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Life (Basel, Switzerland) Sep 2023Proteinopathy is characterized by the accumulation of aggregates of a specific protein in a target organ, tissue, or cell. The aggregation of the same protein can cause... (Review)
Review
Proteinopathy is characterized by the accumulation of aggregates of a specific protein in a target organ, tissue, or cell. The aggregation of the same protein can cause different pathologies as single protein can adopt various amyloidogenic, disease-specific conformations. The conformation governs the interaction of amyloid aggregates with other proteins that are prone to misfolding and, thus, determines disease-specific spectrum of concomitant pathologies. In this regard, a detailed description of amyloid protein conformation as well as spectrum of its interaction with other proteins become a key point for drafting of precise description of the disease. The majority of clinical cases of neuronal proteinopathies is caused by the aggregation of rather limited range of amyloidogenic proteins. Here, we provided the characterization of pathologies, related to the aggregation of amyloid β peptide, tau protein, α-synuclein, TDP-43, and amylin, giving a short description of pathologies themselves, recent advances in elucidation of misfolded protein conformation, with emphasis on those protein aggregates extracted from biological samples, what is known about the interaction of this proteins, and the influence of this interaction on the progression of underlying disease and comorbidities.
PubMed: 37895336
DOI: 10.3390/life13101954 -
Current Heart Failure Reports Feb 2024Obesity is a major driver of heart failure (HF) incidence, and aggravates its pathophysiology. We summarized key reported and ongoing randomized clinical trials of... (Review)
Review
PURPOSE OF REVIEW
Obesity is a major driver of heart failure (HF) incidence, and aggravates its pathophysiology. We summarized key reported and ongoing randomized clinical trials of appetite regulation and/or dietary energy restriction in individuals with HF.
RECENT FINDINGS
Weight loss can be achieved by structured supervised diet programs with behavioural change, medications, or surgery. The new glucagon-like peptide-1 receptor agonists alone or in combination with other agents (e.g., glucose-dependent insulinotropic polypeptide and glucagon receptor agonists or amylin analogues) potently and sustainably reduce appetite, and, taken together with dietary advice, can produce substantial, life-changing, weight loss approaching that achieved by surgery. To date, data from the STEP-HFpEF trial show meaningful improvements in health status (Kansas City Cardiomyopathy Questionnaire). Effective weight management could relieve several drivers of HF, to complement the existing treatments for HF with both reduced and preserved ejection fraction. Further trials of weight loss interventions will provide more definitive evidence to understand their effects on clinical events in patients with HF.
Topics: Humans; Heart Failure; Appetite; Stroke Volume; Health Status; Weight Loss
PubMed: 38133864
DOI: 10.1007/s11897-023-00637-7 -
Molecular Metabolism Apr 2021Therapies for metabolic diseases are numerous, yet improving insulin sensitivity beyond that induced by weight loss remains challenging. Therefore, search continues for... (Review)
Review
BACKGROUND
Therapies for metabolic diseases are numerous, yet improving insulin sensitivity beyond that induced by weight loss remains challenging. Therefore, search continues for novel treatment candidates that can stimulate insulin sensitivity and increase weight loss efficacy in combination with current treatment options. Calcitonin gene-related peptide (CGRP) and amylin belong to the same peptide family and have been explored as treatments for metabolic diseases. However, their full potential remains controversial.
SCOPE OF REVIEW
In this article, we introduce this rather complex peptide family and its corresponding receptors. We discuss the physiology of the peptides with a focus on metabolism and insulin sensitivity. We also thoroughly review the pharmacological potential of amylin, calcitonin, CGRP, and peptide derivatives as treatments for metabolic diseases, emphasizing their ability to increase insulin sensitivity based on preclinical and clinical studies.
MAJOR CONCLUSIONS
Amylin receptor agonists and dual amylin and calcitonin receptor agonists are relevant treatment candidates, especially because they increase insulin sensitivity while also assisting weight loss, and their unique mode of action complements incretin-based therapies. However, CGRP and its derivatives seem to have only modest if any metabolic effects and are no longer of interest as therapies for metabolic diseases.
Topics: Animals; Calcitonin; Calcitonin Gene-Related Peptide; Humans; Insulin Resistance; Islet Amyloid Polypeptide; Metabolic Diseases; Obesity; Receptors, Calcitonin; Receptors, Calcitonin Gene-Related Peptide; Receptors, Cell Surface; Weight Loss
PubMed: 33166741
DOI: 10.1016/j.molmet.2020.101109 -
Diabetes, Obesity & Metabolism Jun 2022The aim of this study was to examine the hypothesis that pramlintide would reduce hypoglycaemia by slowing gastric emptying and reducing postprandial glucagon secretion,...
