Alzheimer's disease (AD) is the most common form of dementia. Characterized by progressive neurodegeneration, AD typically begins with mild cognitive decline escalating to severe impairment in communication and responsiveness. It primarily affects cerebral regions responsible for cognition, memory, and language processing, significantly impeding the functional independence of patients. With nearly 50 million dementia cases worldwide, a number expected to triple by 2050, the need for effective treatments is more urgent than ever. Recent insights into the association between obesity, type 2 diabetes mellitus, and neurodegenerative disorders have led to the development of promising treatments involving antidiabetic and anti-obesity agents. One such novel promising candidate for addressing AD pathology is a lipidized analogue of anorexigenic peptide called prolactin-releasing peptide (palm11-PrRP31). Interestingly, anorexigenic and orexigenic peptides have opposite effects on food intake regulation, however, both types exhibit neuroprotective properties. Recent studies have also identified ghrelin, an orexigenic peptide, as a potential neuroprotective agent. Hence, we employed both anorexigenic and orexigenic compounds to investigate the common mechanisms underpinning their neuroprotective effects in a triple transgenic mouse model of AD (3xTg-AD mouse model) combining amyloid-beta (Aβ) pathology and Tau pathology, two hallmarks of AD. We treated 3xTg-AD mice for 4 months with two stable lipidized anorexigenic peptide analogues - palm11-PrRP31, and liraglutide, a glucagon-like peptide 1 (GLP-1) analogue - as well as Dpr3-ghrelin, a stable analogue of the orexigenic peptide ghrelin, and using the method of immunohistochemistry and western blot demonstrate the effects of these compounds on the development of AD-like pathology in the brain. Palm11-PrRP31, Dpr3-ghrelin, and liraglutide reduced intraneuronal deposits of Aβ plaque load in the hippocampi and amygdalae of 3xTg-AD mice. Palm11-PrRP31 and Dpr3-ghrelin reduced microgliosis in the hippocampi, amygdalae, and cortices of 3xTg-AD mice. Palm11-PrRP31 and liraglutide reduced astrocytosis in the amygdalae of 3xTg-AD mice. We propose that these peptides are involved in reducing inflammation, a common mechanism underlying their therapeutic effects. This is the first study to demonstrate improvements in AD pathology following the administration of both orexigenic and anorexigenic compounds, highlighting the therapeutic potential of food intake-regulating peptides in neurodegenerative disorders.

• Klíčová slova
• 3xTg-AD mice, Alzheimer’s disease, Anorexigenic peptide analogues, Neuroinflammation, Orexigenic peptide analogues,
• MeSH
• Alzheimerova nemoc * farmakoterapie   metabolismus   patologie   MeSH
• amyloidní beta-protein metabolismus   MeSH
• amyloidový prekurzorový protein beta genetika   metabolismus   MeSH
• ghrelin farmakologie   analogy a deriváty   terapeutické užití   metabolismus   MeSH
• hormon uvolňující prolaktin * analogy a deriváty   farmakologie   MeSH
• lidé MeSH
• liraglutid farmakologie   terapeutické užití   MeSH
• modely nemocí na zvířatech * MeSH
• myši inbrední C57BL MeSH
• myši transgenní * MeSH
• myši MeSH
• neuroprotektivní látky farmakologie   terapeutické užití   MeSH
• neurozánětlivé nemoci farmakoterapie   metabolismus   MeSH
• presenilin-1 genetika   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• amyloidní beta-protein MeSH
• amyloidový prekurzorový protein beta MeSH
• ghrelin MeSH
• hormon uvolňující prolaktin * MeSH
• liraglutid MeSH
• neuroprotektivní látky MeSH
• presenilin-1 MeSH

• MeSH
• liraglutid terapeutické užití   MeSH
• plastická chirurgie * MeSH
• zákroky plastické chirurgie * MeSH
• Publikační typ
• dopisy MeSH
• Názvy látek
• liraglutid MeSH

