PracticeUpdate: Endocrinology

EASD 2016

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Platelets from poorly controlled type 2 diabetes patients show impaired ability to protect against cardiac ischaemia/reperfusion injury Platelets from poorly controlled type 2 diabetic patients have been shown to have lost their ability to protect against ischaemia/reperfusion injury, but also induced an increase of infarct size and of lactate dehydrogenase release, a marker of necrosis. T his outcome of an investiga- tion of the direct role of plate- lets to influence infarct size in

Ischaemia and reperfusion are implicated in a variety of clinical conditions including thrombolytic therapy for myocardial infarction. Reperfusion of previously ischae- mic tissue, while essential to prevent irreversible tissue injury, elicits inflammatory responses with increased production of reactive oxy- gen species and soluble mediators, leading to impaired organ function. Dr Russo and colleagues perfused hearts from male Wistar rats in

Langendorff mode with an oxygen- ated Krebs solution at constant flow (9 –10 mL/min/g). After 20 minutes of stabilisation, hearts were divided into three groups: 1.Controls received 20 minutes of oxygenated buffer perfusion 2. A group received 20 minutes of oxygenated buffer containing 30 x 10 6 /mL platelets from healthy subjects (n=6, four males, two females, age 49 ± 3 years) 3. A group received 20 minutes of

oxygenated buffer containing 30 x 10 6 /mL platelets from pa- tients with type 2 diabetes (n=5, four males/one females, age 55 ± 3 years, haemoglobin A1c 14 ± 1%) At the end of platelet-perfusion, the hearts underwent 30 minutes of normothermic global ischaemia fol- lowed by 60 minutes of reperfusion. Lactate dehydrogenase release and infarct size were assessed. In plate- let samples from each subject, the following were also evaluated:

• platelet aggregation to adenosine diphosphate 10 µmoL/L, col- lagen 4 mg/L, arachidonic acid 0.5 mmoL/L (Born’s method) • activation of PI-3 kinase/Akt and MAPK/Erk-1/2 pathways • intraplatelet reactive oxygen spe- cies production • cyclooxygenase-1 expression. In type 2 diabetes, platelet hyperreactivity could hold predictive value of myocardial dysfunction after ischaemia/reperfusion injury. Infarct size was 59 ± 2% of risk area in control hearts and was small- er in hearts pretreated with platelets from healthy subjects (49 ± 3% of risk area; P < 0.05), but higher in hearts pretreated with platelets from type 2 diabetic patients (63 ± 4% of risk area; P < 0.05) than in those pretreated with platelets-from healthy subjects. Lactate dehydrogenase release corroborated the data on infarct size. Perfusion pressure was not affected by any of the treatments. Interest- ingly, platelets from type 2 diabetic patients, in comparison with those from healthy subjects, showed: • A higher trend to aggregate in re- sponse to arachidonic acid (76 ± 11 vs 51 ± 3, P < 0.05); adenosine diphosphate (78 ± 14 vs 63 ± 2, difference not significant); and collagen (89 ± 13 vs 65 ± 2, dif- ference not significant) • A greater increase in basal values of phosphorylated Akt and Erk-2 in response to collagen (2.9 ± 0.2 vs 1.5 ± 0.6, P = 0.07; and 15.6 ± 3.3 vs 5.5 ± 1.2, P < 01.03, re- spectively) and arachidonic acid (2 ± 0.3 vs 1.4 ± 0.6, difference not significant; and 22 ± 4.9 vs 5.4 ± 1.5, P < 0.007) • Greater reactive oxygen species production (mean fluorescence intensity per minute) stimulated by arachidonic acid (73,708 ± 560 vs 35, 350 ± 720, P < 0.0001) • Higher expression of cyclooxyge- nase-1 (arbitrary units 26,643 ± 210 vs 13,200 ± 350, P < 0.0001). Dr Russo concluded that platelets from poorly controlled type 2 diabetic patients lost not only their ability to protect against ischaemia/reperfusion injury but also induced an increase of infarct size and lactate dehydro- genase release, a marker of necrosis. These effects were associated with an increased tendency of plate- lets to aggregate in response to the main physiological proaggregating agents, as well as increased produc- tion of reactive oxygen species and cyclooxygenase-1 expression. These findings suggest that, in type 2 dia- betes, platelet hyperreactivity could hold predictive value of myocardial dysfunction after ischaemia/reperfu- sion injury.

a rat model of ischaemia/reperfusion after infusion of human platelets from type 2 diabetic or healthy sub- jects was reported at the meeting. Isabella Russo, PhD, of the Uni- versity of Turin, Italy, explained that in type 2 diabetes, platelet hyper- reactivity is partially responsible for a switch of the coagulation system toward a prothrombotic state.

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Dual Action NovoMix ® 30 2,3

PBS Information: This product is listed on the PBS for the treatment of diabetes mellitus.

Please review Product Information before prescribing. The Product Information can be accessed at www.novonordisk.com.au

Minimum Product Information. NovoMix ® 30 (insulin aspart (rys)). Indication: Treatment of diabetes mellitus. Contraindications: Hypoglycaemia. Hypersensitivity to insulin aspart or excipients. Precautions: Inadequate dosing or discontinuation of treatment, especially in type 1 diabetes, may lead to hyperglycaemia and diabetic ketoacidosis. Where blood glucose is greatly improved, e.g. by intensified insulin therapy, patients may experience a change in usual warning symptoms of hypoglycaemia, and should be advised accordingly. The impact of the rapid onset of action should be considered in patients where a delayed absorption of food might be expected. Do not use in insulin infusion pumps. No studies in children and adolescents under the age of 18. No clinical experience in pregnancy. When thiazolidinediones (TZDs) are used in combination with insulin, patients should be observed for signs and symptoms of congestive heart failure, weight gain and oedema; discontinuation of TZDs may be required. Insulin administration may cause insulin antibodies to form and, in rare cases, may necessitate adjustment of the insulin dose. Interactions: Oral hypoglycaemic agents, octreotide, lanreotide, monoamine oxidase inhibitors, non-selective beta-adrenergic blocking agents, angiotensin converting enzyme (ACE) inhibitors, salicylates, alcohol, anabolic steroids, alpha-adrenergic blocking agents, quinine, quinidine, sulphonamides, oral contraceptives, thiazides, glucocorticoids, thyroid hormones, sympathomimetics, growth hormone,

diazoxide, asparaginase, nicotinic acid. Adverse Effects: Hypoglycaemia. Dosage and Administration: Dosage as determined by physician. NovoMix ® 30 should be administered immediately before a meal, or when necessary after the start of a meal. Resuspend immediately before use. Discard the needle after each injection. Subcutaneous injection only. NovoMix ® 30 must not be administered intravenously. (July 2014). References: 1. Liebl A et al. Drugs 2012; 72(11): 1495–520. 2. Wu T et al. Diabetes Ther 2015; 6(3): 273–87. 3. NovoMix ® 30 Approved Product Information (Jul 2014). Novo Nordisk Pharmaceuticals Pty Ltd. ABN 40 002 879 996. Level 3, 21 Solent Circuit, Baulkham Hills, NSW 2153. NovoCare ® Customer Care Centre (Australia) 1800 668 626. www.novonordisk.com.au. ® Registered trademark of Novo Nordisk A/S. AU/NM/0116/0004. January 2016.

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