Incremental effect of liraglutide on traditional insulin injections in rats with type 2 diabetes mellitus by maintaining glycolipid metabolism and cardiovascular function.

Type 2 diabetes mellitus (T2DM) is characterized by chronic hyperglycemia, damaged insulin secretion and insulin resistance with high morbidity and mortality. Liraglutide (liragl) and insulin are effective hypoglycemic agents used in T2DM treatment. The potential effect of liragl in combination with insulin on T2DM remains unclear. The aim of the current study was to explore effects of liragl combined with insulin on glycolipid metabolism and cardiovascular function in rats with diabetes. A diabetes model was established in Sprague Dawley rats exposed to a high calorie and high sugar diet in conjunction with intraperitoneal injections of streptozotocin. Results indicated that liragl or insulin used alone decreased glucose and elevated insulin and c-peptide levels. However, their combination revealed greater effects. A significant increase in high-density lipoprotein cholesterol levels along with a decrease in total cholesterol, triglycerides and low-density lipoprotein cholesterol were observed in liragl- and insulin-treated rats compared with STZ-induced diabetes rats. Furthermore, co-administration of liragl and insulin significantly decreased sterol regulatory element-binding protein 1 levels and increased adenosine 5'-monophosphate kinase-α1 and carnitine palmitoyltransferase 1 expression. Combining liragl with insulin reduced myocardial hypertrophy level and gaps between cardiomyocytes compared with liragl or insulin treatment alone. Caspase-3 expression was significantly decreased by combination treatment of liragl and insulin. Oxidative damage was significantly decreased by co-administration of liragl and insulin through enhancing superoxide dismutase expression and reducing malondialdehyde. Furthermore, combination of liragl and insulin significantly reduced myocardial enzyme expression, including myoglobin, creatine kinase-muscle/brain and cardiac troponin I. In summary, the current study demonstrated synergistic effects of liragl and insulin injections on a T2DM rat model by maintaining glycolipid metabolism and cardiovascular function.

[1]  I. Heid,et al.  Association of sleep-disordered breathing with severe chronic vascular disease in patients with type 2 diabetes. , 2018, Sleep medicine.

[2]  Yuejin Yang,et al.  Changes in characteristics, risk factors, and in-hospital mortality among patients with acute myocardial infarction in the capital of China over 40 years. , 2018, International journal of cardiology.

[3]  Q. Guan,et al.  Prevalence, awareness, treatment and control of diabetes mellitus among middle-aged and elderly people in a rural Chinese population: A cross-sectional study , 2018, PloS one.

[4]  M. Metra,et al.  The role of type 2 diabetes mellitus on hypertensive‐related aortic stiffness , 2018, Echocardiography.

[5]  D. Schillinger,et al.  State of Diabetes Self-Management Education in the European Union Member States and Non-EU Countries: The Diabetes Literacy Project , 2018, Journal of diabetes research.

[6]  R. Hovorka,et al.  Glucose‐responsive insulin delivery for type 1 diabetes: The artificial pancreas story , 2017, International journal of pharmaceutics.

[7]  Ming Zhang,et al.  Risk of type 2 diabetes mellitus associated with plasma lipid levels: The rural Chinese cohort study. , 2018, Diabetes research and clinical practice.

[8]  Y. Liu,et al.  Liraglutide and Metformin alone or combined therapy for type 2 diabetes patients complicated with coronary artery disease , 2017, Lipids in Health and Disease.

[9]  Wei Yu,et al.  Hawthorn Leaf Flavonoids Protect against Diabetes-Induced Cardiomyopathy in Rats via PKC-α Signaling Pathway , 2017, Evidence-based complementary and alternative medicine : eCAM.

[10]  Xin Liu,et al.  Effects of Chimonanthus nitens Oliv. Leaf Extract on Glycolipid Metabolism and Antioxidant Capacity in Diabetic Model Mice , 2017, Oxidative medicine and cellular longevity.

