Michaela Diamant

CD36 inhibition prevents lipid accumulation and contractile dysfunction in rat cardiomyocytes.

An increased cardiac fatty acid supply and increased sarcolemmal presence of the long-chain fatty acid transporter CD36 are associated with and contribute to impaired cardiac insulin sensitivity and function. In the present study we aimed at preventing the development of insulin resistance and contractile dysfunction in cardiomyocytes by blocking CD36-mediated palmitate uptake. Insulin resistance and contractile dysfunction were induced in primary cardiomyocytes by 48 h incubation in media containing either 100 nM insulin (high insulin; HI) or 200 μM palmitate (high palmitate; HP). Under both culture conditions, insulin-stimulated glucose uptake and Akt phosphorylation were abrogated or markedly reduced. Furthermore, cardiomyocytes cultured in each medium displayed elevated sarcolemmal CD36 content, increased basal palmitate uptake, lipid accumulation and decreased sarcomere shortening. Immunochemical CD36 inhibition enhanced basal glucose uptake and prevented elevated basal palmitate uptake, triacylglycerol accumulation and contractile dysfunction in cardiomyocytes cultured in either medium. Additionally, CD36 inhibition prevented loss of insulin signalling in cells cultured in HP, but not in HI medium. In conclusion, CD36 inhibition prevents lipid accumulation and lipid-induced contractile dysfunction in cardiomyocytes, but probably independently of effects on insulin signalling. Nonetheless, pharmacological CD36 inhibition may be considered as a treatment strategy to counteract impaired functioning of the lipid-loaded heart.

Overexpression of AMP-activated protein kinase or protein kinase D prevents lipid-induced insulin resistance in cardiomyocytes

During lipid oversupply, the heart becomes insulin resistant, as exemplified by defective insulin-stimulated glucose uptake, and will develop diastolic dysfunction. In the healthy heart, not only insulin, but also increased contractile activity stimulates glucose uptake. Upon increased contraction both AMP-activated protein kinase (AMPK) and protein kinase D (PKD) are activated, and mediate the stimulation of glucose uptake into cardiomyocytes. Therefore, each of these kinases is a potential therapeutic target in the diabetic heart because they may serve to bypass defective insulin-stimulated glucose uptake. To test the preventive potential of these kinases against loss of insulin-stimulated glucose uptake, AMPK or PKD were adenovirally overexpressed in primary cultures of insulin resistant cardiomyocytes for assaying substrate uptake, insulin responsiveness and lipid accumulation. To induce insulin resistance and lipid loading, rat primary cardiomyocytes were cultured in the presence of high insulin (100 nM; HI) or high palmitate (palmitate/BSA: 3/1; HP). HI and HP each reduced insulin responsiveness, and increased basal palmitate uptake and lipid storage. Overexpression of each of the kinases prevented loss of insulin-stimulated glucose uptake. Overexpression of AMPK also prevented loss of insulin signaling in HI- and HP-cultured cardiomyocytes, but did not prevent lipid accumulation. In contrast, overexpression of PKD prevented lipid accumulation, but not loss of insulin signaling in HI- and HP-cultured cardiomyocytes. In conclusion, AMPK and PKD prevent loss of insulin-stimulated glucose uptake into cardiomyocytes cultured under insulin resistance-inducing conditions through different mechanisms. This article is part of a Special Issue entitled Focus on Cardiac Metabolism.

