RESUMEN
Obesity, a global health challenge, necessitates innovative approaches for effective management. Targeting gut peptides in the development of anti-obesity pharmaceuticals has already demonstrated significant efficacy. Ghrelin, peptide YY (PYY), cholecystokinin (CCK), and amylin are crucial in appetite regulation offering promising targets for pharmacological interventions in obesity treatment using both peptide-based and small molecule-based pharmaceuticals. Ghrelin, a sole orexigenic gut peptide, has a potential for anti-obesity therapies through various approaches, including endogenous ghrelin neutralization, ghrelin receptor antagonists, ghrelin O-acyltransferase, and functional inhibitors. Anorexigenic gut peptides, peptide YY, cholecystokinin, and amylin, have exhibited appetite-reducing effects in animal models and humans. Overcoming substantial obstacles is imperative for translating these findings into clinically effective pharmaceuticals. Peptide YY and cholecystokinin analogues, characterized by prolonged half-life and resistance to proteolytic enzymes, present viable options. Positive allosteric modulators emerge as a novel approach for modulating the cholecystokinin pathway. Amylin is currently the most promising, with both amylin analogues and dual amylin and calcitonin receptor agonists (DACRAs) progressing to advanced stages of clinical trials. Despite persistent challenges, innovative pharmaceutical strategies provide a glimpse into the future of anti-obesity therapies.
Asunto(s)
Fármacos Antiobesidad , Regulación del Apetito , Colecistoquinina , Obesidad , Humanos , Animales , Obesidad/tratamiento farmacológico , Fármacos Antiobesidad/farmacología , Fármacos Antiobesidad/uso terapéutico , Colecistoquinina/metabolismo , Colecistoquinina/farmacología , Regulación del Apetito/efectos de los fármacos , Ghrelina/farmacología , Ghrelina/uso terapéutico , Polipéptido Amiloide de los Islotes Pancreáticos/metabolismo , Polipéptido Amiloide de los Islotes Pancreáticos/farmacología , Péptido YY/farmacología , Péptido YY/uso terapéutico , Depresores del Apetito/farmacología , Depresores del Apetito/uso terapéuticoRESUMEN
The American Diabetes Association guidelines (2021) confirmed the importance of raising public awareness of diabetes-induced cognitive impairment, highlighting the links between poor glycemic control and cognitive impairment. The characteristic brain lesions of cognitive dysfunction are neurofibrillary tangles (NFT) and senile plaques formed of amyloid-ß deposition, glycogen synthase kinase 3 beta (GSK3ß), and highly homologous kinase tau tubulin kinase 1 (TTBK1) can phosphorylate Tau proteins at different sites, overexpression of these enzymes produces extensive phosphorylation of Tau proteins making them insoluble and enhance NFT formation, which impairs cognitive functions. The current study aimed to investigate the potential contribution of liraglutide and pramlintide in the prevention of diabetes-induced cognitive dysfunction and their effect on the PI3K/AKT/GSK-3ß/TTBK1 pathway in type 2 diabetic (T2D) rat model. T2D was induced by administration of a high-fat diet for 10 weeks, then injection of a single dose of streptozotocin (STZ); treatment was started with either pramlintide (200 µg/kg/day sc) or liraglutide (0.6 mg/kg/day sc) for 6 weeks in addition to the HFD. At the end of the study, cognitive functions were assessed by novel object recognition and T-maze tests. Then, rats were sacrificed for biochemical and histological assessment of the hippocampal tissue. Both pramlintide and liraglutide treatment revealed equally adequate control of diabetes, prevented the decline in memory function, and increased PI3K/AKT expression while decreasing GSK-3ß/TTBK1 expression; however, liraglutide significantly decreased the number of Tau positive cells better than pramlintide did. This study confirmed that pramlintide and liraglutide are promising antidiabetic medications that could prevent associated cognitive disorders in different mechanisms.
