Ketone ester administration improves glycemia in obese mice.

During periods of prolonged fasting/starvation, the liver generates ketones [i.e., ß-hydroxybutyrate (ßOHB)] that primarily serve as alternative substrates for ATP production. Previous studies have demonstrated that elevations in skeletal muscle ketone oxidation contribute to obesity-related hyperglycemia, whereas inhibition of succinyl CoA:3-ketoacid CoA transferase (SCOT), the rate-limiting enzyme of ketone oxidation, can alleviate obesity-related hyperglycemia. As circulating ketone levels are a key determinant of ketone oxidation rates, we tested the hypothesis that increases in circulating ketone levels would worsen glucose homeostasis secondary to increases in muscle ketone oxidation. Accordingly, male C57BL/6J mice were subjected to high-fat diet-induced obesity, whereas their lean counterparts received a standard chow diet. Lean and obese mice were orally administered either a ketone ester (KE) or placebo, followed by a glucose tolerance test. In tandem, we conducted isolated islet perifusion experiments to quantify insulin secretion in response to ketones. We observed that exogenous KE administration robustly increases circulating ßOHB levels, which was associated with an improvement in glucose tolerance only in obese mice. These observations were independent of muscle ketone oxidation, as they were replicated in mice with a skeletal muscle-specific SCOT deficiency. Furthermore, the R-isomer of ßOHB produced greater increases in perifusion insulin levels versus the S-isomer in isolated islets from obese mice. Taken together, acute elevations in circulating ketones promote glucose-lowering in obesity. Given that only the R-isomer of ßOHB is oxidized, further studies are warranted to delineate the precise role of ß-cell ketone oxidation in regulating insulin secretion.NEW & NOTEWORTHY It has been demonstrated that increased skeletal muscle ketone metabolism contributes to obesity-related hyperglycemia. Since increases in ketone supply are key determinants of organ ketone oxidation rates, we determined whether acute elevations in circulating ketones following administration of an oral ketone ester may worsen glucose homeostasis in lean or obese mice. Our work demonstrates the opposite, as acute elevations in circulating ketones improved glucose tolerance in obese mice.

The Antipsychotic Dopamine 2 Receptor Antagonist Diphenylbutylpiperidines Improve Glycemia in Experimental Obesity by Inhibiting Succinyl-CoA:3-Ketoacid CoA Transferase.

Despite significant progress in understanding the pathogenesis of type 2 diabetes (T2D), the condition remains difficult to manage. Hence, new therapeutic options targeting unique mechanisms of action are required. We have previously observed that elevated skeletal muscle succinyl CoA:3-ketoacid CoA transferase (SCOT) activity, the rate-limiting enzyme of ketone oxidation, contributes to the hyperglycemia characterizing obesity and T2D. Moreover, we identified that the typical antipsychotic agent pimozide is a SCOT inhibitor that can alleviate obesity-induced hyperglycemia. We now extend those observations here, using computer-assisted in silico modeling and in vivo pharmacology studies that highlight SCOT as a noncanonical target shared among the diphenylbutylpiperidine (DPBP) drug class, which includes penfluridol and fluspirilene. All three DPBPs tested (pimozide, penfluridol, and fluspirilene) improved glycemia in obese mice. While the canonical target of the DPBPs is the dopamine 2 receptor, studies in obese mice demonstrated that acute or chronic treatment with a structurally unrelated antipsychotic dopamine 2 receptor antagonist, lurasidone, was devoid of glucose-lowering actions. We further observed that the DPBPs improved glycemia in a SCOT-dependent manner in skeletal muscle, suggesting that this older class of antipsychotic agents may have utility in being repurposed for the treatment of T2D.

The GLP-1 Receptor Agonist Liraglutide Increases Myocardial Glucose Oxidation Rates via Indirect Mechanisms and Mitigates Experimental Diabetic Cardiomyopathy.

