Reduced Plasma Glucose Concentrations Research Articles

Adding fasting-mimicking diet to first-line carboplatin-based chemotherapy is associated with better overall survival in advanced triple-negative breast cancer patients: A subanalysis of the NCT03340935 trial.

Severe calorie restriction, in the form of cyclic fasting or fasting-mimicking diets (FMDs), boosts the antitumor activity of cytotoxic chemotherapy in mouse models of triple-negative breast cancer (TNBC). This effect is mostly mediated by fasting/FMD-induced reduction of plasma glucose concentration and by a boost in antitumor immunity. However, clinical evidence that cyclic FMD may impact on the outcomes of advanced TNBC (aTNBC) patients is lacking. We compared the overall survival (OS) of 14 aTNBC patients receiving first-line carboplatin-gemcitabine plus cyclic FMD in the context of the NCT03340935 trial with the OS of 76 consecutive aTNBC patients treated with carboplatin-based chemotherapy alone at Fondazione IRCCS Istituto Nazionale dei Tumori. Multivariable Cox regression models were used to adjust the prognostic impact of FMD for other prognostic variables. Patients undergoing cyclic FMD in combination with carboplatin-gemcitabine had better OS when compared to patients receiving chemotherapy alone (median OS 30.3 months, 95% CI 18-NR, vs 17.2 months, 95% CI 15.3-25.1, log-rank P value .041). Multivariable analysis confirmed an association between FMD use and better OS (HR: 0.40; 95% CI: 0.19-0.86; P = .019) also after propensity score-based matching according to patient ECOG PS and the presence of de novo metastatic disease (HR: 0.41; 95% CI: 0.21-0.83; P = .013). Cyclic FMD in combination with first-line chemotherapy may improve clinical outcomes in aTNBC patients. Our study paves the way for conducting phase II trials to investigate if cyclic FMD can increase the antitumor activity/efficacy of chemotherapy or chemoimmunotherapy in patients with early-stage TNBC or aTNBC.

Diabetes Mellitus: A Review

Diabetes mellitus (DM), or simply diabetes, is a group of metabolic diseases in which a person has high blood sugar, either because the body does not produce enough insulin, or because cells do not respond to the insulin that is produced. This high blood sugar produces the classical symptoms of polyuria (frequent urination), polydipsia (increased thirst) and polyphagia (increased hunger). Conventionally, diabetes has been divided into three types namely: Type 1 DM or insulin-dependent diabetes mellitus (IDDM) in which body fails to produce insulin, and presently requires the person to inject insulin or wear an insulin pump. This is also termed as "juvenile diabetes". Type 2 DM or non insulin-dependent diabetes mellitus (NIDDM), results from insulin resistance, a condition in which cells fail to use insulin properly, with or without an absolute insulin deficiency. This type was previously referred to as or "adult-onset diabetes". The third main type is gestational diabetes which occurs when women without a previous history of diabetes develop a high blood glucose level during her pregnancy. It may precede development of type 2 DM. Currently available pharmacotherapy for the treatment of diabetes mellitus includes insulin and oral hypoglycemic agents. Such drugs acts by either increasing the secretion of insulin from pancreas or reducing plasma glucose concentrations by increasing glucose uptake and decreasing gluconeogenesis. However these current drugs do not restore normal glucose homeostasis for longer period and they are not free from side effects such as hypoglycemia, kidney diseases, GIT problems, hepatotoxicity, heart risk problems, insulinoma and they have to take rest of life. Various herbal drugs have been also proved effective due to their beneficial contents in treatment of diabetes. The present review therefore is an attempt to focus on the physiological aspects of diabetes, its complications, goals of management, and synthetic and herbal treatment of diabetes.

Impacts of feeding a Saccharomyces cerevisiae fermentation product on productive performance, and metabolic and immunological responses during a feed-restriction challenge of mid-lactation dairy cows.

