Looking into the diabetic brain
Diabetes mellitus is a serious health concern with hundreds of millions of affected individuals worldwide. This disease is characterized by insulin resistance as well as defects in the ability of the pancreas to secrete insulin. Diabetes mellitus is frequently associated with obesity, dyslipidaemia and hypertension. It is now believed that an imbalance between energy intake, expenditure and storage leads to weight gain and eventually to the development of insulin resistance. The hypothalamus in the brain is responsible for detecting changes in the extra-cellular levels of nutrients. The concept behind the EU-funded project 'The diabetic brain' (THE DIABETIC BRAIN) was that in diabetics the brain’s nutrient-sensing mechanisms are disrupted, leading to a metabolic imbalance in the body. Scientists studied the properties of hypothalamic nutrient-sensing neurons in a model of obesity and insulin resistance. They focused on a particular subset of hypothalamic neurons that express melanin-concentrating hormone (MCH). In order to investigate how these cells detect glucose, they worked on a transgenic mouse model where the neurons were fluorescent. Using a specific dye and confocal fluorescence microscopy, scientists observed that MCH neurons exhibited bioenergetic alterations in response to glucose. To understand the connection between obesity, diabetes and hypothalamic physiology, scientists investigated the effect of thiazolidinediones (TZDs). TZDs are a group of drugs widely used in the treatment of type 2 diabetes. They act on specific receptors that are also present in areas of the hypothalamus where they may modulate peripheral metabolism with weight gain as a side effect. The impact of the drug depended on the neuron investigated and effects could be either excitatory or inhibitory. The requirement for both glucose-excited and glucose-inhibited neurons in the hypothalamus to maintain energy balance was shown to be disrupted by a high-fat diet. This effect was mediated by apoptosis in hypothalamic neurons and resulted in diabetes. However, scientists found no plasticity in terms of cell number adjustments during obese and pre-diabetic states. Collectively, the results of the project point towards a complex interaction of metabolism-related signals in the hypothalamus that determine energy homeostasis. Further delineation of the implicated mechanisms will provide invaluable insight into obesity, insulin resistance and diabetes.