[11]  Yuqin Mao,et al.  Liraglutide activates autophagy via GLP-1R to improve functional recovery after spinal cord injury , 2017, Oncotarget.

[12]  X. Ye,et al.  Spatiotemporal delivery of nanoformulated liraglutide for cardiac regeneration after myocardial infarction , 2017, International journal of nanomedicine.

[13]  Xin Wang,et al.  Effects of liraglutide on hemodynamic parameters in patients with heart failure , 2017, Oncotarget.

[14]  T. Davis,et al.  Successful Withdrawal of Insulin Therapy After Post-Treatment Clearance of Hepatitis C Virus in a Man with Type 2 Diabetes , 2017, The American journal of case reports.

[15]  Sonal Singh,et al.  Glucagon‐like peptide‐1 receptor agonists compared with basal insulins for the treatment of type 2 diabetes mellitus: a systematic review and meta‐analysis , 2016, Diabetes, obesity & metabolism.

[16]  Nitesh Kumar,et al.  Insulin Protects against Brain Oxidative Stress with an Apparent Effect on Episodic Memory in Doxorubicin-Induced Cognitive Dysfunction in Wistar Rats. , 2017, Journal of environmental pathology, toxicology and oncology : official organ of the International Society for Environmental Toxicology and Cancer.

[17]  A. Bossowski,et al.  Assessment of preservation of beta-cell function in children with long-standing type 1 diabetes with "ultrasensitive c-peptide" method. , 2017, Pediatric endocrinology, diabetes, and metabolism.

[18]  Xiaofang Fan,et al.  The association between single nucleotide polymorphisms of the Apelin gene and diabetes mellitus in a Chinese population , 2016, Journal of pediatric endocrinology & metabolism : JPEM.

[19]  A. S. Jiménez-Osorio,et al.  Curcumin and insulin resistance—Molecular targets and clinical evidences , 2016, BioFactors.

[20]  Scott R. Drab,et al.  GLP1‐RA Add‐on Therapy in Patients with Type 2 Diabetes Currently on a Bolus Containing Insulin Regimen , 2016, Pharmacotherapy.

[21]  G. Sesti,et al.  The GLP-1 receptor agonists exenatide and liraglutide activate Glucose transport by an AMPK-dependent mechanism , 2016, Journal of Translational Medicine.

[22]  O. Nielsen,et al.  Effects of the glucagon-like peptide-1 receptor agonist liraglutide on systolic function in patients with coronary artery disease and type 2 diabetes: a randomized double-blind placebo-controlled crossover study , 2016, Cardiovascular Diabetology.

[23]  Yating Deng,et al.  [Insulin combined with selenium inhibit p38MAPK/CBP pathway and suppresses cardiomyocyte apoptosis in rats with diabetic cardiomyopathy]. , 2016, Xi bao yu fen zi mian yi xue za zhi = Chinese journal of cellular and molecular immunology.

[24]  L. Rydén,et al.  Clinical Implications of Cardiovascular Outcome Trials in Type 2 Diabetes: From DCCT to EMPA-REG. , 2016, Clinical therapeutics.

[25]  F. Gao,et al.  Mutual inhibition of insulin signaling and PHLPP-1 determines cardioprotective efficiency of Akt in aged heart , 2016, Aging.

[26]  Y. Terauchi,et al.  Early liraglutide treatment improves β-cell function in patients with type 2 diabetes: a retrospective cohort study. , 2015, Endocrine journal.

[27]  B. Zinman,et al.  The Impact of Chronic Liraglutide Therapy on Glucagon Secretion in Type 2 Diabetes: Insight From the LIBRA Trial. , 2015, The Journal of clinical endocrinology and metabolism.

[28]  Zhigang Zeng,et al.  The Glucagon-Like Peptide-1 Analogue Liraglutide Inhibits Oxidative Stress and Inflammatory Response in the Liver of Rats with Diet-Induced Non-alcoholic Fatty Liver Disease. , 2015, Biological & pharmaceutical bulletin.