The physical stability of peptide-based drugs is of great interest to the pharmaceutical industry. Glucagon-like peptide 1 (GLP-1) is a 31-amino acid peptide hormone, the analogs of which are frequently used in the treatment of type 2 diabetes. We investigated the physical stability of GLP-1 and its C-terminal amide derivative, GLP-1-Am, both of which aggregate into amyloid fibrils. While off-pathway oligomers have been proposed to explain the unusual aggregation kinetics observed previously for GLP-1 under specific conditions, these oligomers have not been studied in any detail. Such states are important as they may represent potential sources of cytotoxicity and immunogenicity. Here, we identified and isolated stable, low-molecular-weight oligomers of GLP-1 and GLP-1-Am, using size-exclusion chromatography. Under the conditions studied, isolated oligomers were shown to be resistant to fibrillation or dissociation. These oligomers contain between two and five polypeptide chains and they have a highly disordered structure as indicated by a variety of spectroscopic techniques. They are highly stable with respect to time, temperature, or agitation despite their noncovalent character, which was established using liquid chromatography-mass spectrometry and sodium dodecyl sulfate-polyacrylamide gel electrophoresis. These results provide evidence of stable, low-molecular-weight oligomers that are formed by an off-pathway mechanism which competes with amyloid fibril formation.

• Klíčová slova
• aggregation, amyloid, glucagon-like peptide 1, oligomers, self-assembly,
• MeSH
• amyloid chemie   MeSH
• amyloidní beta-protein chemie   MeSH
• diabetes mellitus 2. typu * MeSH
• gelová chromatografie MeSH
• glukagonu podobný peptid 1 * MeSH
• lidé MeSH
• peptidové fragmenty chemie   MeSH
• peptidy MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• amyloid MeSH
• amyloidní beta-protein MeSH
• glukagonu podobný peptid 1 * MeSH
• peptidové fragmenty MeSH
• peptidy MeSH

INTRODUCTION: Ageing skeletal muscles become both insulin resistant and atrophic. The hormone glucagon-like peptide 1 (GLP-1) facilitates postprandial glucose uptake as well as augmenting muscle perfusion, independent of insulin action. We thus hypothesized exogenous GLP-1 infusions would enhance muscle perfusion and positively affect glucose metabolism during fed-state clamps in older people. METHODS: Eight men (71 ± 1 years) were studied in a randomized crossover trial. Basal blood samples were taken before postprandial (fed-state) insulin and glucose clamps, accompanied by amino acid infusions, for 3 hours. Reflecting this, following insertions of peripheral and femoral vessels cannulae and baseline measurements, peripheral IV infusions of octreotide, insulin (Actrapid), 20% glucose, and mixed amino acids; Vamin 14-EF with or without a femoral arterial GLP-1 infusion were started. GLP-1, insulin, and C-peptide were measured by ELISA. Muscle microvascular blood flow was assessed via contrast enhanced ultrasound. Whole-body glucose handling was assayed by assessing glucose infusion rate parameters. RESULTS: Skeletal muscle microvascular blood flow significantly increased in response to GLP-1 vs feeding alone (5.0 ± 2.1 vs 1.9 ± 0.7 fold-change from basal, respectively; P = 0.008), while also increasing whole-body glucose uptake (area under the curve 16.9 ± 1.7 vs 11.4 ± 1.8 mg/kg-1/180 minutes-1, P = 0.02 ± GLP, respectively). CONCLUSIONS: The beneficial effects of GLP-1 on whole-body glycemic control are evident with insulin clamped at fed-state levels. GLP-1 further enhances the effects of insulin on whole-body glucose uptake in older men, underlining its role as a therapeutic target. The effects of GLP-1 in enhancing microvascular flow likely also affects other glucose-regulatory organs, reflected by greater whole-body glucose uptake.

• Klíčová slova
• extrapancreatic effects, glucagon like peptide 1, microcirculation, microvascular blood flow, microvascular recruitment, muscle glucose metabolism, muscle glucose uptake,
• MeSH
• glukagonu podobný peptid 1 * metabolismus   MeSH
• glukosa metabolismus   MeSH
• inzulin * metabolismus   MeSH
• kosterní svaly metabolismus   MeSH
• krevní glukóza metabolismus   MeSH
• lidé MeSH
• oktreotid farmakologie   MeSH
• perfuze MeSH
• senioři MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• randomizované kontrolované studie MeSH
• Názvy látek
• glukagonu podobný peptid 1 * MeSH
• glukosa MeSH
• inzulin * MeSH
• krevní glukóza MeSH
• oktreotid MeSH

