Glycemic Reduction Research Articles

Durability of Glycemic Control with Dapagliflozin vs. Saxagliptin in Patients with Inadequately Controlled Type 2 Diabetes

Type 2 diabetes (T2D) is a progressive disease requiring add-on antihyperglycemic agents to maintain glycemic goals, although how to escalate therapy remains debatable. The benefits of dapagliflozin (DAPA) over saxagliptin (SAXA) on glycemic control (GC) and weight reduction were demonstrated in a post-hoc analysis (NCT01606007). We now evaluate the failure to sustain GC—the slope of ∆A1c over time regression line (coefficient of failure [CoF])—with DAPA or SAXA add-on to metformin (MET). CoF DAPA vs. SAXA was statistically compared directly over 24 weeks (short term; NCT01606007, patients [pts] with ≥1 ∆A1c value at/post week 18) and indirectly (post-hoc analysis of placebo controlled trials) over 102 weeks (long term; NCT00528879 and NCT00121667, pts with ≥3 ∆A1c values from 3 different visits at/post week 20). A1c CoF was lower for DAPA vs. SAXA both at 24 weeks (1.38%/y greater reduction; p=0.009) and 102 weeks (0.37%/y; p=0.04) (Figure). Fewer DAPA- than SAXA-treated pts required rescue medication or discontinued study for failing to achieve GC over 24 weeks (3.4% vs. 9.4%; p=0.0191). Similarly, the placebo adjusted risk ratio of rescue or study discontinuation for DAPA was numerically lower than SAXA over 102 weeks (0.70 vs. 0.74; p=0.68). These results suggest that in T2D pts inadequately controlled on MET, addition of DAPA is associated with significantly greater durability of GC than SAXA over 102 weeks. Disclosure C.J. Bailey: Advisory Panel; Self; Abbott, AstraZeneca, Boehringer Ingelheim GmbH, Elcelyx Therapeutics, Inc., Janssen Pharmaceuticals, Inc., Eli Lilly and Company, Merck & Co., Inc., Novo Nordisk A/S, Sanofi. S. Del Prato: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, GlaxoSmithKline plc., Intarcia Therapeutics, Inc., Merck & Co., Inc., Novartis Pharmaceuticals Corporation, Novo Nordisk A/S, Servier, Sanofi, Takeda Pharmaceuticals U.S.A., Inc.. Research Support; Self; Merck & Co., Inc., Novartis Pharmaceuticals Corporation, Boehringer Ingelheim Pharmaceuticals, Inc., AstraZeneca. Speaker's Bureau; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Novartis Pharmaceuticals Corporation, Takeda Pharmaceuticals U.S.A., Inc.. Advisory Panel; Self; Janssen Biotech, Inc., Abbott. C. Wei: Employee; Self; AstraZeneca. G. Luporini Saraiva: Employee; Self; AstraZeneca.

PROPRIEDADES FUNCIONAIS DA CASCA DO MARACUJÁ AMARELO (PASSIFLORA EDULIS) NA SÍNDROME METABÓLICA

O objetivo deste estudo foi revisar a literatura sobre o efeito da farinha da casca do maracujá amarelo (Passiflora edulis f. flavicarpa) nos distúrbios metabólicos que compõem a síndrome metabólica. Trata-se de uma revisão sistemática, realizada por meio do levantamento bibliográfico de estudos publicados entre 2005 e 2017, indexados nas bases de dados IBECS, PubMed, CisSaúde, Cochrame, MedCarib, Lilacs, Medline e SciELO, bem como no Google Scholar, bancos de teses e dissertações. Os estudos selecionados avaliaram o efeito do uso da casca do maracujá amarelo (P. edulis) sobre os parâmetros da síndrome metabólica. Os estudos experimentais demonstraram discordâncias quanto ao efeito hipoglicemiante e resultados positivos quanto ao efeito hipotensor. Em pesquisas realizadas com humanos saudáveis, a suplementação com 30 gramas da farinha da casca de P. edulis demonstrou eficiência na redução glicêmica e lipidêmica para LDL e colesterol total, sem toxicidade. Em estudos com portadores de síndrome metabólica e diabetes mellitus tipo 2, os efeitos hipolipemiantes e hipoglicemiantes também foram demonstrados. Entretanto, ainda há escassez de publicações sobre o uso da casca de P. edulis para tratamento de distúrbios metabólicos, sendo necessária padronização metodológica que viabilize sua recomendação na prática clínica.DOI: 10.12957/demetra.2018.28957

A Phenolic Fraction from Catharanthus roseus L. Stems Decreases Glycemia and Stimulates Insulin Secretion.

