- PCB126 inhibits the activation of AMPK-CREB signal transduction required for energy sensing in liver. [Journal Article]
- TSToxicol Sci 2018 Feb 20
- 3,3',4,4',5-pentachlorobiphenyl (PCB126), a dioxin-like PCB, elicits toxicity through a wide array of non-carcinogenic effects, including metabolic syndrome, wasting, and non-alcoholic fatty-liver di...
3,3',4,4',5-pentachlorobiphenyl (PCB126), a dioxin-like PCB, elicits toxicity through a wide array of non-carcinogenic effects, including metabolic syndrome, wasting, and non-alcoholic fatty-liver disease (NAFLD). Previously, we reported decreases in the transcription of several enzymes involved in gluconeogenesis, before the early onset of lipid accumulation. Hence, this study was aimed at understanding the impact of resultant decreases gluconeogenic enzymes on growth, weight and metabolism in the liver, upon extended exposure. Male Sprague-Dawley rats (75-100 g), fed a defined AIN-93G diet, were injected (ip) with single dose of soy oil (5 ml/kg body weight; n = 14) or PCB126 (5 µmol/kg; n = 15), 28 d, prior euthanasia. A subset of rats from each group were fasted for 12h (vehicle (n = 6) and PCB126 (n = 4)). Rats only showed significant weight loss between days 14 and 28 (P < 0.05) and some mortality (P = 0.0413). As in our previous studies, the expression levels of enzymes involved in gluconeogenesis (Pepck-c, G6Pase, Sds, Pc and Ldh-A) and glycogenolysis (Pygl) were strongly downregulated. The decreased expression of these enzymes in PCB126 treated rats after a 12 h fast decreased hepatic glucose production from glycogen and gluconeogenic substrates, exacerbating the hypoglycemia. Additionally, PCB126 caused hepatic steatosis and decreased the expression of the transcription factor Pparα and its targets, necessary for fatty-acid oxidation. The observed metabolic disruption across multiple branches of fasting metabolism resulted from inhibition in the activation of enzyme AMPK and transcription factor CREB signaling, necessary for "sensing" energy-deprivation and the induction of enzymes that respond to the PCB126 triggered fuel crisis in liver.
- Efficacy and safety of canagliflozin as add-on therapy to a glucagon-like peptide-1 receptor agonist in Japanese patients with type 2 diabetes mellitus: a 52-week, open-label, phase IV study. [Journal Article]
- DODiabetes Obes Metab 2018 Feb 23
- Sodium glucose co-transporter 2 (SGLT2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1RAs) are antihyperglycaemic agents with weight-lowering effects. The efficacy and safety of the ...
Sodium glucose co-transporter 2 (SGLT2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1RAs) are antihyperglycaemic agents with weight-lowering effects. The efficacy and safety of the SGLT2 inhibitor canagliflozin as add-on therapy in Japanese patients with type 2 diabetes mellitus (T2DM) and inadequate glycaemic control with a GLP-1RA (≥12 weeks) were evaluated in this phase IV study. Patients received canagliflozin 100 mg once daily for 52 weeks. Efficacy endpoints included the change in glycated haemoglobin (HbA1c), fasting plasma glucose (FPG), bodyweight, systolic blood pressure (SBP), and high-density lipoprotein cholesterol (HDL-C) from baseline to Week 52. Safety endpoints included adverse events (AEs), hypoglycaemia and laboratory tests. Of the 71 patients treated with canagliflozin, 63 patients completed the study. At 52 weeks, HbA1c was significantly reduced from baseline (-0.70%; paired t-test, p <0.001). Significant changes were also observed in FPG (-34.7 mg/dL), bodyweight (-4.46%), SBP (-7.90 mmHg), and HDL-C (7.60%; all p<0.001). The incidence of AEs, adverse drug reactions, and hypoglycaemia was 71.8%, 32.4%, and 9.9%, respectively. All hypoglycaemic events were mild. These findings suggest that the long-term combination of canagliflozin with a GLP-1RA is effective and well tolerated in Japanese patients with T2DM.