AIMS
The aim of this study was to examine the hypothesis that pramlintide would reduce hypoglycaemia by slowing gastric emptying and reducing postprandial glucagon secretion, thus limiting postprandial glycaemic excursions and insulin secretion, and thus to determine the efficacy of pramlintide on frequency and severity of hypoglycaemia in post-bariatric hypoglycaemia (PBH).
MATERIALS AND METHODS
Participants with PBH following gastric bypass were recruited from outpatient clinics at the Joslin Diabetes Center, Boston, Massachusetts for an open-label study of pramlintide efficacy over 8 weeks. Twenty-three participants were assessed for eligibility, 20 participants had at least one pramlintide dose, and 14 completed the study. A mixed-meal tolerance test (MMTT) was performed at baseline and after 8 weeks of subcutaneous pramlintide with a sequential dose increase to a maximum of 120 micrograms (mean 69 ± 32 mcg) three times daily. The primary endpoint was change in glucose excursions during the MMTT. Secondary measures included MMTT insulin response, satiety and dumping score, percentage time with sensor glucose (SG) <3.9 mM, and number of days with minimum SG <3 mM, during masked continuous glucose monitoring.
RESULTS
There were no differences in MMTT glucose, glucagon or insulin between baseline and post treatment. We observed no significant change in satiety or dumping scores. The overall frequency of low SG values did not change, although there was substantial inter-individual variability.
CONCLUSIONS
In PBH, pramlintide does not modulate glycaemic or insulin responses, satiety, or dumping scores during an MMTT and does not impact glycaemic excursions or decrease low SG levels in the outpatient setting.
Topics: Bariatric Surgery; Blood Glucose; Blood Glucose Self-Monitoring; Glucagon; Glucose; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Insulin, Regular, Human; Islet Amyloid Polypeptide
PubMed: 35137513
DOI: 10.1111/dom.14665 -
Scientific Reports Feb 2020A major characteristic of Alzheimer's disease (AD) is the accumulation of misfolded amyloid-β (Aβ) peptide. Several studies linked AD with type 2 diabetes due to...
A major characteristic of Alzheimer's disease (AD) is the accumulation of misfolded amyloid-β (Aβ) peptide. Several studies linked AD with type 2 diabetes due to similarities between Aβ and human amylin. This study investigates the effect of amylin and pramlintide on Aβ pathogenesis and the predisposing molecular mechanism(s) behind the observed effects in TgSwDI mouse, a cerebral amyloid angiopathy (CAA) and AD model. Our findings showed that thirty days of intraperitoneal injection with amylin or pramlintide increased Aβ burden in mice brains. Mechanistic studies revealed both peptides altered the amyloidogenic pathway and increased Aβ production by modulating amyloid precursor protein (APP) and γ-secretase levels in lipid rafts. In addition, both peptides increased levels of B4GALNT1 enzyme and GM1 ganglioside, and only pramlintide increased the level of GM2 ganglioside. Increased levels of GM1 and GM2 gangliosides play an important role in regulating amyloidogenic pathway proteins in lipid rafts. Increased brain Aβ burden by amylin and pramlintide was associated with synaptic loss, apoptosis, and microglia activation. In conclusion, our findings showed amylin or pramlintide increase Aβ levels and related pathology in TgSwDI mice brains, and suggest that increased amylin levels or the therapeutic use of pramlintide could increase the risk of AD.
Topics: Alzheimer Disease; Amyloid Precursor Protein Secretases; Amyloid beta-Protein Precursor; Animals; Cerebral Amyloid Angiopathy; G(M1) Ganglioside; G(M2) Ganglioside; Islet Amyloid Polypeptide; Membrane Microdomains; Mice; Mice, Transgenic; N-Acetylgalactosaminyltransferases; Protein Processing, Post-Translational
PubMed: 32111883
DOI: 10.1038/s41598-020-60664-5 -
ELife May 2022Food intake behavior is regulated by a network of appetite-inducing and appetite-suppressing neuronal populations throughout the brain. The parasubthalamic nucleus...