Catharanthus roseus (L.) G. (C. roseus) is a medicinal plant used traditionally for diabetes mellitus control. Several compounds of an alkaloidal nature have been proposed as hypoglycemic principles. However, little attention has been paid to other compounds in this plant that could also participate in this hypoglycemic activity. This study aimed to analyze the hypoglycemic effect of a polyphenolic fraction from C. roseus, as well as its action on insulin secretion and expression in RINm5F cells. Methods. An alkaloid-free aqueous extract was obtained from C. roseus stems. The hypoglycemic effect of different doses of this extract was evaluated in normal and streptozotocin-induced diabetic mice. This extract was fractionated by bipartition, and the resultant fractions were assessed by their hypoglycemic effects. Subsequently, the fraction with the greater hypoglycemic activity was added to the RINm5F cells, and the expression and secretion of insulin were analyzed. The antioxidant activity was determined by the DPPH method and through chromatographic analysis of the most active fraction by HPLC, using an Econosphere C18 column. Results. The aqueous alkaloid-free extract of C. roseus stems significantly reduced blood glucose in normal and diabetic mice. The fractionation of this extract provided three fractions, one of which (a precipitate) showed significant reductions in glycemia at 6 h (48.1 and 64.5% in normal and diabetic mice, respectively). This precipitate contained phenolic compounds and saponins. Its chromatographic analysis showed that it is formed by several phenolic compounds; gallic acid (0.053%) and chlorogenic acid (0.216%) were identified and quantified. Conclusion. The phenolic fraction of C. roseus containing gallic acid and chlorogenic acid had a hypoglycemic effect that may be explained by an increase in insulin secretion.

Evaluation of Antidiabetic Activity of Aqueous Extract of Leaves from <i>Phragmanthera capitata</i> (Sprengel) S. Balle (Laurenthaceae) in <i>Wistar</i> Albino Rats

Diabetes mellitus is a public health problem affecting about 8.4% of people in the world and knows an alarming progression in sub-Saharan Africa and in Cameroon precisely. The current therapeutic strategies have prohibitive prices, are unavailable and have harmful side-effects. So, this work aimed at contributing to the valorization of medicinal flora and `knowledge of traditional healers in Foumban, West-Cameroon, in the treatment of diabetes. An ethnopharmacological survey was conducted by consulting traditional healers of the District of Foumban. At the end of this investigation, Phragmanthera capitata, which was found to be the most active plant following preliminary tests, was selected for antidiabetic studies on three groups of rats: normal glycaemia, temporary hyperglycemia and diabetic. The first two groups were treated per os, with aqueous extract of leaves from P. capitata, with the doses of D2 (4 mL/kg) obtained from the traditional healers, D1 (half of D2), D3 (double of D2) and by glibenclamide (2.5 mg/kg). The rats of the last group were treated twice per day, with the same doses of extract and glibenclamide for 13 days and were sacrificed on the 14th day. Their blood was collected by cardiac puncture for the determination of biochemical and hematological parameters. Phytochemical screening was performed using standard methods. The administration of aqueous extract of P. capitata led to a hypoglycaemia effect in normal rats, a reduction of glycaemia in the temporary hyperglycaemia and diabetic rats. In addition, an improvement of lipid assessment, renal and hepatic parameters related to the installation of diabetes, as well as an immune-modulator effect of the extract were noted in diabetic rats treated for 13 days. Phytochemical screening indicated that the extract contains saponins, tannins, flavonoids, steroids and terpens. This work along with findings justifies the traditional use of this plant in the treatment of diabetes mellitus.