Saccharomyces cerevisiae fermentation products are commonly used in dairy cattle ration to improve production efficiency and health. However, whether these benefits will persist during feed-restriction-induced negative energy balance is unknown. The objective of this experiment was to examine the effect of a Saccharomyces cerevisiae fermentation product (NT, NutriTek, Diamond V) on performance, metabolic, inflammatory, and immunological responses to a feed-restriction challenge in mid-lactation dairy cows. Sixty Holstein cows were blocked by parity, days in milk, and milk yield and then randomly assigned to 1 of the 2 supplements: NT or placebo (CTL). The supplements were mixed in total mixed ration before feeding at a rate of 19 g/d per cow. The production phase of the experiment lasted 12 wk. Intake and milk yield were recorded daily, and milk composition was measured weekly. After the production trial, a subset of cows (NT: n = 16; CTL: n = 16) were immediately enrolled in a 5-d feed-restriction challenge with 40% ad libitum intake followed by a 5-d realimentation. Milk yield and composition were measured at each milking from d -2 to 10 relative to feed restriction. Blood samples were collected on d -2, -1, 1, 2, 3, 4, 5, 6, 8, and 10 relative to the initiation of feed restriction to measure circulating metabolites, insulin, cortisol, IL-10, tumor necrosis factor-α, lipopolysaccharide binding protein, and haptoglobin. Immune function assessments, including peripheral mononuclear cell proliferation and functional assays of circulating granulocytes, were performed on d -3 and 4 of the feed restriction. No differences were observed in dry matter intake, milk yield, or concentrations or yield of components except for fat yield. An interaction of parity and treatment was observed for milk fat yield that was lower for CTL than NT in primiparous cows, but no differences were observed among treatments in milk fat yield of multiparous cows. Feed restriction successfully induced negative energy balance and its associated metabolic changes, including reduced concentrations of plasma glucose and increased nonesterified fatty acids and β-hydroxybutyrate. Cows fed NT had a similar decrease in milk yield but had a more pronounced reduction in plasma glucose concentration and greater β-hydroxybutyrate concentration during feed restriction than those fed CTL. Feed restriction did not induce evidence of systemic inflammation but did reduce granulocyte functional activity. Compared with CTL, feeding NT improved the reactive oxygen species production by granulocytes after stimulation by extracellular antigens. In conclusion, feeding NT increased milk fat production of first-lactation cows but did not affect overall productive performance. However, supplementation with NT improved induced granulocyte oxidative burst. This may explain the greater glucose utilization by cows fed NT rather than CTL during feed restriction.

Metformin, phenformin, and galegine inhibit complex IV activity and reduce glycerol-derived gluconeogenesis.

SignificanceMetformin is the most commonly prescribed drug for the treatment of type 2 diabetes mellitus, yet the mechanism by which it lowers plasma glucose concentrations has remained elusive. Most studies to date have attributed metformin's glucose-lowering effects to inhibition of complex I activity. Contrary to this hypothesis, we show that inhibition of complex I activity invitro and invivo does not reduce plasma glucose concentrations or inhibit hepatic gluconeogenesis. We go on to show that metformin, and the related guanides/biguanides, phenformin and galegine, inhibit complex IV activity at clinically relevant concentrations, which, in turn, results in inhibition of glycerol-3-phosphate dehydrogenase activity, increased cytosolic redox, and selective inhibition of glycerol-derived hepatic gluconeogenesis both invitro and invivo.

Sodium-glucose cotransporter 2inhibitors: apractical guide for the Dutch cardiologist based on real-world experience.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors include a relatively new class of glucose-lowering drugs that reduce plasma glucose concentrations by inhibiting proximal tubular reabsorption of glucose in the kidney, while increasing its excretion in urine. Recent large randomised controlled trials have demonstrated that many of these agents reduce the occurrence of major adverse cardiovascular events, hospitalisation for heart failure, cardiovascular death and/or chronic kidney disease progression in patients with and without type 2 diabetes mellitus (DM2). Given their unique insulin-independent mode of action and favourable efficacy and adverse-event profile, SGLT2 inhibitors are promising and they offer an interesting therapeutic approach for the cardiologist to incorporate into routine practice. However, despite accumulating data supporting this class of therapy, cardiologists infrequently prescribe SGLT2 inhibitors, potentially due to a lack of familiarity with their use and the reticence to change DM medication. Here, we provide an up-to-date practical guide highlighting important elements of treatment initiation based on real-world evidence and expert opinion. We describe how to change DM medication, including insulin dosing when appropriate, and how to anticipate any adverse events based on real-world experience in patients with DM2 in the Meander Medical Centre in Amersfoort, the Netherlands. This includes a simple algorithm showing how to initiate SGLT2 inhibitor treatment safely, while considering the consequence of the glucosuric effects of these inhibitors for the individual patient.Supplementary InformationThe online version of this article (10.1007/s12471-021-01580-9) contains supplementary material, which is available to authorized users.