Prolactin-releasing peptide (PrRP) is an anorexigenic neuropeptide that has potential for the treatment of obesity and its complications. Recently, we designed a palmitoylated PrRP31 analog (palm11-PrRP31) that is more stable than the natural peptide and able to act centrally after peripheral administration. This analog acted as an anti-obesity and glucose-lowering agent, attenuating lipogenesis in rats and mice with high-fat (HF) diet-induced obesity. In Wistar Kyoto (WKY) rats fed a HF diet for 52 weeks, we explored glucose intolerance, but also prediabetes, liver steatosis and insulin resistance-related changes, as well as neuroinflammation in the brain. A potential beneficial effect of 6 weeks of treatment with palm11-PrRP31 and liraglutide as comparator was investigated. Liver lipid profiles, as well as urinary and plasma metabolomic profiles, were measured by lipidomics and metabolomics, respectively. Old obese WKY rats showed robust glucose intolerance that was attenuated by palm11-PrRP31, but not by liraglutide treatment. On the contrary, liraglutide had a beneficial effect on insulin resistance parameters. Despite obesity and prediabetes, WKY rats did not develop steatosis owing to HF diet feeding, even though liver lipogenesis was enhanced. Plasma triglycerides and cholesterol were not increased by HFD feeding, which points to unincreased lipid transport from the liver. The liver lipid profile was significantly altered by a HF diet that remained unaffected by palm11-PrRP31 or liraglutide treatment. The HF-diet-fed WKY rats revealed astrogliosis in the brain cortex and hippocampus, which was attenuated by treatment. In conclusion, this study suggested multiple beneficial anti-obesity-related effects of palm11-PrRP31 and liraglutide in both the periphery and brain.

• Klíčová slova
• Wistar Kyoto rats, astrocytosis, diet-induced obesity, glucose intolerance, lipid metabolism, lipidomics, liraglutide, metabolomics, prolactin-releasing peptide,
• MeSH
• dieta s vysokým obsahem tuků škodlivé účinky   MeSH
• hormon uvolňující prolaktin farmakologie   MeSH
• hypoglykemika farmakologie   terapeutické užití   MeSH
• inzulinová rezistence * MeSH
• krysa rodu Rattus MeSH
• lipidy MeSH
• liraglutid farmakologie   terapeutické užití   MeSH
• myši MeSH
• obezita farmakoterapie   MeSH
• porucha glukózové tolerance * farmakoterapie   MeSH
• potkani inbrední WKY MeSH
• prediabetes * farmakoterapie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• hormon uvolňující prolaktin MeSH
• hypoglykemika MeSH
• lipidy MeSH
• liraglutid MeSH

Type B trichothecenes commonly contaminate cereal grains and include five structurally related congeners: deoxynivalenol (DON), 3-acetyldeoxynivalenol (3-ADON), 15-acetyldeoxynivalenol (15-ADON), fusarenon X (FX), and nivalenol (NIV). These toxins are known to have negative effects on human and animal health, particularly affecting food intake. However, the pathophysiological basis for anorexic effect is not fully clarified. The purpose of this study is to explore the potential roles of the brain-gut peptides substance P (SP) and glucagon-like peptide-17-36 amide (GLP-1) in anorexic responses induced by type B trichothecenes following both intraperitoneal (IP) and oral administration. SP and GLP-1 were elevated at 1 or 2 h and returned to basal levels at 6 h following exposure to DON and both ADONs. FX induced the production of both brain gut peptides with initial time at 1 or 2 h and duration > 6 h. Similar to FX, exposing IP to NIV caused elevations of SP and GLP-1 at 1 h and lasted more than 6 h, whereas oral exposure to NIV only increased both brain gut peptides at 2 h. The neurokinin-1 receptor (NK-1R) antagonist Emend® dose-dependently attenuated both SP- and DON-induced anorexic responses. Pretreatment with the GLP-1 receptor (GLP-1R) antagonist Exending9-39 induced a dose-dependent attenuation of both GLP-1- and DON-induced anorexic responses. To summarize, the results suggest that both SP and GLP-1 play important roles in anorexia induction by type B trichothecenes.

• Klíčová slova
• anorexia, brain-gut peptide, glucagon-like peptide-17-36 amide, substance P, trichothecene,
• MeSH
• amidy toxicita   MeSH
• anorektika * toxicita   MeSH
• glukagonu podobný peptid 1 toxicita   MeSH
• lidé MeSH
• nechutenství chemicky indukované   MeSH
• substance P toxicita   MeSH
• trichotheceny typu B * MeSH
• trichotheceny * toxicita   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• 15-acetyldeoxynivalenol MeSH Prohlížeč
• 3-acetyldeoxynivalenol MeSH Prohlížeč
• amidy MeSH
• anorektika * MeSH
• deoxynivalenol MeSH Prohlížeč
• fusarenon-X MeSH Prohlížeč
• glukagonu podobný peptid 1 MeSH
• nivalenol MeSH Prohlížeč
• substance P MeSH
• trichothecene MeSH Prohlížeč
• trichotheceny typu B * MeSH
• trichotheceny * MeSH