Recovery of Cardiac Remodeling and Dysmetabolism by Pancreatic Islet Injury Improvement in Diabetic Rats after Yacon Leaf Extract Treatment

Yacon (Smallanthus sonchifolius) is a native Andean plant rich in phenolic compounds, and its effects on dysmetabolism and cardiomyopathy in diabetic rats was evaluated. The rats (10/group) were allocated as follows: C, controls; C + Y, controls treated with Yacon leaf extract (YLE); DM, diabetic controls; and DM + Y, diabetic rats treated with YLE. Type 1 diabetes (T1DM) was induced by the administration of streptozotocin (STZ; 40 mg−1/kg body weight, single dose, i.p.), and treated groups received 100 mg/kg body weight YLE daily via gavage for 30 d. The YLE group shows an improvement in dysmetabolism and cardiomyopathy in the diabetic condition (DM versus DM + Y) promoting a significant reduction of glycemia by 63.39%, an increase in insulin concentration by 49.30%, and a decrease in serum triacylglycerol and fatty acid contents by 0.39- and 0.43-fold, respectively, by ameliorating the pancreatic islet injury, as well as increasing the activity of the antioxidant enzymes (catalase, superoxide dismutase, and glutathione peroxidase) and decreasing the fibrosis and cellular disorganization in cardiac tissue. The apparent benefits of YLE seem to be mediated by ameliorating dysmetabolism and oxidative stress in pancreatic and cardiac tissues.

Influence of low molecular weight compounds associated to cashew (Anacardium occidentale L.) fiber on lipid metabolism, glycemia and insulinemia of normal mice

The objective of this study was to evaluate the effect of cashew fiber wheter or not associated with low molecular weight compounds on lipid profile, abdominal adiposity, glycemia and insulinemia and serum concentration of ghrelin and leptin hormones from normal mice. We evaluated the cashew fiber in its integral form (IcF) and the cashew fiber after being submitted to the process of extraction of low molecular weight metabolites (cFSM). The two fibers were incorporated into the feed of male Swiss mice for 15 weeks. At the end of the treatment, blood glucose, total cholesterol and fractions, triglycerides, urea, AST, ALT, hormone levels of insulin, leptin and ghrelin were analyzed, as well as GSH and hepatic MDA. The consumption of cFSM diet promoted reduction of glycemia, insulin and ghrelin. Animals fed the IcF diet showed hyperlipidemia, hyperleptinemia and increased abdominal fat. In addition, no changes were observed in the lipid profile of the animals, in the abdominal adiposity and in the leptin hormone in the group that received cFSM diet. We conclude that the removal of small molecules is fundamental to use cashew fiber as a functional food with possible health benefits.

The effects of an after-school intervention program on physical activity level, sedentary time, and cardiovascular risk factors in adolescents

Abstract Aim: To ascertain the effects of an after-school intervention on physical activity levels and cardiovascular risk factors in adolescents from Campinas, Brazil. Methods: This was an intervention study with 71 adolescents that was carried out in two schools, randomly assigned to a control group (CG:n=45) or an intervention group (IG:n=26). We performed evaluations of body composition, sexual maturation, blood pressure, level of physical activity, sedentary time (ST), and eating habits, as well as biochemical variables by a portable analyzer. The IG participated in two weekly sessions of physical activities and controlled physical exercises for 14 weeks. The sessions lasted 60’, and were divided into warm-up (5-10’), main part (40-50’), and recovery (5-10’). Results: 30.8% of the IG and 24.4% of the CG were classified as overweight/obese. Additionally, the IG showed significantly lower ST (total: p=0.037; daily: p=0.009) after the intervention, as well as in the post-period (total ST: p=0.043; daily ST: p=0.007). The IG showed a reduction in glycemia (p=0.025). Conclusion: The intervention program generated positive changes in glycemia levels and ST. These results suggest that interventions involving physical exercise should be promoted in the school environment, as physical activity is an important component of a healthy lifestyle.

A pharmacokinetic study on lapatinib in type 2 diabetic rats

Diabetes mellitus (DM) is a complex metabolic disorder which affects the function of numerous tissues and alters the pharmacokinetic parameters of many drugs. As many oncological patients are diabetics, it is important to determine the influence of this chronic disease on the pharmacokinetics (PK) of anticancer drugs. Lapatinib is a tyrosine kinase inhibitor (TKI), approved for the treatment of human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer. The aim of the study was to compare the PK of lapatinib in normal and type 2 diabetes mellitus (T2DM) model rats. Additionally, the effect of lapatinib on blood glucose concentrations was examined. The PK of lapatinib was studied in healthy rats (n=6, the healthy group) and T2DM model rats (n=6, the diabetic group). The rats received lapatinib orally as a single dose of 50mg. Plasma concentrations of lapatinib were measured with high-performance liquid chromatography method coupled with a tandem mass spectrometry. The plasma concentrations of lapatinib were increased in the T2DM model rats. There were statistically significant differences between the groups in Cmax (p=0.0104) and AUC0-t (p=0.0265). The reduction of glycaemia in the range of 1.2-41.5% and in the range of 4.1-36.8% was observed in the diabetic and healthy animals, respectively. Higher concentrations of lapatinib in the diabetic rats may suggest the need for application of lower doses of this TKI in patients with DM.