Pharmacoeconomic evaluation of ipragliflozin in combination with metformin in comparison with other regimens of therapy for type 2 diabetes mellitus

Ipragliflozin is a selective sodium-glucose cotransporter 2 (SGLT2) inhibitor that reduce plasma glucose concentrations by inhibiting glucose reabsorption by the kidney through inhibiting SGLT2 sodium-glucose cotransporter and induce glycosuria. SGLT2 inhibitors are a new class of glucose lowering drugs most recently approved for treatment of type 2 diabetes mellitus (T2DM). Unlike other antidiabetic agents, SGLT2 inhibitors improve glycemic control (by HbA1c) and provide multiple additional benefits, including decreased body weight, blood pressure, and other multiple pleiotropic effects. The completed clinical trials and real world data have provided evidence that including of SGLT2 inhibitors in the treatment of T2DM has benefits of reduction of cardiovascular and renal outcomes. Goal. The aim of the study was to conduct a clinical and economic examination of ipragliflozin in comparison with other regimens of glucose-lowering therapy with other SGLT2 inhibitors. Methods. In carrying out the pharmacoeconomic analysis itself, a cost-effectiveness analysis (CEA) was applied with the calculation of the corresponding cost-effectiveness ratio (CER), incremental cost-effectiveness ratio (ICER) according to the formula, as well as an a «budget impact analysis». Multiple one-way sensitivity analysis, check the robustness of the results of the main scenario results to changes in key parameters such as the cost of drugs and complications of diabetes. The time horizon for analyzing the dynamics of economic consequences when using ipragliflozin as a glucose-lowering therapy for T2DM was 5 years. Results. The weighted average cost per patient per year when using the ipragliflozin treatment strategy is 31,182 rubles. The costs of the empagliflozin strategy are 61,291 rubles per patient. In the case of using dapagliflozin, the weighted average costs are 30,032 rubles per patient per year, the total direct medical costs for the current drug therapy option, calculated on the initial number of target practice in 72,143 patients with type 2 diabetes, amounted to 3,068,642,442 rubles. Analysis of the trend of changes in weighted average costs showed that the broader use of ipragliflozin for the treatment of T2DM in the target population leads to reducing in diabetes related direct medical costs by 6.7 %, while the total economic effect of ipragliflozin introduction over five years will be 501,539,327 rubles. Conclusions. Use of ipragliflozin + metformin in T2DM treatment is a cost-effective strategy compared to empagliflozin + metformin. The combination of ipragliflozin with metformin versus dapagliflozin + metformin is economically feasible in terms of cost-effectiveness.

Structure and hypoglycemic activity of a novel exopolysaccharide of Cordyceps militaris

A novel neutral exopolysaccharide (EPS-III) was isolated from culture broth of Cordyceps militaris (C. militaris). The EPS-III was a homogeneous polysaccharide with Mw of 1.56 × 103 kDa. The yield of EPS-III from culture broth was 123.2 ± 3.1 mg/L and the sugar content was 93.32 ± 0.87%. The backbone of EPS-III was mainly consisted of →4)-α-D-Galp-(1→, while →3, 6)-α-D-Manp-(1→, →4)-α-D-Manp-(1→, →3)-β-D-Galp-(1→ and →3)-α-D-Glcp-(1→ were distributed in the backbone or in the branch chains. The EPS-III had helix structure when dissolved in weak alkaline solution. It also had branched and intertwined form on the surface. The inhibition of α-glucosidase significantly increased as the increase of purity of exopolysaccharides. The EPS-III had effective inhibition on the α-glucosidase with dose-effect relationship. Besides, the results of hypoglycemic activity analysis in vivo indicated that EPS-III can alleviate weight loss, reduce plasma glucose concentration, improve glucose tolerance, protect immune organs and repair dyslipidemia to relieve diabetes in STZ-induced diabetic mice. The manuscript first studied the hypoglycemic activity of exopolysaccharide of by C. militaris, proving and promoting the application value of culture broth. The structure characterization of EPS-III laid experimental foundations on the exploration of structure-activity relationship.

Postprandial Effect of Yogurt Enriched with Anthocyanins from Riceberry Rice on Glycemic Response and Antioxidant Capacity in Healthy Adults.