Asunto(s)
Disfunción Cognitiva , Dieta Alta en Grasa , Glucógeno Sintasa Quinasa 3 beta , Liraglutida , Fosfatidilinositol 3-Quinasas , Proteínas Proto-Oncogénicas c-akt , Proteínas tau , Animales , Proteínas tau/metabolismo , Ratas , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Liraglutida/farmacología , Liraglutida/uso terapéutico , Dieta Alta en Grasa/efectos adversos , Masculino , Disfunción Cognitiva/prevención & control , Disfunción Cognitiva/tratamiento farmacológico , Disfunción Cognitiva/metabolismo , Disfunción Cognitiva/etiología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Fosforilación/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/tratamiento farmacológico , Polipéptido Amiloide de los Islotes Pancreáticos/metabolismo , Polipéptido Amiloide de los Islotes Pancreáticos/farmacología , Hipoglucemiantes/farmacología , Hipoglucemiantes/uso terapéutico , Ratas Sprague-Dawley , Estreptozocina , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/tratamiento farmacológicoRESUMEN
Amylin, a pancreatic hormone, is well-established to suppress feeding by enhancing satiation. Pramlintide, an amylin analog that is FDA-approved for the treatment of diabetes, has also been shown to produce hypophagia. However, the behavioral mechanisms underlying the ability of pramlintide to suppress feeding are unresolved. We hypothesized that systemic pramlintide administration in rats would reduce energy intake, specifically by reducing meal size. Male rats were given b.i.d. administration of intraperitoneal pramlintide or vehicle for 1 week, and chow intake, meal patterns, and body weight were monitored throughout the test period. Consistent with our hypothesis, pramlintide decreased chow intake mainly via suppression of meal size, with corresponding reductions in meal duration on several days. Fewer effects on meal number or feeding rate were detected. Pramlintide also reduced weight gain over the 1-week study. These results highlight that the behavioral mechanisms by which pramlintide produces hypophagia are similar to those driven by amylin itself, and provide important insight into the ability of this pharmacotherapy to promote negative energy balance over a period of chronic administration.
Asunto(s)
Conducta Alimentaria , Polipéptido Amiloide de los Islotes Pancreáticos , Animales , Polipéptido Amiloide de los Islotes Pancreáticos/farmacología , Masculino , Ratas , Conducta Alimentaria/efectos de los fármacos , Ingestión de Alimentos/efectos de los fármacos , Ratas Sprague-Dawley , Peso Corporal/efectos de los fármacos , Ingestión de Energía/efectos de los fármacosRESUMEN
OBJECTIVES: Diabetes mellitus is a complex heterogenous metabolic disease that significantly affects the world population. Although many treatments exist, including medications such as metformin, sulfonylureas, and glucagon-like peptide-1 (GLP) receptor agonist, there is growing interest in finding alternative methods to noninvasively treat this disease. It has been previously shown that low-intensity ultrasound stimulation of pancreatic ß-cells in mice can elicit insulin secretion as a potential treatment for this disease. This is desirable as therapeutic ultrasound has the ability to induce bioeffects while selectively focusing deep within tissues, allowing for modulation of hormone secretion in the pancreas to mitigate insufficient levels of insulin. METHODS: Exactly 800 kHz ultrasound with intensity 0.5 W/cm2 was administered 5 minutes continuously, that is, 100% duty cycle, to donor pancreatic human islets, followed by 1 hour incubation and RT-qPCR to assess the effect of ultrasound stimulation on gene expression. The genes were insulin (INS), glucagon (Glu), amylin (Amy), and binding immunoglobulin protein (BiP). Nine donor pancreatic human islets were used to assess insulin and glucagon secretion, while eight samples were used for amylin and BiP. Fold change (FC) was calculated to analyze the effect of ultrasound stimulation on the gene expression of the donor islet cells. High-glucose and thapsigargin-treated islets were utilized as positive controls. Cell viability testing was done using a Trypan Blue Exclusion Test. RESULTS: Ultrasound stimulation did not cause a statistically significant upregulation in any of the tested genes (INS FC = 1.15, P-value = .5692; Glu FC = 1.60, P-value = .2231; Amy FC, P-value = .2863; BiP FC = 2.68, P-value = .3907). CONCLUSIONS: The results of this study show that the proposed ultrasound treatment parameters do not appear to significantly affect gene expression of any gene tested.
