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International Journal of Molecular... Jan 2024Diabetes mellitus is a devastating chronic metabolic disease. Since the majority of type 2 diabetes mellitus patients are overweight or obese, a novel term-diabesity-has... (Review)
Review
Diabetes mellitus is a devastating chronic metabolic disease. Since the majority of type 2 diabetes mellitus patients are overweight or obese, a novel term-diabesity-has emerged. The gut-brain axis plays a critical function in maintaining glucose and energy homeostasis and involves a variety of peptides. Amylin is a neuroendocrine anorexigenic polypeptide hormone, which is co-secreted with insulin from β-cells of the pancreas in response to food consumption. Aside from its effect on glucose homeostasis, amylin inhibits homeostatic and hedonic feeding, induces satiety, and decreases body weight. In this narrative review, we summarized the current evidence and ongoing studies on the mechanism of action, clinical pharmacology, and applications of amylin and its analogs, pramlintide and cagrilintide, in the field of diabetology, endocrinology, and metabolism disorders, such as obesity.
Topics: Humans; Islet Amyloid Polypeptide; Diabetes Mellitus, Type 2; Hypoglycemic Agents; Insulin; Obesity; Glucose; Amyloid
PubMed: 38338796
DOI: 10.3390/ijms25031517 -
Molecules (Basel, Switzerland) Feb 2024The molecular events of protein misfolding and self-aggregation of tau and amylin are associated with the progression of Alzheimer's and diabetes, respectively. Recent...
The molecular events of protein misfolding and self-aggregation of tau and amylin are associated with the progression of Alzheimer's and diabetes, respectively. Recent studies suggest that tau and amylin can form hetero-tau-amylin oligomers. Those hetero-oligomers are more neurotoxic than homo-tau oligomers. So far, the detailed interactions between the hetero-oligomers and the neuronal membrane are unknown. Using multiscale MD simulations, the lipid binding and protein folding behaviors of hetero-oligomers on asymmetric lipid nanodomains or raft membranes were examined. Our raft membranes contain phase-separated phosphatidylcholine (PC), cholesterol, and anionic phosphatidylserine (PS) or ganglioside (GM1) in one leaflet of the lipid bilayer. The hetero-oligomers bound more strongly to the PS and GM1 than other lipids via the hydrophobic and hydrophilic interactions, respectively, in the raft membranes. The hetero-tetramer disrupted the acyl chain orders of both PC and PS in the PS-containing raft membrane, but only the GM1 in the GM1-containing raft membrane as effectively as the homo-tau-tetramer. We discovered that the alpha-helical content in the heterodimer was greater than the sum of alpha-helical contents from isolated tau and amylin monomers on both raft membranes, indicative of a synergetic effect of tau-amylin interactions in surface-induced protein folding. Our results provide new molecular insights into understanding the cross-talk between Alzheimer's and diabetes.
Topics: Humans; Islet Amyloid Polypeptide; Amyloid beta-Peptides; Alzheimer Disease; G(M1) Ganglioside; Lipid Bilayers; Diabetes Mellitus; Phosphatidylcholines
PubMed: 38338484
DOI: 10.3390/molecules29030740 -
Accounts of Chemical Research Feb 2024ConspectusThe enzyme acetylcholinesterase (AChE) hydrolyzes the neurotransmitter acetylcholine (ACh) at cholinergic synapses of the peripheral and central nervous...