Glucagon-like peptide-1 (GLP-1) receptor agonists mimic the action of the endogenous GLP-1 incretin hormone, improving glycaemic control in type 2 diabetes mellitus (T2DM) by increasing insulin secretion and decreasing glucagon secretion in a glucose-dependent manner. However, as cardiovascular (CV) morbidity and mortality is common in patients with T2DM, several trials with the use of GLP-1 receptor agonists (RAs) have been performed focusing on endpoints related to cardiovascular disease rather than metabolic control of T2DM. Following the positive cardiovascular effects of liraglutide, dulaglutide and semaglutide observed in these trials, major changes in T2DM management guidelines have occurred. This document from a Eastern and Southern European Diabetes Expert Group discusses the results of GLP-1 RA CV outcomes trials, their impact on recent clinical guidelines for the management of T2DM, and some selected combination regimens utilising GLP-1 RAs. We also propose an algorithm for guiding GLP-1 RA-based treatment according to patients' characteristics, which can be easily applied in every day clinical practice.

• Klíčová slova
• Algorithm, Cardiovascular outcomes trials, GLP-1 receptor agonists, Treatment, Type 2 diabetes mellitus,
• MeSH
• agonisté receptoru pro glukagonu podobný peptid 1 MeSH
• diabetes mellitus 2. typu * diagnóza   farmakoterapie   epidemiologie   MeSH
• glukagonu podobný peptid 1 metabolismus   MeSH
• hypoglykemika farmakologie   terapeutické užití   MeSH
• kardiovaskulární nemoci * farmakoterapie   epidemiologie   MeSH
• lidé MeSH
• liraglutid farmakologie   terapeutické užití   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• agonisté receptoru pro glukagonu podobný peptid 1 MeSH
• glukagonu podobný peptid 1 MeSH
• hypoglykemika MeSH
• liraglutid MeSH

BACKGROUND: Guidelines from 2016 onwards recommend early use of SGLT2i or GLP-1 RA for patients with type 2 diabetes (T2D) and cardiovascular disease (CVD), to reduce CV events and mortality. Many eligible patients are not treated accordingly, although data are lacking for Central and Eastern Europe (CEE). METHODS: The CORDIALLY non-interventional study evaluated the real-world characteristics, modern antidiabetic treatment patterns, and the prevalence of CVD and chronic kidney disease (CKD) in adults with T2D at nonhospital-based practices in CEE. Data were retrospectively collated by medical chart review for patients initiating empagliflozin, another SGLT2i, DPP4i, or GLP-1 RA in autumn 2018. All data were analysed cross-sectionally, except for discontinuations assessed 1 year ± 2 months after initiation. RESULTS: Patients (N = 4055) were enrolled by diabetologists (56.7%), endocrinologists (40.7%), or cardiologists (2.5%). Empagliflozin (48.5%) was the most prescribed medication among SGLT2i, DPP4i, and GLP-1 RA; > 3 times more patients were prescribed empagliflozin than other SGLT2i (10 times more by cardiologists). Overall, 36.6% of patients had diagnosed CVD. Despite guidelines recommending SGLT2i or GLP-1 RA, 26.8% of patients with CVD received DPP4i. Patients initiating DPP4i were older (mean 66.4 years) than with SGLT2i (62.4 years) or GLP-1 RA (58.3 years). CKD prevalence differed by physician assessment (14.5%) or based on eGFR and UACR (27.9%). Many patients with CKD (≥ 41%) received DPP4i, despite guidelines recommending SGLT2is owing to their renal benefits. 1 year ± 2-months after initiation, 10.0% (7.9-12.3%) of patients had discontinued study medication: 23.7-45.0% due to 'financial burden of co-payment', 0-1.9% due to adverse events (no patients discontinued DPP4i due to adverse events). Treatment guidelines were 'highly relevant' for a greater proportion of cardiologists (79.4%) and endocrinologists (72.9%) than diabetologists (56.9%), and ≤ 20% of physicians consulted other physicians when choosing and discontinuing treatments. CONCLUSIONS: In CORDIALLY, significant proportions of patients with T2D and CVD/CKD who initiated modern antidiabetic medication in CEE in autumn 2018 were not treated with cardioprotective T2D medications. Use of DPP4i instead of SGLT2i or GLP-1 RA may be related to lack of affordable access, the perceived safety of these medications, lack of adherence to the latest treatment guidelines, and lack of collaboration between physicians. Thus, many patients with T2D and comorbidities may develop preventable complications or die prematurely. Trial registration NCT03807440.

