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Abstract:The UK Prospective Diabetes Study demonstrated that the hypoglycaemic drug metformin is associated with a reduction in cardiovascular events in a group of obese type 2 diabetes patients. The energy sensing enzyme AMP-activated protein kinase (AMPK) has been indicated to play an important protective role in the ischaemic heart and is activated by metformin. The aim of this study was to determine whether a single dose of metformin protects the myocardium against experimentally induced ischaemia 24 hr after the administration, and furthermore to determine whether a single dose of metformin results in an acute increase in myocardial AMPK activity. Wistar rats were given either a single oral dose of metformin (250 mg/kg body weight), or a single oral dose of saline. After 24 hr, the hearts were Langendorff-perfused and subjected to 45 min. of coronary artery occlusion. Infarct size was determined by staining with triphenyltetrazoliumchloride (TTC) and Evans Blue and expressed as a percentage of the risk zone (IS/AAR %). Isoform specific AMPK activity was measured 2 hr after administration of metformin or saline. Infarct size was significantly reduced in the metformin treated (I/R: 19.9 ± 3.9% versus 36.7 ± 3.6%, P < 0.01, n = 8-14) compared to the control group. A single oral dose of metformin resulted in an approximately ~2-fold increase in AMPK-α 2 activity 2 hr after administration (P < 0.015, n = 10). In conclusion, a single dose of metformin results in an acute increase in myocardial AMPK activity measured 2 hr after administration and induces a significant reduction in myocardial infarct size 24 hr after metformin administration. Increased AMPK activity may be an important signal mediator involved in the mechanisms behind the cardioprotective effects afforded by metformin.The biguanide metformin is an effective hypoglycaemic drug that has been widely used for the treatment of type 2 diabetes for more than 50 years. The glucose-lowering effect results from increased glucose utilization and decreased endogenous glucose release due to decreased gluconeogenesis [1]. The UK Prospective Diabetes Study (UKPDS) demonstrated that metformin has a beneficial effect on different cardiovascular risk factors [2]. Metformin treatment resulted in a 30% lower risk of macrovascular diseases compared to the other treatment modalities in the UKPDS. For myocardial infarction alone, the metformin group had a 39% lower risk than the conventional treatment group. Because patients with type 2 diabetes mellitus are at increased risk of developing cardiovascular disease, sufficient treatment of these patients is crucial and the mechanisms whereby the advantageous actions of metformin are mediated require clarification.Recent studies have provided evidence that some of the beneficial glucose-lowering effects of metformin might be mediated through activation of AMP-activated protein kinase (AMPK) [3,4]. AMPK is a serine-threonine kinase that acts as an energy sensor in various cell types. When the cell is exposed to energy depleti...

is associated with type 2 diabetes and depression, which may be related to prenatal stress and insulin resistance as a result of chronic hypothalamic-pituitary-adrenal (HPA) axis hyperactivity. We examined whether treatment with a selective serotonin reuptake inhibitor [escitalopram (ESC)] could downregulate HPA axis activity and restore insulin sensitivity in LBW rats. After 4 -5 wk of treatment, ESC-exposed LBW (SSRI-LBW) and saline-treated control and LBW rats (Cx and LBW) underwent an oral glucose tolerance test or a hyperinsulinemic euglycemic clamp to assess whole body insulin sensitivity. Hepatic phosphoenolpyruvate carboxykinase (PEPCK) mRNA expression and red skeletal muscle PKB Ser 473 phosphorylation were used to assess tissue-specific insulin sensitivity. mRNA expression of the hypothalamic mineralocorticoid receptor was fivefold upregulated in LBW (P Ͻ 0.05 vs. Cx), accompanied by increased corticosterone release during restraint stress and total 24-h urinary excretion (P Ͻ 0.05 vs. Cx), whole body insulin resistance (P Ͻ 0.001 vs. Cx), and impaired insulin suppression of hepatic PEPCK mRNA expression (P Ͻ 0.05 vs. Cx). Additionally, there was a tendency for reduced red muscle PKB Ser 473 phosphorylation. The ESC treatment normalized corticosterone secretion (P Ͻ 0.05 vs. LBW), whole body insulin sensitivity (P Ͻ 0.01) as well as postprandial suppression of hepatic mRNA PEPCK expression (P Ͻ 0.05), and red muscle PKB Ser 473 phosphorylation (P Ͻ 0.01 vs. LBW). We conclude that these data suggest that the insulin resistance and chronic HPA axis hyperactivity in LBW rats can be reversed by treatment with an ESC, which downregulates HPA axis activity, lowers glucocorticoid exposure, and restores insulin sensitivity in LBW rats.selective serotonin reuptake inhibitors STRESS MAY BE INVOLVED IN THE DEVELOPMENT of major Western lifestyle disorders such as cardiovascular disease and the metabolic syndrome (53,59,61). Particularly in humans born with low birth weight (LBW) (e.g., birth weight Ͻ2,500 g), stressrelated psychiatric illness and metabolic disturbances seem to coexist, and the prevalence of conditions associated with psychological stress, such as melancholic depression, is increased in subjects born with LBW (35). In addition, these individuals also have a higher prevalence of type 2 diabetes (23, 57, 80) that is potentially due to early development of insulin resistance. Hence, the LBW condition can be considered as both a predepressive and a prediabetic state. However, the exact mechanisms responsible for these changes and whether they are associated are still debated.Recently, impairments in hippocampal structure and function have been proposed to account for some of the phenotypic characteristics of LBW (21,40,63). Hippocampus regulates the overall circadian tonus of the hypothalamic-pituitary-adrenal (HPA) axis, and accordingly, the processes involved in corticosteroid regulation in LBW have been studied extensively. At this point the HPA axis in LBW has been studied at various developmental ...

