Dietary administration of D-chiro-inositol attenuates sex-specific metabolic imbalances in the 5xFAD mouse model of Alzheimer’s disease

Increasing evidence shows that hypothalamic dysfunction, insulin resistance, and weight loss precede and progress along with the cognitive decline in sporadic Alzheimer’s Disease (AD) with sex differences. This study aimed to determine the effect of oral dietary administration of D-Chiro-inositol (DCI), an inositol used against insulin resistance associated with polycystic ovary, on the occurrence of metabolic disorders in the transgenic 5xFAD mouse model of AD (FAD: Family Alzheimer's Disease). DCI was administered from 6 to 10 months of age to male and female 5xFAD mice and control (non-Tg) littermates. Energy balance and multiple metabolic and inflammatory parameters in the hypothalamus, liver and plasma were evaluated to assess the central and peripheral effects of DCI. Results indicated that weight loss and reduced food intake in 5xFAD mice were associated with decreased neuropeptides controlling food intake and the appearance of a pro-inflammatory state in the hypothalamus. Oral administration of DCI partially restored energy balance and hypothalamic parameters, highlighting an increased expression of Npy and Agrp and female-specific downregulation of Gfap and Igf1. DCI also partially normalized impaired insulin signaling and circulating insulin, GLP-1, and GIP deficiencies in 5xFAD mice. Principal component analysis of metabolic parameters indicated the presence of a female-specific fatty liver in 5xFAD mice: DCI administration reversed hepatic fat accumulation, β-oxidation, inflammation and increased GOT and GPT levels. Our study depicts that metabolic impairment along with the cognitive decline in a mouse model of AD, which is exacerbated in females, can be ameliorated by oral supplementation with insulin-sensitizing DCI.This research was funded by the European Regional Development Funds-European Union (ERDF-EU) and Fatzheimer project EULAC-HEALTH H2020, grant number EU-LACH16/T010131; Ministerio de Economía, Industria y Competitividad, Gobierno de España, grant number RTC-2016-4983-1; EU-ERDF and Instituto de Salud Carlos III (ISCIII), grant numbers PI19/01577 and PI19/00343; Ministerio de Sanidad, Delegación de Gobierno para el Plan Nacional sobre Drogas, grant numbers 2019/040 and 2020/048; Consejería de Transformación Económica, Industria, Conocimiento y Universidades, Junta de Andalucía, grant number P18-TP-5194, INSERM (Institut National de la Santé et de la Recherche Médicale), Nouvelle Aquitaine Region and ANR (grant numbers ANR-18-CE14-0029 MitObesity, Labex BRAIN ANR-10-LABX-43, ANR-10-EQX-008-1 OPTOPATH, ANR-17-CE14-0007 BABrain, ANR-21-CE14-0018-01_StriaPOM to D.C.). A.J.L.-G. (IFI18/00042) holds an “iPFIS” predoctoral contract from the National System of Health, EU-ERDF-ISCIII. B.P.S (IFI21/00024) holds an “iPFIS” predoctoral contract from the National System of Health, EU-ERDF-ISCIII. P.R. (CP19/00068) holds a ‘’Miguel Servet I” research contract from the National System of Health, EU-ERDF-ISCIII. D.M-V. (FI20/00227) holds a “PFIS” pre-doctoral contract from the National System of Health, EU-ERDF-ISCIII. The microscopy for IBA1 and GFAP immunofluorescence was done in the Bordeaux Imaging Center, a service unit of the CNRS-INSERM and Bordeaux University, member of the national infrastructure France BioImaging supported by the LabEX BRAIN and ANR-10-INBS-04. Partial funding for open access charge: Universidad de Málaga

Glucose-lowering interventions and risk assessment in patients with coronary heart disease and disturbed glucose metabolism