Cardiovascular Actions and Clinical Outcomes With Glucagon-Like Peptide-1 Receptor Agonists and Dipeptidyl Peptidase-4 Inhibitors.

Potentiation of glucagon-like peptide-1 (GLP-1) action through selective GLP-1 receptor (GLP-1R) agonism or by prevention of enzymatic degradation by inhibition of dipeptidyl peptidase-4 (DPP-4) promotes glycemic reduction for the treatment of type 2 diabetes mellitus by glucose-dependent control of insulin and glucagon secretion. GLP-1R agonists also decelerate gastric emptying, reduce body weight by reduction of food intake and lower circulating lipoproteins, inflammation, and systolic blood pressure. Preclinical studies demonstrate that both GLP-1R agonists and DPP-4 inhibitors exhibit cardioprotective actions in animal models of myocardial ischemia and ventricular dysfunction through incompletely characterized mechanisms. The results of cardiovascular outcome trials in human subjects with type 2 diabetes mellitus and increased cardiovascular risk have demonstrated a cardiovascular benefit (significant reduction in time to first major adverse cardiovascular event) with the GLP-1R agonists liraglutide (LEADER trial [Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Ourcome Results], -13%) and semaglutide (SUSTAIN-6 trial [Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide], -24%). In contrast, cardiovascular outcome trials examining the safety of the shorter-acting GLP-1R agonist lixisenatide (ELIXA trial [Evaluation of Lixisenatide in Acute Coronary Syndrom]) and the DPP-4 inhibitors saxagliptin (SAVOR-TIMI 53 trial [Saxagliptin Assessment of Vascular Outcomes Recorded in Patients With Diabetes Mellitus-Thrombolysis in Myocardial Infarction 53]), alogliptin (EXAMINE trial [Examination of Cardiovascular Outcomes With Alogliptin Versus Standard of Care in Patients With Type 2 Diabetes Mellitus and Acute Coronary Syndrome]), and sitagliptin (TECOS [Trial Evaluating Cardiovascular Outcomes With Sitagliptin]) found that these agents neither increased nor decreased cardiovascular events. Here we review the cardiovascular actions of GLP-1R agonists and DPP-4 inhibitors, with a focus on the translation of mechanisms derived from preclinical studies to complementary findings in clinical studies. We highlight areas of uncertainty requiring more careful scrutiny in ongoing basic science and clinical studies. As newer more potent GLP-1R agonists and coagonists are being developed for the treatment of type 2 diabetes mellitus, obesity, and nonalcoholic steatohepatitis, the delineation of the potential mechanisms that underlie the cardiovascular benefit and safety of these agents have immediate relevance for the prevention and treatment of cardiovascular disease.

Effect of clarified Brazilian native fruit juices on postprandial glycemia in healthy subjects

Brazilian native fruits have been shown as excellent sources of polyphenols which are associated with multiple biological activities including inhibition of carbohydrate-hydrolyzing enzymes, α-amylase and α-glucosidase. Postmeal blood glucose elevations and high glycemic index diets can play a major role in the development of type 2 diabetes, therefore alternative approaches to reduce postprandial hyperglycemia are of growing interest in order to reduce diabetes risk. Here we investigated the effect of six Brazilian native clarified fruit juices from Amazon, Savannah and Atlantic Forest biomes on postprandial glycemia after consumption of a carbohydrate meal. For this, 23 healthy subjects were selected to consume seven meal tests, with a 1-week interval among them, consisting in 50g white bread plus 300mL of water (control) or cambuci, cagaita, maracujá-alho, cupuaçu, camu-camu and jaboticaba clarified fruit juices. The results showed that serum glucose concentrations were significantly lower after consumption of cambuci, cagaita, camu-camu and jaboticaba juices, whereas maracujá-alho and cupuaçu juices did not decrease the amount of glucose absorbed, compared to control (p<0.05). In addition, cagaita, cambuci, cupuaçu and jaboticaba juices increased the oxygen radical absorbance capacity in plasma, whereas all juices augmented the ferric reducing ability of plasma, except for cambuci (p<0.05). These results indicate that juices from Brazilian native fruits may be considered as adjuvant treatment for reduction of postprandial glycemia in healthy subjects.