Food intake behavior is regulated by a network of appetite-inducing and appetite-suppressing neuronal populations throughout the brain. The parasubthalamic nucleus (PSTN), a relatively unexplored population of neurons in the posterior hypothalamus, has been hypothesized to regulate appetite due to its connectivity with other anorexigenic neuronal populations and because these neurons express Fos, a marker of neuronal activation, following a meal. However, the individual cell types that make up the PSTN are not well characterized, nor are their functional roles in food intake behavior. Here, we identify and distinguish between two discrete PSTN subpopulations, those that express tachykinin-1 (PSTN neurons) and those that express corticotropin-releasing hormone (PSTN neurons), and use a panel of genetically encoded tools in mice to show that PSTN neurons play an important role in appetite suppression. Both subpopulations increase activity following a meal and in response to administration of the anorexigenic hormones amylin, cholecystokinin (CCK), and peptide YY (PYY). Interestingly, chemogenetic inhibition of PSTN, but not PSTN neurons, reduces the appetite-suppressing effects of these hormones. Consistently, optogenetic and chemogenetic stimulation of PSTN neurons, but not PSTN neurons, reduces food intake in hungry mice. PSTN and PSTN neurons project to distinct downstream brain regions, and stimulation of PSTN projections to individual anorexigenic populations reduces food consumption. Taken together, these results reveal the functional properties and projection patterns of distinct PSTN cell types and demonstrate an anorexigenic role for PSTN neurons in the hormonal and central regulation of appetite.
Topics: Animals; Appetite; Appetite Regulation; Corticotropin-Releasing Hormone; Eating; Mice; Neurons; Optogenetics
PubMed: 35507386
DOI: 10.7554/eLife.75470 -
Expert Opinion on Investigational Drugs Dec 2022There have been many recent advances in the treatment of type 1 diabetes (T1D) including in insulin formulations, continuous glucose monitoring (CGM) technology and... (Review)
Review
INTRODUCTION
There have been many recent advances in the treatment of type 1 diabetes (T1D) including in insulin formulations, continuous glucose monitoring (CGM) technology and automated insulin delivery. However, long-term optimal glycemic control is still only achieved in a minority.
AREAS COVERED
Adjunct therapy - the use of therapeutic agents other than insulin - is one strategy aimed at improving outcomes. An ideal adjunct agent would improve glycemic control, reduce weight (or weight gain), reduce insulin requirement and prevent complications (e.g. cardiorenal) without increasing hypoglycemia. The amylin analogue pramlintide has been licensed in the USA, while the sodium glucose co-transporter-2 inhibitor (SGLT2i) dapagliflozin, was briefly (2019 - 2021) licensed for type 1 diabetes in Europe and the UK. However, other agents from the type 2 diabetes (T2D) arena including metformin, other SGLT2is, glucagon-like peptide-1 receptor agonists (GLP-1RA) and dipeptidyl peptidase-IV (DPP-4) inhibitors have been investigated.
EXPERT OPINION
As evidence emerges for cardiorenal protection by SGLT2is and GLP-1RAs in T2D, it has become increasingly important to know whether people with T1D can also benefit. Here, we review recent trials of adjunct agents in T1D and discuss the efficacy and safety of these agents (alone and in combination) in an era in which continuous glucose monitoring is becoming standard of care.
Topics: Humans; Diabetes Mellitus, Type 1; Hypoglycemic Agents; Diabetes Mellitus, Type 2; Blood Glucose Self-Monitoring; Blood Glucose; Sodium-Glucose Transporter 2 Inhibitors; Insulin; Combined Modality Therapy; Glucagon-Like Peptide-1 Receptor
PubMed: 36655950
DOI: 10.1080/13543784.2022.2159806 -
RSC Chemical Biology Nov 2023Metal ions have been implicated in several proteinopathies associated to degenerative and neurodegenerative diseases. While the molecular mechanisms for protein...