Asunto(s)
Insulina , Islotes Pancreáticos , Terapia por Ultrasonido , Humanos , Islotes Pancreáticos/efectos de los fármacos , Islotes Pancreáticos/metabolismo , Terapia por Ultrasonido/métodos , Glucagón , Expresión Génica/efectos de los fármacos , Polipéptido Amiloide de los Islotes Pancreáticos/farmacologíaRESUMEN
Leptin is a tonic appetite-regulating hormone, which is integral for the long-term regulation of energy balance. The current evidence suggests that the typical orexigenic or anorexigenic response of many of these appetite-regulating hormones, most notably ghrelin and cholecystokinin (CCK), require leptin to function whereas glucagon-like peptide-1 (GLP-1) is required for leptin to function, and these responses are altered when leptin injection or gene therapy is administered in combination with these same hormones or respective agonists. The appetite-regulatory pathway is complex, thus peptide tyrosine tyrosine (PYY), brain-derived neurotrophic factor (BDNF), orexin-A (OXA), and amylin also maintain ties to leptin, however these are less well understood. While reviews to date have focused on the existing relationships between leptin and the various neuropeptide modulators of appetite within the central nervous system (CNS) or it's role in thermogenesis, no review paper has synthesised the information regarding the interactions between appetite-regulating hormones and how leptin as a chronic regulator of energy balance can influence the acute appetite-regulatory response. Current evidence suggests that potential relationships exist between leptin and the circulating peripheral appetite hormones ghrelin, GLP-1, CCK, OXA and amylin to exhibit either synergistic or opposing effects on appetite inhibition. Though more research is warranted, leptin appears to be integral in both energy intake and energy expenditure. More specifically, functional leptin receptors appear to play an essential role in these processes.
Asunto(s)
Ghrelina , Leptina , Ghrelina/metabolismo , Polipéptido Amiloide de los Islotes Pancreáticos/metabolismo , Polipéptido Amiloide de los Islotes Pancreáticos/farmacología , Apetito , Ingestión de Energía , Péptido 1 Similar al Glucagón , Péptido YY , Metabolismo Energético , Tirosina/metabolismo , Tirosina/farmacologíaRESUMEN
Piperic acid derivatives were found to affect the islet amyloid polypeptide (IAPP) aggregation process. Structure-activity relationship studies revealed that PAD-13 was an efficient molecular modulator to accelerate IAPP fibril formation by promoting primary and secondary nucleation and reducing its antimicrobial activity.
Asunto(s)
Antiinfecciosos , Polipéptido Amiloide de los Islotes Pancreáticos , Polipéptido Amiloide de los Islotes Pancreáticos/farmacología , Polipéptido Amiloide de los Islotes Pancreáticos/química , Amiloide/química , Ácidos Grasos Insaturados , Antiinfecciosos/farmacologíaRESUMEN
Since hIAPP (human islet amyloid polypeptide) aggregation and microbial infection are recognized as significant risk factors that contribute to the pathogenesis of type II diabetes (T2D), targeting these catastrophic processes simultaneously may have a greater impact on the prevention and treatment of T2D. Different from the well-studied hIAPP inhibitors, here we propose and demonstrate a repurposing strategy for an antimicrobial peptide, aurein, which can simultaneously modulate hIAPP aggregation and inhibit microbial infection. Collective data from protein, cell, and bacteria assays revealed multiple functions of aurein including (i) promotion of hIAPP aggregation at a low molar ratio of aurein:hIAPP = 0.5 : 1-2 : 1, (ii) reduction of hIAPP-induced cytotoxicity in RIN-m5F cells, and (iii) preservation of original antimicrobial activity against E. coli., S.A., and S.E. strains in the presence of hIAPP. These functions of aurein are mainly derived from its strong binding to different hIAPP seeds through conformationally similar ß-sheet association. Our study provides a promising avenue for the repurposing of antimicrobial peptides (such as aurein) as amyloid modulators for blocking at least two pathological pathways in T2D.
