scholarly journals Exendin-4 disrupts responding to reward predictive incentive cues in rats

2018 ◽  
Author(s):  
Ken T. Wakabayashi ◽  
Ajay N. Baindur ◽  
Malte Feja ◽  
Karie Chen ◽  
Kimberly Bernosky-Smith ◽  
...  
Keyword(s):  
Weight Loss ◽  
Receptor Agonist ◽  
Drug Effect ◽  
Sucrose Reward ◽  
Reward Seeking ◽  
Seeking Behavior ◽  
Mesolimbic Dopamine Pathway ◽  
Dose Dependent ◽  
Dose Dependent Effect

AbstractExendin-4 (EX4) is a GLP-1 receptor agonist used clinically to control glycemia in Type-2 Diabetes Mellitus (T2DM), with the additional effect of promoting weight loss. The weight loss seen with EX4 is attributable to the varied peripheral and central effects of GLP-1, with contributions from the mesolimbic dopamine pathway that are implicated in cue-induced reward seeking. GLP-1 receptor agonists reduce preference for palatable foods (i.e. sweet and fat) as well as the motivation to obtain and consume these foods. Accumulating evidence suggest that GLP-1 receptor activity can attenuate cue-induced reward seeking behaviors. In the present study, we tested the effects of EX4 (0.6, 1.2, and 2.4 µg/kg i.p.) on incentive cue (IC) responding. This rat model required rats to emit a nosepoke response during an intermittent audiovisual cue to obtain a sucrose reward (10% solution). EX4 dose-dependently attenuated responding to reward predictive cues, and increased latencies of the cue response and reward cup entry to consume the sucrose reward. Moreover, EX4 dose-dependently decreased the number of nosepokes relative to the number of cue presentations during the session. There was no drug effect on the number of reward cup entries per reward earned during the session, a related reward-seeking behavior with similar locomotor demand. Interestingly, there was a dose-dependent effect of time on the responding to reward predictive cues and nosepoke response latency, such that 2.4 µg/kg of EX4 delayed responding to the initial IC of the behavioral session. Together, these findings suggest that agonism of the GLP-1 receptor with EX4 modulates the incentive properties of cues attributed with motivational significance.

scholarly journals Baseline interleukin1beta expression in peripheral blood monocytes predicts the extent of weight loss and nonalcoholic fatty liver improvement in obese subjects with prediabetes or type 2 diabetes

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
P.G Simeone ◽  
S Costantino ◽  
R Tripaldi ◽  
R Liani ◽  
S Ciotti ◽  
...  
Keyword(s):  
Weight Loss ◽  
Peripheral Blood ◽  
Receptor Agonist ◽  
Mononuclear Cells ◽  
Lifestyle Changes ◽  
Funding Source ◽  
Peripheral Blood Mononuclear ◽  
Blood Mononuclear Cells ◽  
Obese Subjects

Abstract Background Non-alcoholic fatty liver disease (NAFLD) represents a hallmark of metabolic syndrome. Interleukin-1β (IL-1β), a well-studied cytokine involved in obesity-related systemic inflammation as well as in the pathogenesis of type 2 diabetes (T2D), promotes hepatic steatosis by stimulating triglycerides and cholesterol accumulation in primary liver hepatocytes and lipid droplets formation. The most compelling evidence for a major role for IL-1β in metabolic imbalance and inflammation comes from the recent Canakinumab Anti-inflammatory Thrombosis Outcome (CANTOs)trial, where inhibition of IL-1β pathway was associated with a reduction of cardiovascular events in high-risk patients. Purpose The present study was designed to determine: i)whether an equal degree of weight loss by liraglutide or lifestyle changes has a different impact on NAFLD extent and IL-1β expression in peripheral blood mononuclear cells from obese subjects with prediabetes or early T2D; ii)whether baseline IL-1β levels may predict the extent of weight loss and related metabolic changes. Methods Thirty-two metformin-treated obese subjects with prediabetes [impaired fasting glucose (IFG) or impaired glucose tolerance (IGT) or both (n=16)] or newly diagnosed T2D (n=16), were randomized to the glucagon-like peptide receptor agonist (GLP-RA) liraglutide (1.8 mg/d) or lifestyle counselling until achieving a modest and comparable weight loss (−7% of initial body weight). Visceral (VAT) and adipose tissue distribution were assessed by magnetic resonance. Gene expression of IL-1β in peripheral blood mononuclear cells was assessed by real time PCR. Results At baseline, IL-1β positively correlated to body mass index (BMI) (rho=0.421, p=0.016), fasting plasma glucose (rho=0.415, p=0.018), HbA1c (rho=0.349, p=0.050), VAT (rho=0.388, p=0.028), NAFLD (rho=0.454, p=0.009), platelet count (rho=0.510, p=0.003), chemerin (rho=0.455, p=0.009) and interleukin-1 receptor agonist (IL1-RA) (rho=0.519, p=0.002). After achievement of the weight loss target in the two groups, a comparable reduction of IL-1 β (p<0.001 lifestyle changes; p=0.029 liraglutide treatment) was observed in both arms, in parallel with a comparable improvement in glycaemic control, C-reactive protein (CRP),BMI and NAFLD. Furthermore, basal levels of IL-1β correlated directly with delta BMI (p=0.015) and delta NAFLD (p=0.002) (Figure 1). Conclusion In obese patients with initial impairment of glucose metabolism, IL-β-driven inflammation correlates with glycaemic control, adipose tissue distribution and platelet count. Successful weight loss, achieved with either lifestyle changes or an incretin-based therapy, is associated with a significant reduction of both IL-1β levels and NAFLD degree. Of interest, basal levels of IL-1β predicts the extent of weight loss and NAFLD improvement, regardless of the intervention. Our results may set the stage for ad-hoc studies investigating the usefulness of baseline IL-1β a levels as a drug-response biomarker. Figure 1 Funding Acknowledgement Type of funding source: Public Institution(s). Main funding source(s): This study was supported by a grant from the Italian Ministry of University and Research (PRIN no. 2010JS3PMZ to F.S.).