ConspectusThe enzyme acetylcholinesterase (AChE) hydrolyzes the neurotransmitter acetylcholine (ACh) at cholinergic synapses of the peripheral and central nervous system. Thus, it is a prime therapeutic target for diseases that occur with a cholinergic deficit, prominently Alzheimer's disease (AD). Working at a rate near the diffusion limit, it is considered one of nature's most efficient enzymes. This is particularly meritorious considering that its catalytic site is buried at the bottom of a 20-Å-deep cavity, which is preceded by a bottleneck with a diameter shorter than that of the trimethylammonium group of ACh, which has to transit through it. Not only the particular architecture and amino acid composition of its active site gorge enable AChE to largely overcome this potential drawback, but it also offers plenty of possibilities for the design of novel inhibitor drug candidates.In this Account, we summarize our different approaches to colonize the vast territory of the AChE gorge in the pursuit of increased occupancy and hence of inhibitors with increased affinity. We pioneered the use of molecular hybridization to design inhibitors with extended binding at the CAS, reaching affinities among the highest reported so far. Further application of molecular hybridization to grow CAS extended binders by attaching a PAS-binding moiety through suitable linkers led to multisite inhibitors that span the whole length of the gorge, reaching the PAS and even interacting with midgorge residues. We show that multisite AChE inhibitors can also be successfully designed the other way around, by starting with an optimized PAS binder and then colonizing the gorge and CAS. Molecular hybridization from a multicomponent reaction-derived PAS binder afforded a single-digit picomolar multisite AChE inhibitor with more than 1.5 million-fold increased potency relative to the initial hit. This illustrates the powerful alliance between molecular hybridization and gorge occupancy for designing potent AChE inhibitors.Beyond AChE, we show that the stereoelectronic requirements imposed by the AChE gorge for multisite binding have a templating effect that leads to compounds that are active in other key biological targets in AD and other neurological and non-neurological diseases, such as BACE-1 and the aggregation of amyloidogenic proteins (β-amyloid, tau, α-synuclein, prion protein, transthyretin, and human islet amyloid polypeptide). The use of known pharmacophores for other targets as the PAS-binding motif enables the rational design of multitarget agents with multisite binding within AChE and activity against a variety of targets or pathological events, such as oxidative stress and the neuroinflammation-modulating enzyme soluble epoxide hydrolase, among others.We hope that our results can contribute to the development of drug candidates that can modify the course of neurodegeneration and may inspire future works that exploit the power of molecular hybridization in other proteins featuring large cavities.
PubMed: 38333993
DOI: 10.1021/acs.accounts.3c00617 -
BMC Gastroenterology Feb 2024Hepatocellular senescence may be a causal factor in the development and progression of non-alcoholic steatohepatitis (NASH). The most effective currently available...
BACKGROUND
Hepatocellular senescence may be a causal factor in the development and progression of non-alcoholic steatohepatitis (NASH). The most effective currently available treatment for NASH is lifestyle intervention, including dietary modification. This study aimed to evaluate the effects of dietary intervention on hallmarks of NASH and molecular signatures of hepatocellular senescence in the Gubra-Amylin NASH (GAN) diet-induced obese (DIO) and biopsy-confirmed mouse model of NASH.
METHODS
GAN DIO-NASH mice with liver biopsy-confirmed NASH and fibrosis received dietary intervention by switching to chow feeding (chow reversal) for 8, 16 or 24 weeks. Untreated GAN DIO-NASH mice and chow-fed C57BL/6J mice served as controls. Pre-to-post liver biopsy histology was performed for within-subject evaluation of NAFLD Activity Score and fibrosis stage. Terminal endpoints included blood/liver biochemistry, quantitative liver histology, mitochondrial respiration and RNA sequencing.
RESULTS
Chow-reversal promoted substantial benefits on metabolic outcomes and liver histology, as demonstrated by robust weight loss, complete resolution of hepatomegaly, hypercholesterolemia, elevated transaminase levels and hepatic steatosis in addition to attenuation of inflammatory markers. Notably, all DIO-NASH mice demonstrated ≥ 2 point significant improvement in NAFLD Activity Score following dietary intervention. While not improving fibrosis stage, chow-reversal reduced quantitative fibrosis markers (PSR, collagen 1a1, α-SMA), concurrent with improved liver mitochondrial respiration, complete reversal of p21 overexpression, lowered γ-H2AX levels and widespread suppression of gene expression markers of hepatocellular senescence.