[29]  潘旭东,et al.  Dan-gua Fang (丹瓜方) Improves Glycolipid Metabolic Disorders by Promoting Hepatic Adenosine 5’-monophosphate Activated Protein Kinase Expression in Diabetic Goto-kakizaki Rats , 2015 .

[30]  J. González‐Gallego,et al.  Manganese superoxide dismutase and oxidative stress modulation. , 2015, Advances in clinical chemistry.

[31]  Jing Wu,et al.  Dan-gua Fang (丹瓜方) improves glycolipid metabolic disorders by promoting hepatic adenosine 5′-monophosphate activated protein kinase expression in diabetic Goto-Kakizaki rats , 2015, Chinese Journal of Integrative Medicine.

[32]  Yixuan Song,et al.  [Effects of insulin-like growth factor-1 on the myocardium in diabetic rats]. , 2014, Zhonghua yi xue za zhi.

[33]  K. Petersen,et al.  The role of hepatic lipids in hepatic insulin resistance and type 2 diabetes , 2014, Nature.

[34]  Antonio Ayala,et al.  Lipid Peroxidation: Production, Metabolism, and Signaling Mechanisms of Malondialdehyde and 4-Hydroxy-2-Nonenal , 2014, Oxidative medicine and cellular longevity.

[35]  Magdalene Szuszkiewicz-Garcia,et al.  Cardiovascular disease in diabetes mellitus: risk factors and medical therapy. , 2014, Endocrinology and metabolism clinics of North America.

[36]  B. D. de Galan [Prevention of insulin-induced hypoglycaemia in the elderly]. , 2014, Nederlands tijdschrift voor geneeskunde.

[37]  B. Wang,et al.  Liraglutide ameliorates glycometabolism and insulin resistance through the upregulation of GLUT4 in diabetic KKAy mice. , 2013, International journal of molecular medicine.

[38]  P. Shanthi,et al.  Kalpaamruthaa modulates oxidative stress in cardiovascular complication associated with type 2 diabetes mellitus through PKC-β/Akt signaling. , 2013, Canadian journal of physiology and pharmacology.

[39]  Zuyi Yuan,et al.  Insulin ameliorates miR-1-induced injury in H9c2 cells under oxidative stress via Akt activation , 2012, Molecular and Cellular Biochemistry.

[40]  R. Chilton,et al.  The Cardiovascular Effects of GLP-1 Receptor Agonists , 2010, Cardiovascular therapeutics.

[41]  H. Yki-Järvinen Management of Type 2 Diabetes Mellitus and Cardiovascular Risk , 2000, Drugs.

[42]  M. Nauck Incretin-based therapies for type 2 diabetes mellitus: properties, functions, and clinical implications. , 2011, The American journal of medicine.

[43]  Joshua J. Neumiller Differential chemistry (structure), mechanism of action, and pharmacology of GLP-1 receptor agonists and DPP-4 inhibitors. , 2009, Journal of the American Pharmacists Association : JAPhA.

[44]  D. Stoffers,et al.  Role of glucagon-like peptide-1 in the pathogenesis and treatment of diabetes mellitus. , 2006, The international journal of biochemistry & cell biology.

[45]  L. Cai,et al.  Hyperglycemia-induced apoptosis in mouse myocardium: mitochondrial cytochrome C-mediated caspase-3 activation pathway. , 2002, Diabetes.

[46]  G. Sigurdsson,et al.  Coronary heart disease mortality amongst non‐insulin‐dependent diabetic subjects in Iceland: the independent effect of diabetes. The Reykjavik Study 17‐year follow up , 1998, Journal of internal medicine.

[47]  C. Price,et al.  Kinetic glucose dehydrogenase method for glucose measurement with a discrete kinetic analyzer overcomes interference by ascorbate. , 1984, Clinical chemistry.

[48]  D. Kipnis,et al.  Abnormalities in carbohydrate tolerance associated with elevated plasma nonesterified fatty acids. , 1965, The Journal of clinical investigation.