Risk Factors for Nocturnal Hypoglycemia in Insulin-treated Patients With Type 2 Diabetes: A Secondary Analysis of Observational Data Derived From an Integrated Clinical Trial Database

PurposeA trade-off exists in most diabetes therapies between the benefits of good glycemic control and the morbidity of hypoglycemia. Balancing these factors to achieve desired outcomes is a key consideration for personalized diabetes therapy. Hypoglycemia at night (nocturnal hypoglycemia [NH]) is a common but often under-reported problem in insulin-treated patients with type 2 diabetes. To better understand the risk for NH, we pooled data from multiple clinical trials of insulin treatment and specifically examined NH risk factors in relation to glycemic goals. MethodsOf 53 randomized trials involving insulin treatment, 18 trials that collected NH data were included. Risk factors associated with NH were identified by using gradient-boosting methods. A proportional hazards model was used to quantify the hazard ratio (HR) for risk factors. By modeling with individual patient data, a patient-level NH risk score distribution was created. Finally, results of the model were used to quantify an adjustment to the glycemic goal that would fully offset each risk factor, all other factors being equal. FindingsData pooling resulted in the inclusion of 7341 patients with type 2 diabetes from 18 randomized clinical trials. In the mean 6-month treatment period, 43% of patients experienced at least 1 episode of NH (mean [SD], 1.1 [1.5] events/month). Reduction of glycosylated hemoglobin (HbA1c) levels during the trial was a risk factor for NH (HR, 1.40 [95% CI, 1.38-1.43] per –1% of HbA1c). Higher baseline HbA1c level was a protective factor against NH (HR, 0.76 [95% CI, 0.74–0.77] per +1% of HbA1c); and the adjustment to HbA1c goal required to offset 1% higher baseline HbA1c was –0.825%. Patient characteristics for risk of NH included older age (HR, 1.02 [95% CI, 1.01–1.02]) per 1-year increase), female sex (HR, 1.18 [95% CI, 1.15–1.22]), black or African-American race (HR, 1.41 [95% CI, 1.33–1.50] vs white race), longer diabetes duration (HR, 1.02 [95% CI, 1.01–1.02] per 1-year increase), diabetic nephropathy (HR, 1.40 [95% CI, 1.27–1.54]), and concomitant sulfonylurea use (HR, 1.10 [95% CI, 1.05–1.15]). Asian race was associated with a lower risk of NH (HR, 0.50 [95% CI, 0.48–0.53] vs white race); this finding could be offset with a 2.03% adjustment to the HbA1c goal. ImplicationsData on NH are scarce. By pooling multiple clinical trials, this study was able to evaluate patient-level data. A quantitative understanding of the trade-off between individual risk factors for NH and glycemic reduction may help clinicians to personalize patients’ glycemic goals, while effectively managing NH risk. Limitations of the study include that patients were selected through inclusion/exclusion criteria and that patient compliance may be better in a trial setting. Validating the findings in the real world will be helpful.

Does Improved Periodontal Health affect Metabolic and Inflammatory Markers in Patients with Diabetes Mellitus? A Comparative Study

Background: Periodontal disease is considered as the “sixth complication of diabetes mellitus”. Patients suffering from diabetes mellitus (DM) are known to have increased susceptibility to infections which lead to poor metabolic control. Although it has been reported that improved metabolic control may lead to improved periodontal health it is still unclear whether the control of periodontal infections may improve the metabolic control of diabetes.&#x0D; Aim: To compare the effect of periodontal therapy on metabolic and inflammatory markers in diabetic patients.&#x0D; Materials and Methods: The study type was in vivo comparative study. 60 patients were selected for the study using simple random sampling method. The patients were grouped into control and case with 30 in each group. In all patients, plaque index, gingival index, probing pocket depth and clinical attachment level were assessed with the help of with The University of North Carolina probe (UNC-15) probe at baseline, 1 month and 3 month. Similarly, venous blood samples were taken for evaluating fasting glucose level, post prandial glucose level, glycated haemoglobin and C-reactive protein (CRP) at baseline, 1 month and 3 month. In treatment group, full mouth scaling and root planing was done and oral hygiene instructions was provided.&#x0D; Results: The result of the study suggested that non surgical periodontal therapy helps in controlling glycemic level and CRP values in patients with diabetes mellitus.&#x0D; Conclusion: Non-surgical periodontal treatment is associated with improved glycaemic control and reduction in CRP level in patients with DM.

