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Background: There are many hypotheses about the neuropathological origin of sporadic Alzheimer’s disease (AD). The amyloid cascade hypothesis remains the most widely accepted by the scientific community, although the role of amyloid-β (Aβ) as the sole cause of neuropathological features of the non-inherited form of AD is questionable. Methods: The 5xFAD mouse model shows amyloid plaques formation and cognitive impairment from 4 months of age. However, no attention is paid to the effect of genetic load, heterozygous (HTZ) versus homozygous (HZ) condition, on the behaviour, histology, metabolic physiology, and composition of gut microbiota. We studied the phenotype of HTZ and HZ mice of both sexes at 4-6 months (early disease onset) and 10-12 months of age (late disease onset). Results: We described that from 4-6 months old, both HTZ and HZ mice exhibited hippocampal impairment caused by accumulation of Aβ40 and Aβ42, increased neuroinflammatory markers and altered PI3K-Akt pathway. However, only HZ mice showed cognitive impairment in the Y-maze test and the Morris water maze. In addition, dysregulation of insulin-linked metabolic pathways was detected at the peripheral level between HTZ and HZ mice. This striking difference between behavioural, immunopathological and physiological phenotypes extends to the microbiota in terms of Firmicutes/Bacteroidetes ratio, being most pronounced in HZ mice at 10-12 months old. Conclusions: Taken together, our results suggest that Aβ aggregation may not be the sole cause of worsening cognitive impairment, but that other factors such as PI3K-Akt, insulin-linked metabolic pathways, and microbiota composition could be influencing disease progression, allowing for alternative disease-modifying interventions.

The present study characterizes the oral pharmacokinetics of D-Pinitol, a natural insulin mimetic inositol, in human healthy volunteers (14 males and 11 females). D-Pinitol absorption was studied in (a) subjects receiving a single oral dose of 15 mg/kg (n = 10), or (b) 5 mg/kg pure D-Pinitol (n = 6), and (c) subjects receiving D-Pinitol as part of carbohydrate-containing carob pods-derived syrup with a 3.2% D-Pinitol (Dose of 1600 mg/subject, n = 9). The volunteers received a randomly assigned single dose of either D-Pinitol or carob pod-derived syrup. Blood samples were collected at 0, 15, 30, 45, 60, 90, 120, 180, 240, 360 and 1440 min after intake. Plasma concentration of D-Pinitol was measured and pharmacokinetic parameters obtained. The data indicate that when given alone, the oral absorption of D-Pinitol is dose-dependent and of extended duration, with a Tmax reached after almost 4 h, and a half-life greater than 5 h. When the source of D-Pinitol was a carob pods-derived syrup, Cmax was reduced to 40% of the expected based on the data of D-Pinitol alone, suggesting a reduced absorption probably because of competition with monosaccharide transport. In this group, Tmax was reached before that of D-Pinitol alone, but the estimated half-life remained the same. In the D-Pinitol groups, plasma concentrations of glucose, insulin, glucagon, ghrelin, free fatty acids, and pituitary hormones were additionally measured. A dose of 15 mg/kg of D-Pinitol did not affect glucose levels in healthy volunteers, but reduced insulin and increased glucagon and ghrelin concentrations. D-Pinitol did not increase other hormones known to enhance plasma glucose, such as cortisol or GH, which were surprisingly reduced after the ingestion of this inositol. Other pituitary hormones (gonadotropins, prolactin, and thyroid-stimulating hormone) were not affected after D-Pinitol ingestion. In a conclusion, D-Pinitol is absorbed through the oral route, having an extended half-life and displaying the pharmacological profile of an endocrine pancreas protector, a pharmacological activity of potential interest for the treatment or prevention of insulin resistance-associated conditions.

18 Pág. Departamento de Reproducción animal., Recent evidence links brain insulin resistance with neurodegenerative diseases, where hyperphosphorylated tau protein contributes to neuronal cell death. In the present study, we aimed to evaluate if d-pinitol inositol, which acts as an insulin sensitizer, affects the phosphorylation status of tau protein., This research was funded by the European Regional Development Funds-European Union (ERDF-EU), FATZHEIMER project (EU-LAC HEALTH 2020, 16/T010131), “Una manera de hacer Europa”; Ministerio de Economía, Industria y Competitividad, Gobierno de España, Programa Estatal de Investigación, Desarrollo e Innovación Orientada a los Retos de la Sociedad (RTC-2016-4983-1); ERDF-EU-Instituto de Salud Carlos III (ISCIII), Proyectos de investigación en salud (PI19/01577); Consejería de Salud y Familias, Junta de Andalucía, Proyecto de Investigación en Salud (PI-0139-2018); Consejería de Economía, Conocimiento y Universidad, Junta de Andalucía, Plan Andaluz de Investigación, Desarrollo e Innovación (P18-TP-5194); Delegación del Gobierno para el Plan Nacional sobre Drogas, Ministerio de Salud, Gobierno de España (PND2020/048). D.M-V. (FI20/00227) holds a “PFIS” predoctoral contract from the National System of Health, ERDF-EU-Instituto de Salud Carlos III. A.J.L.-G. (IFI18/00042) holds an “iPFIS” predoctoral contract from the National System of Health, ERDF-EU-ISCIII. P.R. (CP19/00068), F.J.P. (CPII19/00022) and J.D. (CP21/00021) hold a “Miguel Servet” research contract from the National System of Health, ISCIII co-funded by European Social Fund, “Investing in your future,” Gobierno de España.

Peptidic agonists of the glucagon-like peptide-1 receptor (GLP-1R) have gained a prominent role in the therapy of type-2 diabetes and are being considered for reducing food intake in obesity. Potential advantages of small molecules acting as positive allosteric modulators (PAMs) of GLP-1R, including oral administration and reduced unwanted effects, could improve the utility of this class of drugs. Here, we describe the discovery of compound 9 (4- {[1-({3-[4-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-5-yl}methyl)- piperidin-3-yl]methyl}morpholine, V-0219) that exhibits enhanced efficacy of GLP-1R stimulation, subnanomolar potency in the potentiation of insulin secretion, and no significant off-target activities. The identified GLP-1R PAM shows a remarkable in vivo activity, reducing food intake and improving glucose handling in normal and diabetic rodents. Enantioselective synthesis revealed oral efficacy for (S)-9 in animal models. Compound 9 behavior bolsters the interest of a small-molecule PAM of GLP-1R as a promising therapeutic approach for the increasingly prevalent obesity-associated diabetes.