We have found that cardioprotection by l-glutamate mimics protection by classical ischaemic preconditioning (IPC). We investigated whether the effect of IPC involves amino acid transamination and whether IPC modulates myocardial glutamate metabolism. In a glucoseperfused, isolated rat heart model subjected to 40 min global no-flow ischaemia and 120 min reperfusion, the effects of IPC (2 cycles of 5 min ischaemia and 5 min reperfusion) and continuous glutamate (20 mm) administration during reperfusion on infarct size and haemodynamic recovery were studied. The effect of inhibiting amino acid transamination was evaluated by adding the amino acid transaminase inhibitor amino-oxyacetate (AOA; 0.025 mm) during reperfusion. Changes in coronary effluent, interstitial (microdialysis) and intracellular glutamate ([GLUT] i ) concentrations were measured. Ischaemic preconditioning and postischaemic glutamate administration reduced infarct size to the same extent (41 and 40%, respectively; P < 0.05 for both), without showing an additive effect. Amino-oxyacetate abolished infarct reduction by IPC and glutamate, and increased infarct size in both control and IPC hearts in a dose-dependent manner. Ischaemic preconditioning increased [GLUT] i before ischaemia (P < 0.01) and decreased the release of glutamate during the first 10 min of reperfusion (P = 0.03). A twofold reduction in [GLUT] i from the preischaemic state to 45 min of reperfusion (P = 0.0001) suggested increased postischaemic glutamate utilization in IPC hearts. While IPC and AOA changed haemodynamics in accordance with infarct size, glutamate decreased haemodynamic recovery despite reduced infarct size. In conclusion, ischaemic cardioprotection of the normal and IPC-protected heart depends on amino acid transamination and activity of the malate-aspartate shuttle during reperfusion. Underlying mechanisms of IPC include myocardial glutamate metabolism.

Late pre-conditioning protects against myocardial ischaemic-reperfusion injury. AMP-activated protein kinase (AMPK) is activated by exercise and 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR). Early pre-conditioning involves AMPK activation and increased myocardial glucose uptake. The aim of the present study was to determine whether AICAR activates myocardial AMPK and induces late pre-conditioning and whether myocardial glucose uptake during reperfusion was modulated. Twenty-four hours after AICAR treatment or exercise, Wistar rats were subjected to ischaemia and reperfusion in a Langendorff model and compared to control rats. AMPK activity increased immediately 2.5-fold in AICAR-treated animals (P < 0.01) and twofold in exercised animals (P < 0.05). AICAR and exercise reduced infarct size by 60% and 50% (both P < 0.01), respectively, and increased myocardial glucose uptake during reperfusion (AICAR; 45%, P < 0.05, exercise; 40%, P < 0.05). In conclusion, AICAR induces late pre-conditioning and increases myocardial glucose uptake during reperfusion in rat hearts. AICAR and exercise activate AMPK, suggesting a role of AMPK in the signalling mechanisms behind late pre-conditioning.