The pigment of riceberry rice has been reported to contain anthocyanins which act as a free radical scavenger and inhibitor of carbohydrate digestive enzymes. Since the probiotic yogurt incorporated with the pigment of riceberry rice extract was previously developed, the present study was aimed to investigate the acute effect of riceberry rice yogurt consumption on postprandial glycemic response, antioxidant capacity, and subjective ratings in healthy adults. In a cross-over design, 19 healthy participants were randomized to consume 350 g of yogurt supplemented with 0.25% (w/w) riceberry rice extract or the control yogurt. Postprandial plasma glucose, antioxidant status, and subjective ratings were measured at fasting and intervals (0–3 h) after ingestion of yogurt. The primary outcome was glycemic response; the secondary outcomes were plasma antioxidant capacity. In comparison to the yogurt control, riceberry rice yogurt reduced plasma glucose concentration after 30 min of consumption. The incremental area under the curve (iAUC) was significantly lower after riceberry rice yogurt load than after the control yogurt load. The consumption of riceberry yogurt caused an acute increase in plasma ferric reducing ability of plasma (FRAP), Trolox equivalent antioxidant capacity (TEAC), and oxygen radical absorbance capacity (ORAC) from the baseline values after 60 min of 0.25 ± 0.06 mM FeSO4, 253.7 ± 35.5 mM Trolox equivalents, and 166.8 ± 28.9 mM Trolox equivalents, respectively. Furthermore, the iAUCs for FRAP, TEAC, ORAC, and protein thiol were higher in riceberry yogurt consumption compared with the control yogurt (1.6-, 1.6-, 2.9-, and 1.9-fold, respectively). A decrease in iAUC for plasma malondialdehyde (MDA) concentration was also observed in the riceberry yogurt group. However, consumption of riceberry rice yogurt and control yogurt showed similar subjective rating scores of hunger, desire to eat, fullness, and satiety. In conclusion, acute consumption of riceberry rice yogurt suppressed postprandial glucose level and improved plasma antioxidant capacity in healthy volunteers.

Improvement of skeletal muscle insulin sensitivity by 1 week of SGLT2 inhibitor use.

Background and Aims:It is currently unclear whether sodium–glucose co-transporter 2 (SGLT2) inhibitor administration can improve the insulin sensitivity as well as rapidly reduce plasma glucose concentrations in humans during the early phase of treatment initiation. This study aimed to investigate the effect of SGLT2 inhibitor on insulin sensitivity in the early phase of treatment initiation.Methods and ResultsThis single-center, open label, and single-arm prospective study recruited 20 patients (14 men) with type 2 diabetes mellitus (T2DM). We examined the patients’ metabolic parameters before and 1 week after SGLT2 inhibitor (10 mg/day of empagliflozin) administration. The glucose infusion rate (GIR) was evaluated using the euglycemic hyperinsulinemic glucose clamp technique. Changes in laboratory and anthropometric parameters before and after SGLT2 inhibitor administration were analyzed according to the change in the GIR. The BMI, body fat amount, skeletal muscle amount, systolic blood pressure, and triglyceride level significantly decreased along with the treatment, while urinary glucose level and log GIR value significantly increased. Notably, changes in the GIR after SGLT2 inhibitor administration, which indicated improvement in peripheral insulin sensitivity, were negatively correlated with T2DM duration and positively with reduction in fluctuation of daily plasma glucose profiles before and after treatment.ConclusionSGLT2 inhibitor improved insulin sensitivity in the skeletal muscle independent of anthropometric changes. Patients with short duration of T2DM and insulin resistance can be good candidates for short-term SGLT2 inhibitor administration to improve insulin sensitivity in the skeletal muscle.

Use of SGLT2 inhibitors in type 2 diabetes: weighing the risks and benefits.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors belong to a novel class of glucose-lowering medications that reduce plasma glucose concentrations by inhibiting glucose reabsorption by the kidney, inducing glucosuria. Their actions encompass reductions in HbA1c, fasting and postprandial blood glucose levels, body weight and BP. To date, empagliflozin and canagliflozin have additionally been shown to improve cardiovascular outcomes in high-risk individuals and to slow the progression of diabetic kidney disease. Adverse effects associated with this class include urinary frequency, dehydration, genitourinary tract infections and, rarely, euglycaemic diabetic ketoacidosis. Of the SGLT2 inhibitors, only canagliflozin has been linked to a higher risk of lower-extremity amputations and bone fractures compared with placebo. Optimal prescribing of agents within this relatively new drug category requires a full understanding of their risks in addition to their benefits.