- Effect of exenatide QW or placebo, both added to titrated insulin glargine, in uncontrolled type 2 diabetes: the DURATION-7 randomized study. [Journal Article]
- DODiabetes Obes Metab 2018 Feb 23
- CONCLUSIONS: Among patients with inadequate glycaemic control, exenatide QW significantly improved glucose control and decreased body weight, without increased hypoglycaemia or unexpected safety findings. (ClinicalTrials.gov identifier: NCT02229383).
- Body mass index influences the plasma glucose concentration during iatrogenic hypoglycemia in people with type 2 diabetes mellitus: a cross-sectional study. [Journal Article]
- PPeerJ 2018; 6:e4348
- Hypoglycemia 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 ...
Hypoglycemia 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.
- The short-term economic burden of gestational diabetes mellitus in Italy. [Journal Article]
- BPBMC Pregnancy Childbirth 2018 Feb 23; 18(1):58
- CONCLUSIONS: The economic burden of GDM in Italy is substantial even accounting for short-term medical costs only. Future research also addressing long-term consequences from a broader societal perspective is recommended.
- [PROGNOSTIC SIGNIFICANCE OF CHANGES OF BLOOD GLUCOSE LEVEL IN PATIENTS WITH THORACOABDOMINAL INJURIES.] [Journal Article]
- ARAnesteziol Reanimatol 2016; 61(4):293-296
- CONCLUSIONS: High blood glucose levels ( 8,0 mmol / L) in the first day of hospital treatment is a predictor ofpoor outcome in patients with thoracoabdominal injuries.
- [Type 2 Diabetes Diabetes in Older Adults: Example for Patient-Centered Drug Therapy]. [Journal Article]
- DMDtsch Med Wochenschr 2018; 143(4):253-261
- Diabetes in older adults has a high prevalence and is frequently associated with comorbidities of the cardiovascular system, dysfunction of cognition as well as depression and impaired mobility or in...
Diabetes in older adults has a high prevalence and is frequently associated with comorbidities of the cardiovascular system, dysfunction of cognition as well as depression and impaired mobility or increased frailty. Furthermore, impaired renal function, heart failure, risk for hypoglycemia and polypharmacy has to be considered in the decision about the diabetes treatment strategy. The goal of blood glucose management is driven by patient relevant issues and patient self-esteem, quality of life defined by the patient, preservation of physical and social mobility rather than potential long-term effects on reduction of cardio- and microvascular events in the future, which is limited by patient-inherent reduced life expectancy of the aged individual. Therefore, long-term diabetes medication should avoid hypoglycemia and prevent acute hyperglycemia or short-term complications on morbidity and clinical course of geriatric syndromes associated with regular blood glucose levels above 200 mg/dl (11.1 mmol/l). The therapy should be safe, easy to handle for the patient and possibly affect co-morbidities positively. However, there are limited data available about efficacy, safety and pharmacokinetics of drugs in patients over 75 years of age or older. Since more than 5 % of the population in Germany is older than 80 years means that more than 1 million of these individuals suffer from diabetes. It is time to ask for data in these elderly subpopulations by policy makers in health care.
- Bidirectional GPR119 agonism requires peptide YY and glucose for activity in mouse and human colon mucosa. [Journal Article]
- EEndocrinology 2018 Feb 19
- The lipid sensor GPR119 is highly expressed by enteroendocrine L-cells and pancreatic β-cells that release the hormones, PYY and GLP-1, and insulin, respectively. Endogenous oleoylethanolamide (OEA) ...
