receptor agonist, which has shown a potent induction of weight loss. Interestingly, cagrilintide is a Dual Amylin and... (Comparative Study)
Comparative Study
Does receptor balance matter? - Comparing the efficacies of the dual amylin and calcitonin receptor agonists cagrilintide and KBP-336 on metabolic parameters in preclinical models.
Cagrilintide is a novel long-acting amylin receptor agonist, which has shown a potent induction of weight loss. Interestingly, cagrilintide is a Dual Amylin and Calcitonin Receptor Agonist (DACRA) derived from an amylin backbone. Another class of long-acting DACRAs exists, namely the KBPs. These are salmon calcitonin-based and have shown preclinical potential; however, how and if they differentiate from amylin-derived molecules remain to be studied. Here, we compare cagrilintide to the DACRA KBP-336 with respect to receptor activation balance in vitro and using metabolic in vivo models. Peptide potencies were assessed using receptor-specific assays in vitro and in vivo. In vivo efficacies on body weight and glucose homeostasis were investigated head-to-head in high-fat diet (HFD) fed obese and T2D (ZDF) rat models. Both peptides activate the amylin and the calcitonin receptor in vitro and in vivo, with KBP-336 being more potent, and showing a CTR bias. KBP-336 and cagrilintide induced a potent and dose-dependent weight loss in HFD rats, with the highest dose of KBP-336 being superior to cagrilintide. In diabetic ZDF rats, DACRA treatment improved fasting blood glucose, HbA1c levels, and insulin action, with KBP-336 being superior to cagrilintide in improving glucose control. In summary, both KBP-336 and cagrilintide are DACRAs, however with KBP-336 being biased towards the CTR resulting in a different receptor activation balance. Interestingly, KBP-336 showed superior long-term efficacy on both weight loss and glucose control, supporting relevance of the receptor balance, and highlighting KBP-336 as a promising agent for the treatment of obesity and T2D.
Topics: Animals; Rats; Amylin Receptor Agonists; Blood Glucose; Diabetes Mellitus, Type 2; Islet Amyloid Polypeptide; Obesity; Rats, Sprague-Dawley; Receptors, Calcitonin; Weight Loss
PubMed: 36242844
DOI: 10.1016/j.biopha.2022.113842 -
The Journal of Biological Chemistry May 2023Islet amyloid polypeptide (amylin) secreted from the pancreas crosses from the blood to the brain parenchyma and forms cerebral mixed amylin-β amyloid (Aβ) plaques in...
Islet amyloid polypeptide (amylin) secreted from the pancreas crosses from the blood to the brain parenchyma and forms cerebral mixed amylin-β amyloid (Aβ) plaques in persons with Alzheimer's disease (AD). Cerebral amylin-Aβ plaques are found in both sporadic and early-onset familial AD; however, the role of amylin-Aβ co-aggregation in potential mechanisms underlying this association remains unknown, in part due to lack of assays for detection of these complexes. Here, we report the development of an ELISA to detect amylin-Aβ hetero-oligomers in brain tissue and blood. The amylin-Aβ ELISA relies on a monoclonal anti-Aβ mid-domain antibody (detection) and a polyclonal anti-amylin antibody (capture) designed to recognize an epitope that is distinct from the high affinity amylin-Aβ binding sites. The utility of this assay is supported by the analysis of molecular amylin-Aβ codeposition in postmortem brain tissue obtained from persons with and without AD pathology. By using transgenic AD-model rats, we show that this new assay can detect circulating amylin-Aβ hetero-oligomers in the blood and is sensitive to their dissociation to monomers. This is important because therapeutic strategies to block amylin-Aβ co-aggregation could reduce or delay the development and progression of AD.
Topics: Animals; Mice; Rats; Alzheimer Disease; Amyloid beta-Peptides; Brain; Islet Amyloid Polypeptide; Mice, Transgenic; Pancreas; Rats, Transgenic
PubMed: 37030503
DOI: 10.1016/j.jbc.2023.104682