Diabetes mellitus: An Overview

Diabetes mellitus is a metabolic disorder resulting from a defect in insulin secretion, insulin action or both. The condition itself introduces a need for patient's lifestyle adjustment to the disease and a number of everyday therapeutic and diagnostic restrictions. The main indication of diabetes mellitus is a hyperglycemia in blood which is due to inappropriate pancreatic insulin secretion or low insulin-directed fostering of glucose by target cells. It is silent killer disease and affects millions of people in the world. It is estimated that in 2010 there was globally 285 million people suffering from this disease. This number is estimated to increase to 430 million in the absence of better control or cure. Different types of diabetes mellitus, type 1, type 2, gestational diabetes and other types of diabetes mellitus are compared in terms of diagnostic criteria, etiology and genetics. As the disease progresses tissue or vascular damage ensures leading to severe diabetic complications such as retinopathy, neuropathy, nephropathy, cardiovascular complications and ulceration. Currently available pharmacotherapy for the treatment of diabetes mellitus includes insulin and hypoglycemic agents. These drugs act by increasing the secretion of insulin form pancreas or reducing plasma glucose concentrations by increasing glucose uptake and decreasing gluconeogenesis.Comobrid mental diseases can further negatively influence the course of diabetes. They are specially depression, anxiety disorders, eating disorders and cognitive disorders including dementia. Various herbal drugs have been also proved effective due to their beneficial contents in treatment of diabetes. This article focuses on the causes, types, diagnosis and treatment of diabetes.

A Review on Diabetes Mellitus Current Update on Management and Treatment

Diabetes mellitus (DM), or simply diabetes, is a group of metabolic diseases in which a person has high blood sugar, either because the body does not produce enough insulin, or because cells do not respond to the insulin that is produced. This high blood sugar produces the classical symptoms of polyuria (frequent urination), polydipsia (increased thirst) and polyphagia (increased hunger). Conventionally, diabetes has been divided into three types namely: Type 1 DM or insulin-dependent diabetes mellitus (IDDM) in which body fails to produce insulin, and presently requires the person to inject insulin or wear an insulin pump. This is also termed as juvenile Type 2 DM or non-insulin-dependent diabetes mellitus (NIDDM), results from insulin resistance, a condition in which cells fail to use insulin properly, with or without an absolute insulin deficiency. This type was previouslyreferred to as or adult-onset The third main type is gestational diabetes which occurs when women without a previous history of diabetes develop a high blood glucose level during her pregnancy. It may precede development of type 2 DM. Currently available pharmacotherapy for the treatment of diabetes mellitus includes insulin and oral hypoglycemic agents. Such drugs acts by either increasing the secretion of insulin from pancreas or reducing plasma glucose concentrations by increasing glucose uptake and decreasing gluconeogenesis. However these current drugs do not restore normal glucose homeostasis for longer period and they are not free from side effects such as hypoglycemia, kidney diseases, GIT problems, hepatotoxicity, heart risk problems, insulinoma and they have to take rest of life. Various herbal drugs have been also proved effective due to their beneficial contents in treatment of diabetes. The present review therefore is an attempt to focus on the physiological aspects of diabetes, its complications, goals of management, and synthetic and herbal treatment of diabetes.

Glucose-lowering effects and mechanisms of the bile acid-sequestering resin sevelamer.

Sevelamer, a non-absorbable amine-based resin used for treatment of hyperphosphataemia, has been demonstrated to have a marked bile acid-binding potential alongside beneficial effects on lipid and glucose metabolism. The aim of this study was to investigate the glucose-lowering effect and mechanism(s) of sevelamer in patients with type 2 diabetes. In this double-blinded randomized controlled trial, we randomized 30 patients with type 2 diabetes to sevelamer (n = 20) or placebo (n = 10). Participants were subjected to standardized 4-hour liquid meal tests at baseline and after 7 days of treatment. The main outcome measure was plasma glucagon-like peptide-1 excursions as measured by area under the curve. In addition, blood was sampled for measurements of glucose, lipids, glucose-dependent insulinotropic polypeptide, C-peptide, glucagon, fibroblast growth factor-19, cholecystokinin and bile acids. Assessments of gastric emptying, resting energy expenditure and gut microbiota composition were performed. Sevelamer elicited a significant placebo-corrected reduction in plasma glucose with concomitant reduced fibroblast growth factor-19 concentrations, increased de novo synthesis of bile acids, a shift towards a more hydrophilic bile acid pool and increased lipogenesis. No glucagon-like peptide-1-mediated effects on insulin, glucagon or gastric emptying were evident, which points to a limited contribution of this incretin hormone to the glucose-lowering effect of sevelamer. Furthermore, no sevelamer-mediated effects on gut microbiota composition or resting energy expenditure were observed. Sevelamer reduced plasma glucose concentrations in patients with type 2 diabetes by mechanisms that seemed to involve decreased intestinal and hepatic bile acid-mediated farnesoid X receptor activation.