The lipid sensor GPR119 is highly expressed by enteroendocrine L-cells and pancreatic β-cells that release the hormones, PYY and GLP-1, and insulin, respectively. Endogenous oleoylethanolamide (OEA) and the dietary metabolite, 2-monoacylglycerol (2-OG) can each activate GPR119. Here we compared mucosal responses to selective, synthetic GPR119 agonists (AR440006, AR231453) and the lipids, OEA, 2-OG and N-oleoyldopamine (OLDA) monitoring epithelial ion transport as a read-out for L-cell activity in native mouse and human gastrointestinal (GI) mucosae. We also assessed GPR119 modulation of colonic motility in wild-type (WT), GPR119-/- and PYY-/- mice.The water-soluble GPR119 agonist, AR440006 (that cannot traverse epithelial tight-junctions) elicited responses when added apically or basolaterally in mouse and human colonic mucosas. In both species, GPR119 responses were PYY, Y1 receptor-mediated and glucose-dependent. AR440006 efficacy matched the GI distribution of L-cells in WT tissues but was absent from GPR119-/- tissue. OEA and 2-OG responses were significantly reduced in GPR119-/- colon, but OLDA responses were unchanged. Alternative L-cell activation via free fatty acid receptors FFA1, FFA3, FFA4, the bile acid receptor TGR5, or by melanocortin MC4 were unchanged in GPR119-/- tissues. GPR119 agonism slowed transit in WT, but not PYY-/- colon in vitro. AR440006 (i.p.) slowed WT colonic and upper GI transit significantly in vivo.This data indicates that luminal or blood borne GPR119 agonism can stimulate L-cell PYY release with paracrine consequences and slower motility. We suggest that this glucose-dependent L-cell response to a gut-restricted GPR119 stimulus has potential therapeutic advantage in modulating insulinotropic signalling with reduced risk of hypoglycemia.
- The safety of gliptins : updated data in 2018. [Journal Article]
- EOExpert Opin Drug Saf 2018 Feb 22
- Dipeptidyl peptidase-4 inhibitors (DPP-4is) are generally considered as glucose-lowering agents with a safe profile in type 2 diabetes. Areas covered: An updated review of recent safety data from ran...
Dipeptidyl peptidase-4 inhibitors (DPP-4is) are generally considered as glucose-lowering agents with a safe profile in type 2 diabetes. Areas covered: An updated review of recent safety data from randomised controlled trials, observational studies, meta-analyses, pharmacovigilance reports regarding alogliptin, linagliptin, saxagliptin, sitagliptin, and vildagliptin, with a special focus on risks of hypoglycaemia, pancreatitis and pancreatic cancer, major cardiovascular events, hospitalisation for heart failure and other new safety issues, such as bone fractures and arthralgia. The safety of DPP-4i use in special populations, elderly patients, patients with renal impairment, liver disease or heart failure, will also be discussed. Expert opinion: The good tolerance/safety profile of DPP-4is has been largely confirmed, including in more fragile populations, with no gastrointestinal adverse effects and a minimal risk of hypoglycaemia. DPP-4is appear to be associated with a small increased incidence of acute pancreatitis in placebo-controlled trials, although most observational studies are reassuring. Of note, the incidence of pancreatic cancer is reduced. Most recent studies with DPP-4is do not confirm the increased risk of hospitalisation for heart failure reported with saxagliptin in SAVOR-TIMI 53, but further post-marketing surveillance is still recommended. New adverse events have been reported such as arthralgia, yet a causal relationship remains unclear.
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- Decrease of γ-aminobutyric acid and zinc ions in the islet periportal circulation stimulates glucagon secretion during hypoglycemia. [Journal Article]
- ETExp Ther Med 2018; 15(3):2507-2511
- The present study assessed the effects of γ-aminobutyric acid (GABA) from β-cells on glucose levels and glucagon secretion, and identified channels via which glucagon secretion is initiated. Anin viv...
The present study assessed the effects of γ-aminobutyric acid (GABA) from β-cells on glucose levels and glucagon secretion, and identified channels via which glucagon secretion is initiated. Anin vivoexperiment was performed containing three groups: Intrapancreatic artery infusion of GABA alone, GABA plus insulin or insulin alone in rats with diabetes. Rats infused with GABA and insulin were also subdivided in groups receiving additional infusion of K+-channel activator diazoxide (DIA), K+-channel blocker tolbutamide (TLB) and calcium channel blocker nifedipine (NIF). In the hypoglycemic state, termination of infusion of insulin and insulin plus GABA resulted in signaling to the α-cells to secrete glycogen, while that of GABA alone did not. However, intrapancreatic artery infusion of K+-channel activator DIA, K+-channel blocker TLB or calcium channel blocker NIF in addition to GABA and insulin had no effect on glucagon secretion. In conclusion, if the delivery of insulin or GABA plus insulin in rats with hypoglycemia is terminated, β-cells are stimulated and signal the α-cells to secrete glucagon. Thus, the detection of a sudden decrease in zinc levels by β-cells as well as a decrease in GABA in the periportal circulation induces signaling to α-cells to stimulate them to secrete glucagon.