BACKGROUND: Type 2 diabetes (T2D) increases risk for cardiovascular disease. Of interest, liraglutide, a therapy for T2D that activates the glucagon-like peptide-1 receptor to augment insulin secretion, reduces cardiovascular-related death in people with T2D, though it remains unknown how liraglutide produces these actions. Notably, the glucagon-like peptide-1 receptor is not expressed in ventricular cardiac myocytes, making it likely that ventricular myocardium-independent actions are involved. We hypothesized that augmented insulin secretion may explain how liraglutide indirectly mediates cardioprotection, which thereby increases myocardial glucose oxidation. METHODS: C57BL/6J male mice were fed either a low-fat diet (lean) or were subjected to experimental T2D and treated with either saline or liraglutide 3× over a 24-hour period. Mice were subsequently euthanized and had their hearts perfused in the working mode to assess energy metabolism. A separate cohort of mice with T2D were treated with either vehicle control or liraglutide for 2 weeks for the assessment of cardiac function via ultrasound echocardiography. RESULTS: Treatment of lean mice with liraglutide increased myocardial glucose oxidation without affecting glycolysis. Conversely, direct treatment of the isolated working heart with liraglutide had no effect on glucose oxidation. These findings were recapitulated in mice with T2D and associated with increased circulating insulin levels. Furthermore, liraglutide treatment alleviated diastolic dysfunction in mice with T2D, which was associated with enhanced pyruvate dehydrogenase activity, the rate-limiting enzyme of glucose oxidation. CONCLUSIONS: Our data demonstrate that liraglutide augments myocardial glucose oxidation via indirect mechanisms, which may contribute to how liraglutide improves cardiovascular outcomes in people with T2D.

The Impact of Antidiabetic Therapies on Diastolic Dysfunction and Diabetic Cardiomyopathy.

Diabetic cardiomyopathy is more prevalent in people with type 2 diabetes mellitus (T2DM) than previously recognized, while often being characterized by diastolic dysfunction in the absence of systolic dysfunction. This likely contributes to why heart failure with preserved ejection fraction is enriched in people with T2DM vs. heart failure with reduced ejection fraction. Due to revised mandates from major health regulatory agencies, all therapies being developed for the treatment of T2DM must now undergo rigorous assessment of their cardiovascular risk profiles prior to approval. As such, we now have data from tens of thousands of subjects with T2DM demonstrating the impact of major therapies including the sodium-glucose co-transporter 2 (SGLT2) inhibitors, glucagon-like peptide-1 receptor (GLP-1R) agonists, and dipeptidyl peptidase 4 (DPP-4) inhibitors on cardiovascular outcomes. Evidence to date suggests that both SGLT2 inhibitors and GLP-1R agonists improve cardiovascular outcomes, whereas DPP-4 inhibitors appear to be cardiovascular neutral, though evidence is lacking to determine the overall utility of these therapies on diastolic dysfunction or diabetic cardiomyopathy in subjects with T2DM. We herein will review the overall impact SLGT2 inhibitors, GLP-1R agonists, and DPP-4 inhibitors have on major parameters of diastolic function, while also highlighting the potential mechanisms of action responsible. A more complete understanding of how these therapies influence diastolic dysfunction will undoubtedly play a major role in how we manage cardiovascular disease in subjects with T2DM.

Pimozide Alleviates Hyperglycemia in Diet-Induced Obesity by Inhibiting Skeletal Muscle Ketone Oxidation.

Perturbations in carbohydrate, lipid, and protein metabolism contribute to obesity-induced type 2 diabetes (T2D), though whether alterations in ketone body metabolism influence T2D pathology is unknown. We report here that activity of the rate-limiting enzyme for ketone body oxidation, succinyl-CoA:3-ketoacid-CoA transferase (SCOT/Oxct1), is increased in muscles of obese mice. We also found that the diphenylbutylpiperidine pimozide, which is approved to suppress tics in individuals with Tourette syndrome, is a SCOT antagonist. Pimozide treatment reversed obesity-induced hyperglycemia in mice, which was phenocopied in mice with muscle-specific Oxct1/SCOT deficiency. These actions were dependent on pyruvate dehydrogenase (PDH/Pdha1) activity, the rate-limiting enzyme of glucose oxidation, as pimozide failed to alleviate hyperglycemia in obese mice with a muscle-specific Pdha1/PDH deficiency. This work defines a fundamental contribution of enhanced ketone body oxidation to the pathology of obesity-induced T2D, while suggesting pharmacological SCOT inhibition as a new class of anti-diabetes therapy.