Body mass index influences the plasma glucose concentration during iatrogenic hypoglycemia in people with type 2 diabetes mellitus: a cross-sectional study.

BackgroundHypoglycemia occurs in an appreciable number of individuals with type 2 diabetes mellitus (T2DM) who are receiving glycemic therapy. Iatrogenic hypoglycemia induces not only complications but also a substantial medical expense. Intervention for relevant risk factors may help avert severe hypoglycemia and enhance quality of life in at-risk individuals. This study investigates the relationship between body mass index (BMI) and plasma glucose concentration during iatrogenic hypoglycemia in people with T2DM.MethodsEnrollment criteria were people above 20 years of age, with existing diagnosis of T2DM, a documented plasma glucose level ≤70 mg/dL, and acute cognitive impairment requiring hospitalization. Participants were classified into two groups according to their BMI. Specifically, lower BMI subgroup denotes individuals whose BMI fall within lower half of the study population, and vice versa. Plasma glucose concentration, length of hospital stay, and serum electrolyte level at hospitalization were compared between these BMI subgroups. Moreover, multivariate regression analysis was performed to identify covariates associated with plasma glucose level during iatrogenic hypoglycemia.ResultsThis study enrolled 107 participants for whom 54 were assigned to a higher BMI subgroup and the remainder to a lower BMI subgroup. People with lower BMI harbored substantially reduced plasma glucose concentration during iatrogenic hypoglycemia compared to those with higher BMI (30.1 ± 9.6 mg/dL vs. 38.4 ± 12.3 mg/dL, P < 0.001). Nonetheless, the length of stay (6.2 ± 4.6 days vs. 5.7 ± 4.0 days, P = 0.77) and serum potassium level (3.7 ± 0.9 meq/L vs. 3.9 ± 0.8 meq/L, P = 0.14) were comparable between subgroups. Multivariate regression analysis identified BMI as a determinant of plasma glucose concentration in diabetic individuals with iatrogenic hypoglycemia (β coefficient: 0.72, P = 0.008).DiscussionIn individuals with T2DM who experience severe iatrogenic hypoglycemia, BMI influences the plasma glucose level at hospitalization. People with lower BMI harbored appreciably reduced plasma glucose concentration relative to their higher BMI counterparts. In lower weight people, therefore, appropriate dosing of antidiabetic medications, frequent self-monitoring of blood glucose level and adequate nutritional support may help avert more severe hypoglycemia. Overall, BMI potentially influences the severity of iatrogenic hypoglycemia in people with T2DM.

Effects of chronic exposure to 12‰ saltwater on the endocrine physiology of juvenile American alligator (Alligator mississippiensis)

American alligator (Alligator mississippiensis) habitats are prone to saltwater intrusion following major storms, hurricanes or droughts. Anthropogenic impacts affecting hydrology of freshwater systems may exacerbate saltwater intrusion into freshwater habitats. The endocrine system of alligators is susceptible to changes in the environment but it is currently not known how the crocodilian physiological system responds to environmental stressors such as salinity. Juvenile alligators were exposed to 12‰ saltwater for 5 weeks to determine the effects of chronic exposure to saline environments. Following 5 weeks, plasma levels of hormones [e.g. progesterone, testosterone, estradiol, corticosterone, aldosterone (ALDO), angiotensin II (ANG II)] were quantified using liquid chromatography and tandem mass spectrometry. Compared with freshwater-kept subjects, saltwater-exposed alligators had significantly elevated plasma levels of corticosterone, 11-deoxycortisol, 17α-hydroxyprogesterone, testosterone, 17β-estradiol, estrone and estriol whereas pregnenolone and ANG II were significantly depressed and ALDO levels were unchanged (slightly depressed). On the one hand, saltwater exposure did not affect gene expression of renal mineralocorticoid and glucorticoid and angiotensin type 1 (AT-1) receptors or morphology of lingual glands. On the other hand, saltwater exposure significantly reduced plasma glucose concentrations whereas parameters diagnostic of perturbed liver function (aspartate aminotransferase and alanine aminotransferase) and kidney function (creatinine and creatine kinase) were significantly elevated. Except for plasma potassium levels (K+), plasma ions Na+ and Cl- were significantly elevated in saltwater alligators. Overall, this study demonstrated significant endocrine and physiological effects in juvenile alligators chronically exposed to a saline environment. Results provide novel insights into the effects of a natural environmental stressor (salinity) on the renin-angiotensin-aldosterone system and steroidogenesis of alligators.