CONCLUSIONS
Dietary intervention (chow reversal) substantially improves metabolic, biochemical and histological hallmarks of NASH and fibrosis in GAN DIO-NASH mice. These benefits were reflected by progressive clearance of senescent hepatocellular cells, making the model suitable for profiling potential senotherapeutics in preclinical drug discovery for NASH.
Topics: Mice; Animals; Non-alcoholic Fatty Liver Disease; Carcinoma, Hepatocellular; Liver Neoplasms; Diet, High-Fat; Mice, Inbred C57BL; Liver; Obesity; Liver Cirrhosis; Disease Models, Animal; Biopsy
PubMed: 38308212
DOI: 10.1186/s12876-024-03141-x -
Biophysical Chemistry Apr 2024Type 2 diabetes (T2D) is the most common form of diabetes and represents a growing health concern. A characteristic feature of T2D is the aggregation of islet amyloid...
Type 2 diabetes (T2D) is the most common form of diabetes and represents a growing health concern. A characteristic feature of T2D is the aggregation of islet amyloid polypeptide (IAPP), which is thought to be associated with the death of pancreatic β-cells. Inhibiting IAPP aggregation is a promising therapeutic avenue to treat T2D, but the mechanisms of aggregation and toxicity are not yet fully understood. Caenorhabditis elegans is a well-characterised multicellular model organism that has been extensively used to study protein aggregation diseases. In this study, we aimed to develop a simple in vivo model to investigate IAPP aggregation and toxicity based on expression in the C. elegans body wall muscle cells. We show that IAPP tagged with green fluorescent protein (GFP) localises to mitochondria not only in muscle cells but also when expressed in the intestine, in line with previous observations in mouse and human pancreatic β-cells. The IAPP-GFP fusion protein forms solid aggregates, which have a filamentous appearance as seen by electron microscopy. However, the animals expressing IAPP-GFP in the body wall muscle cells do not display a strong motility phenotype, suggesting that the IAPP-GFP aggregates are not considerably toxic. Nevertheless, the mitochondrial localisation and aggregate formation may be useful read-outs to screen for IAPP-solubilizing compounds as a therapeutic strategy for T2D.
Topics: Mice; Animals; Humans; Islet Amyloid Polypeptide; Diabetes Mellitus, Type 2; Caenorhabditis elegans; Green Fluorescent Proteins; Protein Aggregates; Mitochondria; Amyloid
PubMed: 38241827
DOI: 10.1016/j.bpc.2024.107180 -
Computational and Structural... Dec 2024β-Structure-rich amyloid fibrils are hallmarks of several diseases, including Alzheimer's (AD), Parkinson's (PD), and type 2 diabetes (T2D). While amyloid fibrils...
β-Structure-rich amyloid fibrils are hallmarks of several diseases, including Alzheimer's (AD), Parkinson's (PD), and type 2 diabetes (T2D). While amyloid fibrils typically consist of parallel β-sheets, the anti-parallel β-hairpin is a structural motif accessible to amyloidogenic proteins in their monomeric and oligomeric states. Here, to investigate implications of β-hairpins in amyloid formation, potential β-hairpin-forming amyloidogenic segments in the human proteome were predicted based on sequence similarity with β-hairpins previously observed in Aβ, α-synuclein, and islet amyloid polypeptide, amyloidogenic proteins associated with AD, PD, and T2D, respectively. These three β-hairpins, established upon binding to the engineered binding protein β-wrapin AS10, are characterized by proximity of two sequence segments rich in hydrophobic and aromatic amino acids, with high β-aggregation scores according to the TANGO algorithm. Using these criteria, 2505 potential β-hairpin-forming amyloidogenic segments in 2098 human proteins were identified. Characterization of a test set of eight protein segments showed that seven assembled into Thioflavin T-positive aggregates and four formed β-hairpins in complex with AS10 according to NMR. One of those is a segment of prostatic acid phosphatase (PAP) comprising amino acids 185-208. PAP is naturally cleaved into fragments, including PAP(248-286) which forms functional amyloid in semen. We find that PAP(185-208) strongly decreases the protein concentrations required for fibril formation of PAP(248-286) and of another semen amyloid peptide, SEM1(86-107), indicating that it promotes nucleation of semen amyloids. In conclusion, β-hairpin-forming amyloidogenic protein segments could be identified in the human proteome with potential roles in functional or disease-related amyloid formation.