Effect of variable antidiabetic treatments strategy on oxidative stress markers in obese patients with T2DM

AimTo evaluate the effect of different anti-diabetic treatment strategy on oxidative stress markers in patients with type 2 diabetes mellitus (T2DM).Subject and methodsA total of 93 patients with T2DM treated with metformin (G1 = 25), OHA (G2 = 22), OA and insulin (G3 = 26) and insulin alone (G4 = 20). In all patients, lipid profile and glycemic indices were assessed using routine laboratory tests. MDA and Oxidized LDL were assessed using commercially available ELISA kits. Laboratory tests were performed at baseline and at a control visit after 24 weeks of treatment.ResultsA significant decrease in the levels of MDA with improvement of glycemic control was observed in the group receiving OHA in combination with insulin therapy. A similar decrease of oxLDL was observed in all diabetic subgroups with borderline significance in those receiving metformin alone. The remaining clinical and biochemical parameters were not changed during follow-up in any of the involved groups.ConclusionA combination therapy with insulin was more effective in glycemic control and MDA reduction in T2DM. Whereas, a significant oxLDLc reduction was observed in T2DM irrespective of categories of antidiabetic treatment or glycemic control.

Effects of guar gum as a fat substitute in low fat meat emulsions

The physicochemical, oxidative, and sensory properties were determined for low fat meat emulsions containing varying levels of guar gum (0.5, 1.0, and 1.5%) as a fat substitute. Reduction of fat and incorporation of guar gum resulted in higher emulsion stability and cooking yield but lower penetration force. Color evaluation revealed that low fat formulations had significantly lower lightness and higher redness values than high fat control formulation (p .05). pH value was higher in low-fat formulation containing 1.5% guar gum (p .05). The MetMb % of the high fat emulsion formulation was higher than low fat formulations (p < .05). The significant increase of TBARS value, protein carbonyl groups and loss of protein sulfhydryl groups in high fat formulation reflect the more oxidative degradation of the lipids and muscle proteins during the preparation of meat emulsion than low fat formulations (p < .05). Microstructure observations using SEM shows that increase in guar gum levels lead to formation of gel network, which holds more water. Sensory evaluation indicates that low fat formulation supplemented with 0.5% gum had quality characteristics that were similar to those of the high fat control. Practical applications Nowadays consumers demand healthier meat products that are low in salt, fat, cholesterol, and calories and contain in addition health-promoting bioactive components such as fibers and natural antioxidants. Thus, use of fat replacers with health promoting properties needs research studies. The study of emulsions with added fat replacers is important because the parameters studied in this work facilitate prediction of changes in the final product. Furthermore, the fat replacer guar gum used in this study is a source of soluble dietary fiber in food products and a number of clinical studies have shown a reduction in postprandial glycemia and insulinemia on consumption of it. Since traditional meat products of India especially in the state of Jammu and Kashmir, contain higher amounts of animal fat and no work has done on such products to reduce fat content with alternate ingredients having health benefits with minimal effects on the product quality. Thus, this research work was conducted to study the properties of low fat meat emulsions, because quality of the final product depends on emulsion characteristics.