The effect of pomegranate fresh juice versus pomegranate seed powder on metabolic indices, lipid profile, inflammatory biomarkers, and the histopathology of pancreatic islets of Langerhans in streptozotocin-nicotinamide induced type 2 diabetic Sprague\u2013Dawley rats

BackgroundType 2 diabetes mellitus (T2DM) is associated with hyperglycemia, inflammatory disorders and abnormal lipid profiles. Several functional foods have therapeutic potential to treat chronic diseases including diabetes. The therapeutic potential of pomegranate has been stated by multitudinous scientists. The present study aimed to evaluate the effects of pomegranate juice and seed powder on the levels of plasma glucose and insulin, inflammatory biomarkers, lipid profiles, and health of the pancreatic islets of Langerhans in streptozotocin (STZ)-nicotinamide (NAD) induced T2DM Sprague Dawley (SD) rats.MethodsForty healthy male SD rats were induced to diabetes with a single dose intra-peritoneal administration of STZ (60 mg/kg b.w.) - NAD (120 mg/kg b.w.). Diabetic rats were orally administered with 1 mL of pomegranate fresh juice (PJ) or 100 mg pomegranate seed powder in 1 mL distilled water (PS), or 5 mg/kg b.w. of glibenclamide every day for 21 days. Rats in all groups were sacrificed on day 22. The obtained data was analyzed by SPSS software (v: 22) using One-way analysis of variance (ANOVA).ResultsThe results showed that PJ and PS treatment had slight but non-significant reduction of plasma glucose concentration, and no impact on plasma insulin compared to diabetic control (DC) group. PJ lowered the plasma total cholesterol (TC) and triglyceride (TG) significantly, and low-density lipoproteins (LDL) non-significantly compared to DC group. In contrast, PS treatment significantly raised plasma TC, LDL, and high-density lipoproteins (HDL) levels compared to the DC rats. Moreover, the administration of PJ and PS significantly reduced the levels of plasma inflammatory biomarkers, which were actively raised in diabetic rats. Only PJ treated group showed significant repairment and restoration signs in islets of Langerhans. Besides, PJ possessed preventative impact against 2,2-diphenyl-1-picrylhydrazyl (DPPH) radicals almost 2.5 folds more than PS.ConclusionsOur findings suggest that active constituents with high antioxidant properties present in PJ are responsible for its anti-hyperlipidemic and anti-inflammatory effects, likewise the restoration effect on the damaged islets of Langerhans in experimental rats. Hence, the pharmacological, biochemical, and histopathological profiles of PJ treated rats obviously indicated its helpful effects in amelioration of diabetes-associated complications.

Comparing glucose and insulin data from the two-hour oral glucose tolerance test in metabolic syndrome subjects and marathon runners.

Glucose is the main energy source of the body's cells and is essential for normal metabolism. Two pancreatic hormones, insulin and glucagon, are involved in glucose home-ostasis. Alteration in the plasma glucose and insulin concentrations could lead to distinct symptoms and diseases, ranging from mental function impairment to coma and even death. Type 2 diabetes, insulin resistance and metabolic syndrome are typical examples of abnormal glucose metabolism that increase the risk for cardiovascular disease and mortality. The oral glucose tolerance test (OGTT) is a medical test used to screen for prediabetes, type 2 diabetes and insulin resistance. In the 5-sample 2-hour OGTT, plasma glucose and insulin concentrations are measured after a fast and then after oral intake of glucose, at intervals of 30 minutes. In this work, a statistical analysis is carried out to find significant differences between the five stages of the OGTT for plasma glucose and insulin data. In addition, the behavior of the glucose and insulin data is compared between subjects with the metabolic syndrome and marathon runners. Results show that marathon runners have plasma glucose and insulin levels significantly lower (p <; 0.05) than people with the metabolic syndrome in all the stages of the OGTT. Insulin secretion decreases in marathon runners due to a significant reduction in plasma glucose concentration, but insulin secretion does not decrease in metabolic syndrome subjects due to insulin resistance, consequently plasma glucose concentration does not achieve normal levels.