Asunto(s)
Diabetes Mellitus Tipo 2 , Polipéptido Amiloide de los Islotes Pancreáticos , Humanos , Polipéptido Amiloide de los Islotes Pancreáticos/farmacología , Polipéptido Amiloide de los Islotes Pancreáticos/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Simulación de Dinámica Molecular , Escherichia coli/metabolismo , Proteínas AmiloidogénicasRESUMEN
It is well known that the cytokine-induced apoptosis inhibitor 1 (CIAPIN1) protein plays an important role in biological progresses as an anti-apoptotic protein. Human islet amyloid peptide (hIAPP), known as amylin, is caused to pancreatic ß-cell death in type 2 diabetes mellitus (T2DM). However, the function of CIAPIN1 protein on T2DM is not yet well studied. Therefore, we investigated the effects of CIAPIN1 protein on a hIAPP-induced RINm5F cell and T2DM animal model induced by a high-fat diet (HFD) and streptozotocin (STZ). The Tat-CIAPIN1 protein reduced the activation of mitogen-activated protein kinase (MAPK) and regulated the apoptosis-related protein expression levels including COX-2, iNOS, Bcl-2, Bax, and Caspase-3 in hIAPP-induced RINm5F cells. In a T2DM mice model, the Tat-CIAPIN1 protein ameliorated the pathological changes of pancreatic ß-cells and reduced the fasting blood glucose, body weight and hemoglobin Alc (HbAlc) levels. In conclusion, the Tat-CIAPIN1 protein showed protective effects against T2DM by protection of ß-cells via inhibition of hIAPP toxicity and by regulation of a MAPK signal pathway, suggesting CIAPIN1 protein can be a therapeutic protein drug candidate by beneficial regulation of T2DM.
Asunto(s)
Diabetes Mellitus Tipo 2 , Células Secretoras de Insulina , Islotes Pancreáticos , Ratones , Animales , Humanos , Diabetes Mellitus Tipo 2/metabolismo , Islotes Pancreáticos/metabolismo , Células Secretoras de Insulina/metabolismo , Polipéptido Amiloide de los Islotes Pancreáticos/farmacología , Polipéptido Amiloide de los Islotes Pancreáticos/metabolismo , Apoptosis , Amiloide/metabolismo , Modelos Animales de Enfermedad , Productos del Gen tat/metabolismo , Proteínas Quinasas Activadas por Mitógenos/metabolismoRESUMEN
The islet amyloid polypeptide (IAPP), a pancreas-produced peptide, has beneficial functions in its monomeric form. However, IAPP aggregates, related to type 2 diabetes mellitus (T2DM), are toxic not only for the pancreas, but also for the brain. In the latter, IAPP is often found in vessels, where it is highly toxic for pericytes, mural cells that have contractile properties and regulate capillary blood flow. In the current study, we use a microvasculature model, where human brain vascular pericytes (HBVP) are co-cultured together with human cerebral microvascular endothelial cells, to demonstrate that IAPP oligomers (oIAPP) alter the morphology and contractility of HBVP. Contraction and relaxation of HBVP was verified using the vasoconstrictor sphingosine-1-phosphate (S1P) and vasodilator Y27632, where the former increased, and the latter decreased, the number of HBVP with round morphology. Increased number of round HBVP was also seen after oIAPP stimulation, and the effect was reverted by the IAPP analogue pramlintide, Y27632, and the myosin inhibitor blebbistatin. Inhibition of the IAPP receptor with the antagonist AC187 only reverted IAPP effects partially. Finally, we demonstrate by immunostaining of human brain tissue against laminin that individuals with high amount of brain IAPP levels show significantly lower capillary diameter and altered mural cell morphology compared to individuals with low brain IAPP levels. These results indicate that HBVP, in an in vitro model of microvasculature, respond morphologically to vasoconstrictors, dilators, and myosin inhibitors. They also suggest that oIAPP induces contraction of these mural cells and that pramlintide can reverse such contraction.