PubMed: 38223341
DOI: 10.1016/j.csbj.2023.12.023 -
Molecular Metabolism Feb 2024Aggregation of human islet amyloid polypeptide (hIAPP), a β-cell secretory product, leads to islet amyloid deposition, islet inflammation and β-cell loss in type 2...
OBJECTIVE
Aggregation of human islet amyloid polypeptide (hIAPP), a β-cell secretory product, leads to islet amyloid deposition, islet inflammation and β-cell loss in type 2 diabetes (T2D), but the mechanisms that underlie this process are incompletely understood. Receptor interacting protein kinase 3 (RIPK3) is a pro-death signaling molecule that has recently been implicated in amyloid-associated brain pathology and β-cell cytotoxicity. Here, we evaluated the role of RIPK3 in amyloid-induced β-cell loss using a humanized mouse model of T2D that expresses hIAPP and is prone to islet amyloid formation.
METHODS
We quantified amyloid deposition, cell death and caspase 3/7 activity in islets isolated from WT, Ripk3, hIAPP and hIAPP; Ripk3 mice in real time, and evaluated hIAPP-stimulated inflammation in WT and Ripk3 bone marrow derived macrophages (BMDMs) in vitro. We also characterized the role of RIPK3 in glucose stimulated insulin secretion (GSIS) in vitro and in vivo. Finally, we examined the role of RIPK3 in high fat diet (HFD)-induced islet amyloid deposition, β-cell loss and glucose homeostasis in vivo.
RESULTS
We found that amyloid-prone hIAPP mouse islets exhibited increased cell death and caspase 3/7 activity compared to amyloid-free WT islets in vitro, and this was associated with increased RIPK3 expression. hIAPP; Ripk3 islets were protected from amyloid-induced cell death compared to hIAPP islets in vitro, although amyloid deposition and caspase 3/7 activity were not different between genotypes. We observed that macrophages are a source of Ripk3 expression in isolated islets, and that Ripk3 BMDMs were protected from hIAPP-stimulated inflammatory gene expression (Tnf, Il1b, Nos2). Following 52 weeks of HFD feeding, islet amyloid-prone hIAPP mice exhibited impaired glucose tolerance and decreased β-cell area compared to WT mice in vivo, whereas hIAPP; Ripk3 mice were protected from these impairments.
CONCLUSIONS
In conclusion, loss of RIPK3 protects from amyloid-induced inflammation and islet cell death in vitro and amyloid-induced β-cell loss and glucose intolerance in vivo. We propose that therapies targeting RIPK3 may reduce islet inflammation and β-cell loss and improve glucose homeostasis in the pathogenesis of T2D.
Topics: Animals; Humans; Mice; Amyloid; Amyloid beta-Peptides; Caspase 3; Diabetes Mellitus, Type 2; Glucose; Glucose Intolerance; Inflammation; Islet Amyloid Polypeptide; Receptor-Interacting Protein Serine-Threonine Kinases
PubMed: 38218538
DOI: 10.1016/j.molmet.2024.101877 -
IScience Jan 2024Olanzapine is a second-generation antipsychotic (AP) used in the management of schizophrenia. Although effective at reducing psychoses, APs cause rapid hyperglycemia,...