14. Liraglutide Decreases Food Related CNS Activation after Short-Term, but Not after Longer-Term Treatment in Patients with Diabetes (159-OR)

SamenvattingThe central nervous system (CNS) is a major player in the regulation of feeding. Gut-derived hormones, such as glucagon- like peptide-1 (GLP-1), may relay information about the nutritional status to the CNS. Treatment with GLP-1 agonists, such as liraglutide, is associated with reduced appetite and weight loss. We hypothesized that these effects are mediated by effects on the CNS. We performed a randomized cross-over study in patients with type 2 diabetes (n = 20, mean ± SD, age 59.3 ± 4.1 yr, BMI 32 ± 4.7 kg/m2). Each individual underwent 2 periods of 12 week treatment with either liraglutide or insulin glargine with a 12 week wash-out period. Using fMRI, we determined the effects of treatment on CNS activation to food vs. nonfood pictures in areas regulating reward when fasted and 30 min. after a standardized meal. FMRI scans were performed at baseline, after 10 days and 12 weeks of treatment. After 12 weeks, the decrease in HbA1c was larger with liraglutide vs. insulin (Δ -0.7% vs. -0.2%, p difference < 0.001). Body weight decreased during liraglutide vs insulin (Δ -3.3 kg vs. +0.8 kg, p difference < 0.001). After 10 days, before weight changes had occurred, patients treated with liraglutide, compared to insulin, showed decreased activation to food pictures in left putamen in the postprandial condition. After 10 days, in comparison with insulin, liraglutide enhanced the reducing effect of the meal intake on CNS activation to food pictures in left putamen and amygdala. These differences between liraglutide and insulin were not observed after 12 weeks. Compared to insulin, liraglutide decreased CNS activations in response to food pictures in reward areas after short term, but not after longer term treatment. Our findings suggest that the GLP-1 mediated altered CNS activation may contribute to the induction of weight loss. However the absence of effects after longer term treatment might explain why weight loss does not proceed after the initial treatment period with liraglutide.

24. Brain Reward-System Activation in Response to Anticipation and Consumption of Palatable Food Is Altered by GLP-1 Receptor Activation in Humans (384-OR)

SamenvattingIt has been suggested that obese individuals have increased brain reward system activation while anticipating food intake, which may lead to cravings for food, and decreased reward system activation during actual food consumption, which may induce overeating. Gut-derived hormones, such as glucagon-like peptide-1 (GLP-1), are likely involved in the regulation of food intake. GLP-1 receptor agonists improve glycemic control and reduce food intake and body weight. We hypothesized that food intake reduction following GLP-1 receptor activation is mediated through brain areas regulating anticipatory and consummatory food reward. Using functional MRI, we determined the effects of GLP-1 receptor activation on brain responses to anticipation and receipt of chocolate milk vs. tasteless solution. Obese T2DM patients, normoglycemic obese and lean subjects (n = 48) underwent three functional MRI sessions at separate visits with intravenous infusion of A) the GLP-1 receptor agonist exenatide, B) exenatide with prior GLP-1 receptor blockade by exendin 9-39 or C) placebo; during somatostatin pituitary-pancreatic clamps. We found that BMI negatively correlated with brain responses to receipt of chocolate milk and positively correlated with anticipation of receipt of chocolate milk in brain areas regulating reward, appetite and motivation. Exenatide vs. placebo increased brain responses to receipt of chocolate milk and decreased anticipation of receipt of chocolate milk, paralleled by reductions in food intake. Exendin 9-39 largely prevented these effects. GLP-1 receptor activation decreased anticipatory food reward, which may reduce cravings for food, and increased consummatory food reward, which may prevent overeating. Our findings provide novel insights into the mechanisms by which GLP-1 regulates food intake and how GLP-1 receptor agonists induce weight loss.

PS16 - 2. Low birth weight is associated with alterations in dietary intake in later life independent of genetic factors

Low birth weight is associated with an increased risk of type 2 diabetes and cardiovascular disease. These associations may, in part, be explained by alterations in dietary intake in later life. We examined whether low birth weight is associated with alterations in food intake, and whether this association is due to intrauterine environmental or genetic factors.

PS12 - 6. Selective cognitive decline is related to focal brain volume loss in type 1 diabetes patients with microangiopathy: a 4 year follow-up

Cross-sectional studies showed cognitive and structural brain changes in type 1 diabetes (T1DM) patients, predominantly in those with peripheral microangiopathy. Whether these brain changes progress over time is not well known.