Asunto(s)
Diabetes Mellitus Tipo 2 , Polipéptido Amiloide de los Islotes Pancreáticos , Humanos , Polipéptido Amiloide de los Islotes Pancreáticos/farmacología , Polipéptido Amiloide de los Islotes Pancreáticos/química , Pericitos , Células Endoteliales , AmiloideRESUMEN
AIMS: The extracellular matrix (ECM) is fundamental for the normal endocrine functions of pancreatic islet cells and plays key roles in the pathophysiology of type 2 diabetes. Here we investigated the turnover of islet ECM components, including islet amyloid polypeptide (IAPP), in an obese mouse model treated with semaglutide, a glucagon-like peptide type 1 receptor agonist. MAIN METHODS: Male one-month-old C57BL/6 mice were fed a control diet (C) or a high-fat diet (HF) for 16 weeks, then treated with semaglutide (subcutaneous 40 µg/kg every three days) for an additional four weeks (HFS). The islets were immunostained and gene expressions were assessed. KEY FINDINGS: Comparisons refer to HFS vs HF. Thus, IAPP immunolabeling and beta-cell-enriched beta-amyloid precursor protein cleaving enzyme (Bace2, -40 %) and heparanase immunolabeling and gene (Hpse, -40 %) were mitigated by semaglutide. In contrast, perlecan (Hspg2, +900 %) and vascular endothelial growth factor A (Vegfa, +420 %) were enhanced by semaglutide. Also, semaglutide lessened syndecan 4 (Sdc4, -65 %) and hyaluronan synthases (Has1, -45 %; Has2, -65 %) as well as chondroitin sulfate immunolabeling, and collagen type 1 (Col1a1, -60 %) and type 6 (Col6a3, -15 %), lysyl oxidase (Lox, -30 %) and metalloproteinases (Mmp2, -45 %; Mmp9, -60 %). SIGNIFICANCE: Semaglutide improved the turnover of islet heparan sulfate proteoglycans, hyaluronan, chondroitin sulfate proteoglycans, and collagens in the islet ECM. Such changes should contribute to restoring a healthy islet functional milieu and should reduce the formation of cell-damaging amyloid deposits. Our findings also provide additional evidence for the involvement of islet proteoglycans in the pathophysiology of type 2 diabetes.
Asunto(s)
Diabetes Mellitus Tipo 2 , Islotes Pancreáticos , Ratones , Animales , Masculino , Ratones Obesos , Factor A de Crecimiento Endotelial Vascular/metabolismo , Receptor del Péptido 1 Similar al Glucagón/metabolismo , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Ratones Endogámicos C57BL , Islotes Pancreáticos/metabolismo , Péptidos Similares al Glucagón/farmacología , Matriz Extracelular/metabolismo , Polipéptido Amiloide de los Islotes Pancreáticos/genética , Polipéptido Amiloide de los Islotes Pancreáticos/metabolismo , Polipéptido Amiloide de los Islotes Pancreáticos/farmacología , DietaRESUMEN
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.
Asunto(s)
Agonistas de los Receptores de Amilina , Diabetes Mellitus Tipo 2 , Animales , Ratas , Agonistas de los Receptores de Amilina/farmacología , Agonistas de los Receptores de Amilina/uso terapéutico , Glucemia/metabolismo , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Polipéptido Amiloide de los Islotes Pancreáticos/farmacología , Polipéptido Amiloide de los Islotes Pancreáticos/uso terapéutico , Obesidad/tratamiento farmacológico , Ratas Sprague-Dawley , Receptores de Calcitonina/agonistas , Receptores de Calcitonina/uso terapéutico , Pérdida de PesoRESUMEN
Pramlintide is an equipotent amylin analogue that reduces food intake and body weight in obese subjects and has been clinically approved as an adjunctive therapy for the treatment of adult diabetic patients. However, due to its extremely short half-life in vivo, a regimen of multiple daily administrations is required for achieving clinical effectiveness. Herein is described the development of prototypical long-acting pramlintide bioconjugates, in which pramlintide's disulfide-linked macrocycle was replaced by a cyclic thioether motif. This modification enabled stable chemical conjugation to a half-life extending antibody. In contrast to pramlintide (t1/2 < 0.75 h), bioconjugates 35 and 38 have terminal half-lives of â¼2 days in mice and attain significant exposure levels that are maintained up to 7 days. Single dose subcutaneous administration of 35 in lean mice, given 18-20 h prior to oral acetaminophen (AAP) administration, significantly reduced gastric emptying (as determined by plasma AAP levels). In a separate study, similar administration of 35 in fasted lean mice effected a reduction in food intake for up to 48 h. These data are consistent with durable amylinomimetic responses and provide the basis for further development of such long-acting amylinomimetic conjugates for the potential treatment of obesity and associated pathologies.