• Klíčová slova
• Cardiovascular disease (CVD), Cardiovascular outcomes trials (CVOTs), Cardiovascular safety, Chronic kidney disease (CKD), Dipeptidyl peptidase-4 inhibitors (DPP4i), Glucagon-like peptide-1 receptor agonists (GLP-1 RA), Glucose-lowering drug, Sodium-glucose cotransporter-2 inhibitors (SGLT2i), Type 2 diabetes,
• MeSH
• benzhydrylové sloučeniny MeSH
• chronická renální insuficience * diagnóza   farmakoterapie   epidemiologie   MeSH
• diabetes mellitus 2. typu * diagnóza   farmakoterapie   epidemiologie   MeSH
• dospělí MeSH
• glifloziny * škodlivé účinky   MeSH
• glukagonu podobný peptid 1 terapeutické užití   MeSH
• glukosidy MeSH
• hypoglykemika škodlivé účinky   MeSH
• kardiovaskulární nemoci * diagnóza   epidemiologie   prevence a kontrola   MeSH
• lidé MeSH
• průřezové studie MeSH
• receptor pro glukagonu podobný peptid 1 MeSH
• retrospektivní studie MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• benzhydrylové sloučeniny MeSH
• empagliflozin MeSH Prohlížeč
• glifloziny * MeSH
• glukagonu podobný peptid 1 MeSH
• glukosidy MeSH
• hypoglykemika MeSH
• receptor pro glukagonu podobný peptid 1 MeSH

Antipsychotics (APDs) represent a core treatment for severe mental disorders (SMEs). Providing symptomatic relief, APDs do not exert therapeutic effects on another clinically significant domain of serious mental disorders, cognitive impairment. Moreover, adverse metabolic effects (diabetes, weight gain, dyslipidemia, and increased cardiovascular risk) are common during treatment with APDs. Among pharmacological candidates reversing APD-induced metabolic adverse effects, glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1 RAs), approved for both diabetes and recently for obesity treatment, stand out due to their favorable effects on peripheral metabolic parameters. Interestingly, GLP-1 RAs are also proposed to have pro-cognitive effects. Particularly in terms of dual therapeutic mechanisms potentially improving both central nervous system (CNS) deficits and metabolic burden, GLP-1 RAs open a new perspective and assume a clinically advantageous position.

• Klíčová slova
• GLP-1 receptor agonist, antipsychotic, metabolic adverse effects, pro-cognitive, schizophrenia,
• MeSH
• agonisté receptoru pro glukagonu podobný peptid 1 MeSH
• antipsychotika * škodlivé účinky   MeSH
• diabetes mellitus 2. typu * farmakoterapie   MeSH
• glukagonu podobný peptid 1 terapeutické užití   MeSH
• hmotnostní přírůstek MeSH
• hypoglykemika terapeutické užití   MeSH
• lidé MeSH
• obezita chemicky indukované   farmakoterapie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• agonisté receptoru pro glukagonu podobný peptid 1 MeSH
• antipsychotika * MeSH
• glukagonu podobný peptid 1 MeSH
• hypoglykemika MeSH

Dulaglutide is a frequently used GLP-1 analogue and one of the most potent antidiabetic drugs. Practical aspects of treatment with dulaglutide are presented in this article, together with new data from AWARD-11 study with higher concentrations of dulaglutide, especially the effects on diabetes control, body weight and side effects.

• Klíčová slova
• GLP1 receptor agonists, diabetes, dulaglutide, heart failure, pharmacotherapy,
• MeSH
• diabetes mellitus 2. typu * farmakoterapie   MeSH
• glukagonu podobné peptidy analogy a deriváty   MeSH
• glukagonu podobný peptid 1 MeSH
• glykovaný hemoglobin analýza   MeSH
• hypoglykemika škodlivé účinky   MeSH
• imunoglobuliny - Fc fragmenty MeSH
• lidé MeSH
• motivace * MeSH
• receptor pro glukagonu podobný peptid 1 MeSH
• rekombinantní fúzní proteiny MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• dulaglutide MeSH Prohlížeč
• glukagonu podobné peptidy MeSH
• glukagonu podobný peptid 1 MeSH
• glykovaný hemoglobin MeSH
• hypoglykemika MeSH
• imunoglobuliny - Fc fragmenty MeSH
• receptor pro glukagonu podobný peptid 1 MeSH
• rekombinantní fúzní proteiny MeSH