Background Abnormal glucose regulation (AGR) including impaired glucose tolerance (IGT) and diabetes mellitus type 2 (T2DM) are common in patients with stable and unstable coronary artery disease (CAD) and impair their prognosis. Available glucose lowering interventions have not fully succeeded in improving the detrimental prognosis and accurate screening methods and new treatment strategies are needed. The aims of this thesis were to 1. decrease the restenosis rate after percutaneous coronary intervention (PCI) in patients with T2DM 2. validate the oral glucose tolerance test (OGTT) for the detection of glucose disturbances in patients with acute coronary syndromes (ACS) 3. evaluate the accuracy of a technique for continuous glucose monitoring in patients in the coronary care unit (CCU) 4. improve beta-cell function in patients with ACS and newly detected AGR Restenosis in patients with T2DM (Study I) The restenosis rate six months after PCI was investigated in 93 patients with T2DM randomised to either intensive glucose control by means of insulin (I group; n=44) or to continue ongoing glucoselowering treatment (C group; n=49). At the end of the follow-up period restenosis rate was available in 82 patients. The glucose control did not differ between the two groups (change in HbA1c -0.2 vs.-0.1%; p=0.3 and in fasting blood glucose +0.2 vs. -0.3 mmol/L; p=0.3 in the I and C groups). The restenosis rate was 41% in the I and 44% in the C group (p=0.8). Independent predictors for restenosis were previous myocardial infarction (OR 8.0, 95% CI 2.5–25.7; p<0.001) and fasting blood glucose at baseline (OR 1.4, 95% CI 1.1–1.9; p=0.015). Screening for glucose abnormalities in ACS (Studies II and III) The value of an OGTT for screening of unknown AGR in patients with ACS was explored. Infarct size did not influence the result but patients with transmural myocardial infarctions (MI) (n=70) had higher glucose levels at admission and fasting during the next two days (7.0, 5.7, 5.4 mmol/L) compared to those with subendocardial MI (n=102; 6.0, 5.3, 5.0 mmol/L; p<0.001, p=0.01, p=0.004; Study II). More patients were classified as T2DM according to OGTT (n=27) compared to fasting plasma glucose (n=10) and HbA1c (n=2; Study III). Continuous glucose monitoring in the coronary care unit (Study IV) The accuracy of an intravenously inserted microdialysis catheter intended for continuous glucose monitoring was validated in 14 patients in a CCU setting. Although predominantly delivering correct values, the stability over time was insufficient. Thus the microdialysis technique requires further improvements to be useful in this setting. Beta-cell function in ACS (Study V) The effect of a DPP-IV inhibitor on beta-cell function, expressed as insulinogenic index (IGI) and acute insulin response to glucose (AIRg), in patients with ACS and newly discovered AGR was investigated by randomising 34 such patients to sitagliptin (S) and 37 to placebo (P). After 12 weeks of treatment the IGI improved in the sitagliptin group (S: 69.9 to 85.0 vs. P: 66.4 to 58.1 pmol/mmol; p=0.019) as did the AIRg (S:1394 to 1909 vs. P:1106 to 1043 pmol • l-1 • min-1; p<0.0001). Insulin resistance remained unaffected. Conclusion It is difficult to achieve glucose normalisation in patients with T2DM and CAD by means of available drugs. Early detection of AGR in patients with ACS is essential and an OGTT is a useful tool. New technology in the form of equipment for continuous glucose monitoring and novel treatment strategies e.g. DPP-IV inhibitors deserves further attention in attempts to improve the management and thereby prognosis in this vulnerable patient category

Annual report of the officers of the town of Meredith year ending January 31, 1933.

This is an annual report containing vital statistics for a town/city in the state of New Hampshire

Current insights on the use of insulin and the potential use of insulin mimetics in targeting insulin signalling in Alzheimer’s disease

Alzheimer’s disease (AD) and type 2 diabetes (T2D) are chronic diseases that share several pathological mechanisms, including insulin resistance and impaired insulin signalling. Their shared features have prompted the evaluation of the drugs used to manage diabetes for the treatment of AD. Insulin delivery itself has been utilized, with promising effects, in improving cognition and reducing AD related neuropathology. The most recent clinical trial involving intranasal insulin reported no slowing of cognitive decline; however, several factors may have impacted the trial outcomes. Long-acting and rapid-acting insulin analogues have also been evaluated within the context of AD with a lack of consistent outcomes. This narrative review provided insight into how targeting insulin signalling in the brain has potential as a therapeutic target for AD and provided a detailed update on the efficacy of insulin, its analogues and the outcomes of human clinical trials. We also discussed the current evidence that warrants the further investigation of the use of the mimetics of insulin for AD. These small molecules may provide a modifiable alternative to insulin, aiding in developing drugs that selectively target insulin signalling in the brain with the aim to attenuate cognitive dysfunction and AD pathologies

Complex Pharmacology of Free Fatty Acid Receptors

G protein-coupled receptors (GPCRs) are historically the most successful family of drug targets. In recent times it has become clear that the pharmacology of these receptors is far more complex than previously imagined. Understanding of the pharmacological regulation of GPCRs now extends beyond simple competitive agonism or antagonism by ligands interacting with the orthosteric binding site of the receptor to incorporate concepts of allosteric agonism, allosteric modulation, signaling bias, constitutive activity, and inverse agonism. Herein, we consider how evolving concepts of GPCR pharmacology have shaped understanding of the complex pharmacology of receptors that recognize and are activated by nonesterified or “free” fatty acids (FFAs). The FFA family of receptors is a recently deorphanized set of GPCRs, the members of which are now receiving substantial interest as novel targets for the treatment of metabolic and inflammatory diseases. Further understanding of the complex pharmacology of these receptors will be critical to unlocking their ultimate therapeutic potential

Regional Intestinal Drug Absorption

The gastrointestinal tract (GIT) can be broadly divided into several regions: the stomach, the small intestine (which is subdivided to duodenum, jejunum, and ileum), and the colon. The conditions and environment in each of these segments, and even within the segment, are dependent on many factors, e.g., the surrounding pH, fluid composition, transporters expression, metabolic enzymes activity, tight junction resistance, different morphology along the GIT, variable intestinal mucosal cell differentiation, changes in drug concentration (in cases of carrier-mediated transport), thickness and types of mucus, and resident microflora. Each of these variables, alone or in combination with others, can fundamentally alter the solubility/dissolution, the intestinal permeability, and the overall absorption of various drugs. This is the underlying mechanistic basis of regional-dependent intestinal drug absorption, which has led to many attempts to deliver drugs to specific regions throughout the GIT, aiming to optimize drug absorption, bioavailability, pharmacokinetics, and/or pharmacodynamics. In the book "Regional Intestinal Drug Absorption: Biopharmaceutics and Drug Formulation" we aim to highlight the current progress and to provide an overview of the latest developments in the field of regional-dependent intestinal drug absorption and delivery, as well as pointing out the unmet needs of the field