Asunto(s)
Agonistas de los Receptores de Amilina , Agonistas de los Receptores de Amilina/farmacología , Agonistas de los Receptores de Amilina/uso terapéutico , Amiloide , Animales , Peso Corporal , Humanos , Hipoglucemiantes/uso terapéutico , Polipéptido Amiloide de los Islotes Pancreáticos/farmacología , Ratones , Obesidad/inducido químicamente , Obesidad/tratamiento farmacológicoRESUMEN
This paper is based on a presentation given at the Annual Meeting of the Society for the Study of Ingestive Behavior in July 2021 and provides a personal view on some of the milestones in the discovery of amylin as a constituent of pancreatic islet amyloid deposits, as a pancreatic beta-cell hormone, and on its role in physiology and pathophysiology. Only selected effects of amylin are discussed here because we recently published extensive reviews on the physiology and pathophysiology of amylin. Amylin was discovered as the main constituent of islet amyloid that is predominantly found in pancreatic islets in type 2 diabetics. These deposits, and in particular small oligomer aggregates of amylin seem to contribute to the progressive beta-cell damage seen in type 2 diabetics. Amylin is also a physiologically relevant circulating hormone with diverse metabolic functions, e.g. inhibition of eating, of pancreatic glucagon secretion and of gastric emptying. Knowledge of these types of functions and amylin's mechanisms of action lead to the development of amylin analogues that are now among the most promising anti-obesity targets in clinical testing. With this review, I want to give a short overview of 35 exciting years of amylin research.
Asunto(s)
Amiloide , Polipéptido Amiloide de los Islotes Pancreáticos , Amiloide/metabolismo , Conducta Alimentaria , Vaciamiento Gástrico/fisiología , Humanos , Polipéptido Amiloide de los Islotes Pancreáticos/metabolismo , Polipéptido Amiloide de los Islotes Pancreáticos/farmacología , ObesidadRESUMEN
PURPOSE OF REVIEW: To summarize recent developments of long-acting amylin analogues for the treatment of obesity and to outline their mode of action. RECENT FINDINGS: Amylin is a pancreatic hormone acting to control energy homeostasis and body weight. Activity at the calcitonin and amylin receptors in the area postrema seems to - at least partly - be responsible for these effects of amylin. Both preclinical and early-stage clinical studies investigating long-acting amylin receptor analogues demonstrate beneficial effects on body weight in obesity. Cagrilintide, a novel amylin analogue suitable for once-weekly administration, is in phase II clinical development and has shown promising body weight reducing effects alone and in combination with the glucagon-like peptide 1 receptor agonist semaglutide. SUMMARY: Long-acting amylin analogues have emerged as a possible pharmacotherapy against obesity, but more studies are needed to support the utility and long-term effects of this strategy in relevant populations.
Asunto(s)
Polipéptido Amiloide de los Islotes Pancreáticos , Obesidad , Peso Corporal , Humanos , Polipéptido Amiloide de los Islotes Pancreáticos/farmacología , Polipéptido Amiloide de los Islotes Pancreáticos/uso terapéutico , Obesidad/tratamiento farmacológico , Pérdida de PesoRESUMEN
The metabolic peptide hormone amylin, in concert with other metabolic peptides like insulin and leptin, has an important role in metabolic homeostasis and has been intimately linked to Alzheimer's disease (AD). Interestingly, this pancreatic amyloid peptide is known to self-aggregate much like amyloid-beta and has been reported to be a source of pathogenesis in both Type II diabetes mellitus (T2DM) and Alzheimer's disease. The traditional "gain of toxic function" properties assigned to amyloid proteins are, however, contrasted by several reports highlighting neuroprotective effects of amylin and a recombinant analog, pramlintide, in the context of these two diseases. This suggests that pharmacological therapies aimed at modulating the amylin receptor may be therapeutically beneficial for AD development, as they already are for T2DMM. However, the nature of amylin receptor signaling is highly complex and not well studied in the context of CNS function. Therefore, to begin to address this pharmacological paradox in amylin research, the goal of this review is to summarize the current research on amylin signaling and CNS functions and critically address the paradoxical nature of this hormone's signaling in the context of AD pathogenesis.