Lixisenatide—Once-daily Glucagon-like Peptide-1 Receptor Agonist in the Management of Type 2 Diabetes

2010 ◽  
Vol 8 (1) ◽  
pp. 12 ◽  
Author(s):  
Celeste C L Quianzon ◽  
Mansur E Shomali ◽  
◽  
Keyword(s):  
Type 2 Diabetes ◽  
Weight Loss ◽  
Receptor Agonist ◽  
Potential Role ◽  
Glycosylated Haemoglobin ◽  
Once Daily ◽  
Glucagon Suppression ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

The glucagon-like peptide-1 receptor agonist diabetes medications have become important due to their unique features, such as their potency of glycosylated haemoglobin (HbA1C) lowering, durability of effect, glucose-depending insulin secretion resulting in a low risk of hypoglycaemia, glucagon suppression and weight loss. Lixisenatide is an investigational compound in this class, exhibits all of these features, and has some unique properties, which are highlighted in this review. The pharmacology of lixisenatide, the results of recent clinical trials investigating this agent, and its potential role in the management of type 2 diabetes will be discussed.

Lixisenatide—Once-daily Glucagon-like Peptide-1 Receptor Agonist in the Management of Type 2 Diabetes

2011 ◽  
Vol 07 (02) ◽  
pp. 104
Author(s):  
Celeste C L Quianzon ◽  
Mansur E Shomali ◽  
◽  
Keyword(s):  
Type 2 Diabetes ◽  
Weight Loss ◽  
Receptor Agonist ◽  
Potential Role ◽  
Glycosylated Hemoglobin ◽  
Once Daily ◽  
Glucagon Suppression ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

The glucagon-like peptide-1 receptor agonist diabetes medications have become important due to their unique features, such as their potency of glycosylated hemoglobin (HbA1C) lowering, durability of effect, glucose-depending insulin secretion resulting in a low risk of hypoglycemia, glucagon suppression, and weight loss. Lixisenatide is an investigational compound in this class, exhibits all of these features, and has some unique properties, which are highlighted in this review. The pharmacology of lixisenatide, the results of recent clinical trials investigating this agent, and its potential role in the management of type 2 diabetes will be discussed.

scholarly journals Case Report: Hemolysis in a G6PD-deficient patient, a dose-dependent effect of metformin

F1000Research ◽  
2020 ◽  
Vol 9 ◽  
pp. 1234
Author(s):  
Yusra Irshad ◽  
Mahum Nadeem ◽  
Usman Khan ◽  
Ezza Tariq ◽  
Aemen Khakwani
Keyword(s):  
Genetic Disorder ◽  
Middle Eastern ◽  
Kidney Injury ◽  
Cumulative Effect ◽  
Hemodynamic Instability ◽  
Phosphate Deficiency ◽  
White Blood Count ◽  
Dose Dependent ◽  
Dose Dependent Effect

Glucose-6-phosphate deficiency is an X-linked genetic disorder, which predisposes erythrocytes to oxidative stress, resulting in hemolysis. It is the most common enzymatic deficiency, and typically affects African, Asian, Mediterranean, and Middle Eastern lineages. It can be induced by some medications, chemicals, and foods. Metformin is an uncommon drug to cause hemolysis in G6PD-deficient patients. We report a case of a 52-year old African American male with G6PD-related hemolysis secondary to toxic metformin accumulation with acute kidney injury (AKI). The patient was a type-2 diabetic and was taking metformin (500mg twice daily) for three years. He presented to the ER with nausea, vomiting, and diarrhea for last three days with severe hemodynamic instability. Labs revealed hemoglobin 15mg/dl, white blood count 28 mm3/L, creatinine 10 mg/dl, blood urea nitrogen 100 mg/dl, bicarbonate 7 mEq/L, lactic acid 17 mg/dl, pH 6.8, pCO2 21mmHg, metformin 41 mcg/ml, albumin-globulin 41. Severe sepsis protocol was activated; IV fluids 30ml/kg bolus and antibiotics were given. CT abdomen revealed colitis. The patient was started on continuous renal replacement therapy. The next day, the patient’s hemoglobin dropped to 12.6 mg/dl. A hemolytic panel was unswerving with hemolysis and G6PD levels reported low at 1.72. The patient improved with antibiotics, but the hemolysis continued. Metformin toxicity induced hemolysis was suspected. The patient’s hemoglobin dropped to 6g/dl and he received blood transfusions. His hemoglobin started to improve with hemodialysis sessions, as metformin levels started to normalize, emphasizing the fact that patient was clearing metformin. Unlike most cases reported, in which hemolysis occurs within days to months of starting metformin, in our patient it occurred due to the cumulative effect of metformin because of the patient’s underlying AKI. This led us to propose that the hemolytic effect of metformin may not only be time-dependent but also dose-dependent.

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