Loss of hepatic DEPTOR alters the metabolic transition to fasting

ObjectiveThe mechanistic target of rapamycin (mTOR) is a serine/threonine kinase that functions into distinct protein complexes (mTORC1 and mTORC2) that regulates growth and metabolism. DEP-domain containing mTOR-interacting protein (DEPTOR) is part of these complexes and is known to reduce their activity. Whether DEPTOR loss affects metabolism and organismal growth in vivo has never been tested. MethodsWe have generated a conditional transgenic mouse allowing the tissue-specific deletion of DEPTOR. This model was crossed with CMV-cre mice or Albumin-cre mice to generate either whole-body or liver-specific DEPTOR knockout (KO) mice. ResultsWhole-body DEPTOR KO mice are viable, fertile, normal in size, and do not display any gross physical and metabolic abnormalities. To circumvent possible compensatory mechanisms linked to the early and systemic loss of DEPTOR, we have deleted DEPTOR specifically in the liver, a tissue in which DEPTOR protein is expressed and affected in response to mTOR activation. Liver-specific DEPTOR null mice showed a reduction in circulating glucose upon fasting versus control mice. This effect was not associated with change in hepatic gluconeogenesis potential but was linked to a sustained reduction in circulating glucose during insulin tolerance tests. In addition to the reduction in glycemia, liver-specific DEPTOR KO mice had reduced hepatic glycogen content when fasted. We showed that loss of DEPTOR cell-autonomously increased oxidative metabolism in hepatocytes, an effect associated with increased cytochrome c expression but independent of changes in mitochondrial content or in the expression of genes controlling oxidative metabolism. We found that liver-specific DEPTOR KO mice showed sustained mTORC1 activation upon fasting, and that acute treatment with rapamycin was sufficient to normalize glycemia in these mice. ConclusionWe propose a model in which hepatic DEPTOR accelerates the inhibition of mTORC1 during the transition to fasting to adjust metabolism to the nutritional status.

Effects of Exenatide on both fat mass loss and cardiometabolic risk in obese subjects with type 2 diabetes mellitus

Objective: The regulation of glucose and adipose tissue metabolism by GLP1-receptor agonist is a possible treatment of T2D and obesity. These new pharmacologic agents target insulin resistance and metabolic disorders. Methods: Eighteen patients, 7 males and 11 females, were studied with T2D, divided into two groups: the first (I) was poorly controlled by metformin and sulfonylureas; the second (II) was treated only with metformin. Exenatide was administered at an initial dose of 5 μg twice a day for one month, and then the dose was adjusted to 10 μg twice a day throughout 24-26 weeks. From the beginning of therapy, each group was analyzed at time 0 and at 1 month (T1) and then 6 months (T2). At every time, anthropometric data, body composition by DXA and biochemical parameters were recorded. Results: At baseline, all patients enrolled showed metabolic disorders and obesity. The comparison of both groups between baseline and T2 showed a significant decrease of body weight, total Fat Mass (FM) and HbA1c (%), only in group (I) a statical reduction of Glycaemia and Total Cholesterol was observed. The Free Fat Mass (FFM) was never seen significantly different. The patients with HbA1c levels >75 mmol/mol (9%) at baseline showed a greater decline of HbA1c when compared to the patients with HbA1c <75 mmol/mol. Conclusion: Exenatide improves glucose metabolism and total cholesterol levels. Moreover, Exenatide reduced total FM and did not affect FFM. Exenatide could be used to treat obesity in diabetic but also non-diabetic patients. Summary: Exenatide, a GLP1-receptor agonist, is a pharmacological agent against obesity and type 2 diabetes mellitus. Exenatide decreases insulin resistance and lipids metabolism, and could be able to reduce fat mass and cardiovascular risk.

Low-power laser irradiation in salivary glands reduces glycemia in streptozotocin-induced diabetic female rats.

Low-power laser irradiation (LPLI) has been extensively employed to modulate inflammation in vitro and in vivo. Previous reports from our group indicated that LPLI might regulate glycemia in diabetic animals. Diabetes results in chronic hyperglycemia and therefore chronic inflammation by upregulation of inflammatory markers such as the high mobility group box 1 (HMGB1) protein. Thus this study aimed to analyze the LPLI effects upon blood glucose levels, plasma insulin and HMGB1 concentrations in a diabetes experimental rat model. Streptozotocin-induced diabetic rats were irradiated in the salivary glands area with a diode laser applied at 660nm, 70mW, 20J/cm2 , 22.4J, with a spot area of 0.028cm2 and its effects were evaluated. LPLI significantly reduced diabetic rat hyperglycemia, without changing insulin or HMGB1 plasma levels, but possibly by ameliorating the insulin resistance in these animals. These findings suggest that LPLI might have a systemic effect, but more studies are necessary to better understand its mechanisms. Fasting blood glucose measured by peroxidase-glucose oxidase (PGO) method (A), showing a reduction of diabetic animals glycemia after LPLI. LPLI probably reduced the hyperglycemia in diabetes by improving the insulin resistance in these animals (B). C n=10, CL n=10, D n=7 and DL n=8. Data are expressed as mean ± SD; * P <0.05 vs. respective control group; # P<0.05 vs. D group.

Testosterone supplementation and body composition: results from a meta-analysis of observational studies.