Olanzapine is a second-generation antipsychotic (AP) used in the management of schizophrenia. Although effective at reducing psychoses, APs cause rapid hyperglycemia, insulin resistance, and dyslipidemia, an effect mediated in part by glucagon. We tested if amylin, a hormone that reduces glucagon, or the amylin receptor agonist pramlintide would protect against acute olanzapine-induced impairments in glucose and lipid homeostasis alone or in combination with other glucose-lowering agents such as liraglutide. We demonstrated that pramlintide lowered olanzapine-induced increases in glucagon:insulin ratio with a trend to protect against excursions in blood glucose. There was an additive effect of pramlintide and liraglutide in protecting against olanzapine-induced hyperglycemia, which was mirrored by reductions in glucagon and attenuated markers of dyslipidemia. Our findings provide evidence that pramlintide, although moderately protective against some aspects of olanzapine-induced metabolic dysfunction, can be used to enhance the protective effects of other interventions against acute olanzapine-induced metabolic dysfunction.
PubMed: 38188526
DOI: 10.1016/j.isci.2023.108628 -
American Journal of Translational... 2023Vascular endothelium, the innermost monolayer of endothelial cells lining the vessel wall, plays a vital physiologic role in the functional integrity of the aorta....
OBJECTIVES
Vascular endothelium, the innermost monolayer of endothelial cells lining the vessel wall, plays a vital physiologic role in the functional integrity of the aorta. Endothelial-derived nitric oxide (NO) is an important molecule regulating vascular endothelial function by its vasodilatory properties and inhibiting pathological inflammatory and oxidative consequences of vascular aging and cardiovascular disorders. Sirtuin 1 (Sirt1), has recently emerged as an important regulator of vascular endothelial NO production. The effect of niacin on Sirt1 in human arterial tissue has not been studied.
METHODS
Using primary cultures of human aortic endothelial cells (HAEC), we examined the effect of niacin on endothelial Nicotinamide Adenine Dinucleotide+ (NAD), Sirt1 and NO production.
RESULTS
In HAEC, we show that pharmacologically relevant doses of niacin at 0.2-0.3 mM for 24 h significantly increased cellular NAD levels, Sirt1 activity, and NO production as compared to controls. Using silencing of Sirt1 by siRNA, we observed that Sirt1 mediates niacin-induced NO production.
CONCLUSIONS
Translationally, these findings suggest that Sirt1 activation by niacin may be one of the mechanisms of action of niacin acting on NO to improve endothelial function and mitigate human vascular aging and its deleterious cardiovascular consequences.
PubMed: 38186996
DOI: No ID Found -
Peptides Mar 2024Options for the treatment of type 2 diabetes mellitus (T2DM) and obesity have recently been expanded by the results of several large clinical trials with incretin-based...
Options for the treatment of type 2 diabetes mellitus (T2DM) and obesity have recently been expanded by the results of several large clinical trials with incretin-based peptide therapies. Most of these studies have been conducted with the glucagon-like peptide-1 (GLP-1) receptor agonist semaglutide, which is available as a once weekly subcutaneous injection and once daily tablet, and the once weekly injected dual agonist tirzepatide, which interacts with receptors for GLP-1 and glucose-dependent insulinotropic polypeptide (GIP). In individuals with T2DM these therapies have achieved reductions of glycated haemoglobin (HbA1c) by > 2% and lowered body weight by > 10%. In some studies, these agents tested in non-diabetic, obese individuals at much higher doses have lowered body weight by > 15%. Emerging evidence suggests these agents can also offer cardio-protective and potentially reno-protective effects. Other incretin-based peptide therapies in early clinical development, notably a triple GLP-1/GIP/glucagon receptor agonist (retatrutide) and a combination of semaglutide with the amylin analogue cagrilintide (CagriSema), have shown strong efficacy. Although incretin therapies can incur adverse gastrointestinal effects these are for most patients mild-to-moderate and transient but result in cessation of treatment in some cases. Thus, the efficacy of new incretin-based peptide therapies is enhancing the opportunity to control body weight and blood glucose and improve the treatment of T2DM and obesity.
Topics: Humans; Diabetes Mellitus, Type 2; Incretins; Gastric Inhibitory Polypeptide; Obesity; Glucagon-Like Peptide 1; Body Weight; Glucagon-Like Peptide-1 Receptor; Hypoglycemic Agents
PubMed: 38184193
DOI: 10.1016/j.peptides.2024.171149