Asunto(s)
Enfermedad de Alzheimer , Diabetes Mellitus Tipo 2 , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Amiloide , Péptidos beta-Amiloides/metabolismo , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Humanos , Polipéptido Amiloide de los Islotes Pancreáticos/metabolismo , Polipéptido Amiloide de los Islotes Pancreáticos/farmacología , Polipéptido Amiloide de los Islotes Pancreáticos/uso terapéutico , Receptores de Polipéptido Amiloide de Islotes PancreáticosRESUMEN
Amylin, a 37 amino acid peptide pancreatic hormone co-secreted with insulin, normalizes the altered eating patterns induced by chronic stress in the rat. Because these stress-induced changes are driven, in part, by brain corticotropin-releasing factor and corticosterone, and because alterations in the activity of these molecules and the stress system are commonly associated with neuropsychiatric diseases like anxiety, depression, and schizophrenia, we hypothesized that amylin might mitigate behavioral states associated with stress. Therefore, we tested the effects of rat amylin in rodent-based behavioral assays sensitive to neuropsychiatric drugs, including anxiolytic, antidepressant, antipsychotic, and cognitive enhancing drugs: stress-induced hyperthermia (SIH); marble burying; elevated plus maze (EPM)), forced swim test (FST), pre-pulse inhibition, and phencyclidine-induced locomotion. To assess the neural underpinnings of amylin's anxiolytic-like effects, we examined the effect of amylin on SIH after lesioning the area postrema (AP), which mediates amylin's metabolic effects. Amylin injection (IP, 0.1, 1.0, & 10 mg/kg) significantly (P < 0.05) decreased SIH (97% below vehicle) and AP lesions inhibited this effect. Amylin also reduced marble burying (72% below vehicle), but had no effect in the EPM. Together, these effects suggest anxiolytic-like activity or potential. Amylin injection also enhanced cognitive performance in the novel object recognition test. When administered continuously by implanted osmotic pumps, amylin (300 mg/kg/d) blocked SIH when tested at 1 and 4 weeks. Compared to vehicle, amylin infusion (1 and 3 mg/kg/d) reduced the time immobile in the FST (P < 0.05; 30% below vehicle), suggesting antidepressant-like potential. Although further testing is needed, our findings support a potential for peripherally administered amylin to access and benefit pathways that regulate memory, emotion, and mood.
Asunto(s)
Ansiolíticos , Polipéptido Amiloide de los Islotes Pancreáticos , Animales , Ansiolíticos/farmacología , Área Postrema , Cognición , Ingestión de Alimentos/fisiología , Polipéptido Amiloide de los Islotes Pancreáticos/farmacología , RatasRESUMEN
Objective: Amylin acts on the lateral dorsal tegmental nucleus (LDT), resulting in anorexic and weight-loss effects and activates thermogenesis in the interscapular brown adipose tissue (IBAT). In addition, it induces neuronal nitric oxide synthase (nNOS) and choline acetyltransferase (ChAT)-mediated feeding. However, the influence of the intact sympathetic nervous system (SNS) in mediating amylin's effects has not been fully characterised. We investigated whether extracellular signal-regulated kinase (ERK), nNOS, and ChAT activities in the LDT are responsible for amylin's anorexigenic effects and whether this requires an intact SNS.Methods: C57BL/6J mice [wild-type (WT), sham, and sympathetic denervation of IBAT] were used. Food consumption, body weight, and distribution of pERK, nNOS, and ChAT positive neurons in the brain were examined following acute and chronic amylin administration.Results: Food intake was significantly decreased in WT and sham animals following acute amylin injection, but not in the denervated mice. Chronic amylin reduced body weight and serum glucose levels after 6 weeks, but increased insulin levels; no changes were observed in the denervated mice. Acute amylin increased the expression of nNOS, ChAT, and uncoupling protein-1 in the IBAT of WT and sham mice, while no changes were observed in the denervated mice and pERK from the above effect.Conclusions: Intact SNS of IBAT influences amylin-induced suppression of food intake and body weight, thus affecting nNOS and ChAT signalling in the LDT and locus coeruleus.