A ketogenic diet increases transport and oxidation of ketone bodies in RG2 and 9L gliomas without affecting tumor growth.

The dependence of tumor cells, particularly those originating in the brain, on glucose is the target of the ketogenic diet, which creates a plasma nutrient profile similar to fasting: increased levels of ketone bodies and reduced plasma glucose concentrations. The use of ketogenic diets has been of particular interest for therapy in brain tumors, which reportedly lack the ability to oxidize ketone bodies and therefore would be starved during ketosis. Because studies assessing the tumors' ability to oxidize ketone bodies are lacking, we investigated in vivo the extent of ketone body oxidation in 2 rodent glioma models. Ketone body oxidation was studied using (13)C MR spectroscopy in combination with infusion of a (13)C-labeled ketone body (beta-hydroxybutyrate) in RG2 and 9L glioma models. The level of ketone body oxidation was compared with nontumorous cortical brain tissue. The level of (13)C-beta-hydroxybutyrate oxidation in 2 rat glioma models was similar to that of contralateral brain. In addition, when glioma-bearing animals were fed a ketogenic diet, the ketone body monocarboxylate transporter was upregulated, facilitating uptake and oxidation of ketone bodies in the gliomas. These results demonstrate that rat gliomas can oxidize ketone bodies and indicate upregulation of ketone body transport when fed a ketogenic diet. Our findings contradict the hypothesis that brain tumors are metabolically inflexible and show the need for additional research on the use of ketogenic diets as therapy targeting brain tumor metabolism.

SGLT2 Inhibitors and Cardiovascular Risk: Lessons Learned From the EMPA-REG OUTCOME Study.

Although cardiovascular (CV) mortality is the principal cause of death in individuals with type 2 diabetes (T2DM), reduction of plasma glucose concentration has little effect on CV disease (CVD) risk. Thus, novel strategies to reduce CVD risk in T2DM patients are needed. The recently published BI 10773 (Empagliflozin) Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME) study demonstrated that in T2DM patients with high CVD risk empagliflozin reduced the primary major adverse cardiac event end point (CV death, nonfatal myocardial infarction, nonfatal stroke) by 14%. This beneficial effect was driven by a 38% reduction in CV mortality with no significant decrease in nonfatal myocardial infarction or stroke. Empagliflozin also caused a 35% reduction in hospitalization for heart failure without affecting hospitalization for unstable angina. Although sodium-glucose cotransporter 2 inhibitors exert multiple metabolic benefits (decreases in HbA1c, body weight, and blood pressure and an increase in HDL cholesterol), all of which could reduce CVD risk, it is unlikely that the reduction in CV mortality can be explained by empagliflozin's metabolic effects. More likely, hemodynamic effects, specifically reduced blood pressure and decreased extracellular volume, are responsible for the reduction in CV mortality and heart failure hospitalization. In this Perspective, we will discuss possible mechanisms for these beneficial effects of empagliflozin and their implications for the care of T2DM patients.

Optimization of a Dicarboxylic Series for in Vivo Inhibition of Citrate Transport by the Solute Carrier 13 (SLC13) Family.

Inhibition of the sodium-coupled citrate transporter (NaCT or SLC13A5) has been proposed as a new therapeutic approach for prevention and treatment of metabolic diseases. In a previous report, we discovered dicarboxylate 1a (PF-06649298) which inhibits the transport of citrate in in vitro and in vivo settings via a specific interaction with NaCT. Herein, we report the optimization of this series leading to 4a (PF-06761281), a more potent inhibitor with suitable in vivo pharmacokinetic profile for assessment of in vivo pharmacodynamics. Compound 4a was used to demonstrate dose-dependent inhibition of radioactive [(14)C]citrate uptake in liver and kidney in vivo, resulting in modest reductions in plasma glucose concentrations.