The concept of testosterone (T) supplementation (TS) as a new anti-obesity medication in men with testosterone deficiency syndrome (TDS) is emerging. Data from placebo-controlled trials are more conflicting. The aim of this study is to systematically review and meta-analyze available observational and register studies reporting data on body composition in studies on TS in TDS. An extensive MEDLINE, Embase, and Cochrane search was performed including the following words: "testosterone" and "body composition." All observational studies comparing the effect of TS on body weight and other body composition and metabolic endpoints were considered. Out of 824 retrieved articles, 32 were included in the study enrolling 4513 patients (mean age 51.7±6.1years). TS was associated with a time-dependent reduction in body weight and waist circumference (WC). The estimated weight loss and WC reduction at 24months were -3.50 [-5.21; -1.80] kg and -6.23 [-7.94; -4.76] cm, respectively. TS was also associated with a significant reduction in fat and with an increase in lean mass as well as with a reduction in fasting glycemia and insulin resistance. In addition, an improvement of lipid profile (reduction in total cholesterol as well as of triglyceride levels and an improvement in HDL cholesterol levels) and in both systolic and diastolic blood pressure was observed. Present data support the view of a positive effect of TS on body composition and on glucose and lipid metabolism. In addition, a significant effect on body weight loss was observed, which should be confirmed by a specifically designed RCT.

Glycemic reductions following water- and land-based exercise in patients with type 2 diabetes mellitus

PurposeTo assess the acute glucose responses to the first sessions of three mesocycles of water- and land-based aerobic exercise. MethodsThe water-based exercise group (WBE, n = 14; 54.1 ± 9.1 years) performed deep water walking and/or running, while the land-based exercise group (LBE, n = 11; 60.1 ± 7.3 years) performed walking and/or running on athletic track. In the first mesocycle, patients trained at 85–90% of their anaerobic threshold (AT) for 35 min, progressing to 90–95% of the AT in the second mesocycle, and 95–100% of the AT in the last mesocycle. Capillary glucose was assessed before and immediately after the first session of each mesocycle. ResultsThere was glycemic reduction (p < 0.001) in all sessions, with relative reductions of 19%, 29% and 24% for the WBE and 24%, 29% and 27% for the LBE in the mesocycles 1, 2 and 3, respectively. There were no found differences between groups and between mesocycles. ConclusionsThe acute response of blood glucose to aerobic training between 85 and 100% of the heart rate of AT is effective and independent of the environment in which it is performed. Clinical trial reg. no. NCT01956357, clinicaltrials.gov.

Efficacy and safety of short-term sensor-augmented insulin-pump therapy for poorly controlled patients with type 1 diabetes mellitus

Objective To evaluate the efficacy and safety of short-term sensor-augmented insulin-pump (SAP) therapy for poorly controlled patients with type 1 diabetes mellitus (T1DM). Methods Sixty T1DM patients with glycosylated hemoglobin (HbA1c)>9.0% were randomly assigned to 2 groups treated with SAP or multiple daily insulin injection (MDI) for 6 days, then all patients converted to MDI therapy. Results Compared with MDI group and before therapy, the mean blood glucose concentration (MBG), SD of blood glucose, mean amplitude of glycemic excursion (MAGE) and 24-h area under curve at 10.0 (AUC10.0) levels in SAP group significantly decreased after 6-day therapy (compared with MDI group: t=1.761, P=0.028, t=2.569, P=0.037, t=2.712, P=0.020, t=2.985, P=0.014, compared with before therapy: t=3.128, P=0.006, t=2.689, P=0.024, t=2.966, P=0.013, t=3.076, P=0.009); while there was no difference in 24-h area under curve at 3.9 (AUC3.9) between groups (P>0.05). After 1 month follow-up HbA1c levels decreased in SAP group (t=2.344, P=0.023) and were significantly lower than those in MDI group (t=1.844, P=0.035). There was no difference in daily insulin dosage, fasting C peptide (FCP) and postprandial 2 h C peptide (2 hCP) between two groups (P>0.05). Age (t=2.125, P=0.012) and SAP therapy (t=3.376, P=0.009) were independently correlated with the HbA1c after 1 month. Conclusion Short-term SAP therapy is effective and safe for poorly controlled T1DM patients with rapid glucose lowering and glycemic excursions reduction. Key words: Diabetes mellitus, type 1; Insulin infusion systems; Continuous glucose monitoring; Treatment outcome