Cardiovascular biology of the GIP receptor.

Glucose-dependent insulinotropic polypeptide (GIP) is a gut hormone secreted primarily from enteroendocrine K cells in the duodenum and proximal jejunum following nutrient ingestion, primarily acting on islet ß-cells to potentiate insulin secretion in a glucose-dependent manner. New discoveries of GIP receptor (GIPR) biology in adipose tissue, as well as findings that co-agonists for the glucagon-like peptide-1 receptor (GLP-1R) and GIPR induce greater weight loss than that seen with GLP-1R agonists alone, has led to continued interest in manipulating GIPR activity for the treatment of obesity/type 2 diabetes mellitus (T2DM). As cardiovascular diseases represent the number one cause of death in people with T2DM, there has also been growing interest in understanding the cardiovascular actions of the GIP/GIPR axis. Although controversy surrounds whether GIPR agonism or antagonism will induce weight loss in obesity/T2DM, such actions undoubtedly will impact cardiovascular function and outcomes since obesity is a major risk factor for cardiovascular disease. Furthermore, GIPR agonism is associated with reduced progression of atherosclerotic lesions in preclinical studies. Conversely, genetic deletion of GIPR activity within cardiac myocytes of the heart results in robust protection against experimental myocardial infarction. Nonetheless, interrogation of the GIP/GIPR axis on cardiac function in humans will involve the systemic actions of the GIPR within the myocardium and other systems (e.g. adipose tissue, vasculature), which will influence the long-term future of GIPR modification for the treatment of obesity/T2DM.

[Importance and distribution of serological findings of ornithosis-psittacosis in semi-domestic pigeons]. / Importance et répartition de la réponse sérologique de l'ornithose-psittacose chez des pigeons semi-domestiques.

Ornithosis-psittacosis is a widely distributed disease in birds throughout the world. A serological study by the complement-fixation test and a few isolation of Chlamyqia were performed on feral pigeon population of Antwerpen city. The incidence of positive cases in Antwerpen averages 58.51 %. For each serum, a serological index (S. I.) was calculated with regard to the intensity of immunological response in different dilutions: S. I. seems to suggest an endemic status of the disease in Antwerpen. Evolution in time of the prevalence and the serological response shows the presence of two peaks: the first one in spring and the last one in summer. This might be explained by some factors influencing the transmission of the infection: between them, one must emphasize the pigeons habits and the ectoparasites.

Physiological and morphological characters in two pyrimethamine-resistant lines of Plasmodium berghei SP11 after cryopreservation.

The authors describe the characters in two pyrimethamine-resistant lines of Plasmodium berghei berghei SP 11-RR after long storage at very low temperatures. In one case the line had maintained its original virulence but lost its resistance to pyrimethamine. Gametocytogenesis increased and cyclical transmission was successful. Furthermore, parasites crossed the blood-brain barrier and provoked cerebral malaria. In the other case no physiological changes could be detected. The authors conclude that, after cryopreservation, biological behaviour should always be carefully observed.

[Study of chromosome characteristics of artificially-induced ascite tumors]. / Etude des caractéristiques chromosomiques de tumeurs d'ascites induites artificiellement

Some ascite tumours have been induced in rat by intraperitoneal injection of RadLV and in mouse by intraperitoneal injection of RadLV, or of protozoa such as Trypanosoma brucei and Toxoplasma gondii. Cytological examination of the resulting ascite tumours has shown that chromosome aberrations were associated with the presence of C and A viral particles.