Metal ions have been implicated in several proteinopathies associated to degenerative and neurodegenerative diseases. While the molecular mechanisms for protein aggregation are still under investigation, recent findings from Cryo-EM point out to polymorphisms in aggregates obtained from patients, as compared to those formed , suggesting that several factors may impact aggregation . One of these factors could be the direct binding of metal ions to the proteins engaged in aggregate formation. In this opinion article, three case studies are discussed to address the question of how metal ion binding to a peptide or protein may impact its conformation, folding, and aggregation, and how this may be relevant in understanding the polymorphic nature of the aggregates related to disease. Specifically, the impact of Cu ions in the amyloid aggregation of amyloid-β and amylin (or IAPP- islet amyloid polypeptide) are discussed and then contrasted to the case of Cu-induced non-amyloid aggregation of human lens γ-crystallin proteins. For the intrinsically disordered peptides amyloid-β and IAPP, the impact of Cu ion binding is highly dependent on the relative location of the metal binding site and the hydrophobic regions involved in β-sheet folding and amyloid formation. Further structural studies of how Cu binding impacts amyloid aggregation pathways and the molecular structure of the final amyloid fibril, both, and , will certainly shed light into the molecular origins of the polymorphisms observed in diseased tissue. Finally, contrasting these cases to that of Cu-induced non-amyloid aggregation of γ-crystallins, it is evident that, although the impact in aggregation - and the nature of the aggregate - may differ in each system, at the molecular level there is a competition between metal ion coordination and the stability of β-sheet structures. Considering the importance of the β-sheet fold in biology, it is fundamental to understand the energetics and molecular details behind such competition. This opinion article aims to highlight future research directions in the field that can help tackle the important question of how metal ion binding may impact protein folding and aggregation and how this relates to disease.
PubMed: 38033729
DOI: 10.1039/d3cb00145h -
Surgery For Obesity and Related... Jan 2023The aim of this study was to perform a comprehensive literature review regarding the relevant hormonal and histologic changes observed after Roux-en-Y gastric bypass... (Review)
Review
The aim of this study was to perform a comprehensive literature review regarding the relevant hormonal and histologic changes observed after Roux-en-Y gastric bypass (RYGB). We aimed to describe the relevant hormonal (glucagon-like peptides 1 and 2 [GLP-1 and GLP-2], peptide YY [PYY], oxyntomodulin [OXM], bile acids [BA], cholecystokinin [CCK], ghrelin, glucagon, gastric inhibitory polypeptide [GIP], and amylin) profiles, as well as the histologic (mucosal cellular) adaptations happening after patients undergo RYGB. Our review compiles the current evidence and furthers the understanding of the rationale behind the food intake regulatory adaptations occurring after RYGB surgery. We identify gaps in the literature where the potential for future investigations and therapeutics may lie. We performed a comprehensive database search without language restrictions looking for RYGB bariatric surgery outcomes in patients with pre- and postoperative blood work hormonal profiling and/or gut mucosal biopsies. We gathered the relevant study results and describe them in this review. Where human findings were lacking, we included animal model studies. The amalgamation of physiologic, metabolic, and cellular adaptations following RYGB is yet to be fully characterized. This constitutes a fundamental aspiration for enhancing and individualizing obesity therapy.
Topics: Animals; Humans; Gastric Bypass; Glucagon-Like Peptide 1; Obesity; Gastric Inhibitory Polypeptide; Cholecystokinin; Peptide YY; Blood Glucose
PubMed: 36243547
DOI: 10.1016/j.soard.2022.08.020 -
Stroke Jun 2021Recent histological analyses of human brains show that small vessel-type injuries in the setting of type-2 diabetes colocalize with deposits of amylin, an... (Review)
Review
Recent histological analyses of human brains show that small vessel-type injuries in the setting of type-2 diabetes colocalize with deposits of amylin, an amyloid-forming hormone secreted by the pancreas. Amylin inclusions are also identified in circulating red blood cells in people with type-2 diabetes and stroke or cardiovascular disease. In laboratory models of type-2 diabetes, accumulation of aggregated amylin in blood and the cerebral microvasculature induces brain microhemorrhages and reduces cerebral blood flow leading to white matter ischemia and neurological deficits. At the cellular level, aggregated amylin causes cell membrane lipid peroxidation injury, downregulation of tight junction proteins, and activation of proinflammatory signaling pathways which, in turn, induces macrophage activation and macrophage infiltration in vascular areas positive for amylin deposition. We review each step of this cascade based on experimental and clinical evidence and propose the hypothesis that systemic amylin dyshomeostasis may underlie the disparity between glycemic control and stroke risk and may be a therapeutic target to reduce the risk of small vessel ischemic stroke in patients with type-2 diabetes.
Topics: Biomarkers; Cerebral Small Vessel Diseases; Diabetes Mellitus, Type 2; Humans; Ischemic Stroke; Islet Amyloid Polypeptide
PubMed: 33947210
DOI: 10.1161/STROKEAHA.121.034363