Asunto(s)
Tejido Adiposo Pardo , Polipéptido Amiloide de los Islotes Pancreáticos , Tejido Adiposo Pardo/metabolismo , Animales , Peso Corporal , Ingestión de Alimentos , Polipéptido Amiloide de los Islotes Pancreáticos/metabolismo , Polipéptido Amiloide de los Islotes Pancreáticos/farmacología , Ratones , Ratones Endogámicos C57BL , Sistema Nervioso SimpáticoRESUMEN
Amylin is a peptide hormone involved in the control of energy balance, making the amylin system a potential target for pharmacotherapies to treat obesity. Pramlintide, an amylin analogue, is an FDA-approved medication for the treatment of diabetes that also has food intake- and body weight-suppressive effects. However, it is unknown whether pramlintide may preferentially reduce intake of highly palatable, energy dense food, the overconsumption of which is thought to play a role in the etiology of obesity. Here, we investigate the effects of pramlintide on food intake and body weight in rats given a choice of chow and high fat diet (HFD). Systemic pramlintide injection in rats reduced HFD intake at 3h post-injection, with no effects at other times and no significant effects on chow intake, body weight, or percent preference for HFD. In a separate experiment, the effects of central injection of pramlintide on food intake and body weight were similarly evaluated. Intracerebroventricular pramlintide significantly reduced HFD intake throughout the 24h post-injection, with some suppressive effects on chow intake, and also decreased 24h body weight change. Again, no significant changes were observed in the proportion of calories obtained from HFD. The same intracerebroventricular doses of pramlintide did not induce pica, suggesting that pramlintide-mediated reductions in feeding are not due to nausea/malaise. Our results suggest that pramlintide reduces food intake in rats largely via reductions in intake of HFD versus chow, supporting the idea that the potent effects of pramlintide on palatable food intake may have utility in the treatment of obesity.
Asunto(s)
Preferencias Alimentarias , Polipéptido Amiloide de los Islotes Pancreáticos/farmacología , Animales , Dieta Alta en Grasa , Ingestión de Energía , RatasRESUMEN
A hallmark of the pancreatic hormone amylin is its high propensity toward the formation of amyloid fibrils, which makes it a challenging drug design effort. The amylin analogue pramlintide is commercially available for diabetes treatment as an adjunct to insulin therapy but requires three daily injections due to its short half-life. We report here the development of the stable, lipidated long-acting amylin analogue cagrilintide (23) and some of the structure-activity efforts that led to the selection of this analogue for clinical development with obesity as an indication. Cagrilintide is currently in clinical trial and has induced significant weight loss when dosed alone or in combination with the GLP-1 analogue semaglutide.
Asunto(s)
Desarrollo de Medicamentos , Hipoglucemiantes/farmacología , Polipéptido Amiloide de los Islotes Pancreáticos/antagonistas & inhibidores , Relación Dosis-Respuesta a Droga , Humanos , Hipoglucemiantes/síntesis química , Hipoglucemiantes/química , Polipéptido Amiloide de los Islotes Pancreáticos/síntesis química , Polipéptido Amiloide de los Islotes Pancreáticos/química , Polipéptido Amiloide de los Islotes Pancreáticos/metabolismo , Polipéptido Amiloide de los Islotes Pancreáticos/farmacología , Modelos Moleculares , Estructura Molecular , Relación Estructura-ActividadRESUMEN
Amylin aggregation is one of the factors in the development of diabetes mellitus, which is classified as a civilization disease. The aim of this research was to find whether non-aggregating fragments 1-7, 8-12, 13-17 and 28-32 of amylin would inhibit the aggregation of the amyloidogenic cores 18-22, 23-27, 33-37 of hormone. In the study of the inhibitory potential of non-aggregating amylin fragments, a set of independent methods were used to study aggregation properties (spectroscopic and fluorescence studies with the use of indicators, microscopic studies, circular dichroism studies) and the method of prediction of aggregation properties. The performed research allowed to select the cyclic fragment (1-7) H-KCNTATC-OH with disulfide bond as an inhibitor capable of inhibiting the aggregation of all amyloidogenic cores 18-22, 23-27, 33-37 of the hormone. Additionally, it was found that this peptide inhibits insulin hot spot aggregation, which may indicate its universal utility in inhibiting the process of aggregation of hormones regulating carbohydrate metabolism directly related to the development of diabetes. Research on the possibility of the extensive use of the cyclic fragment (1-7) of H-KCNTATC-OH as a peptide inhibitor of the polypeptide/protein aggregation process is ongoing.