Abstract
Studies in rodents have demonstrated that insulin in the central nervous system induces satiety. In humans, these effects are less well established. Insulin detemir is a basal insulin analog that causes less weight gain than other basal insulin formulations, including the current standard intermediate-long acting Neutral Protamine Hagedorn (NPH) insulin. Due to its structural modifications, which render the molecule more lipophilic, it was proposed that insulin detemir enters the brain more readily than other insulins. The aim of this study was to investigate whether insulin detemir treatment differentially modifies brain activation in response to food stimuli as compared to NPH insulin. In addition, cerebral spinal fluid (CSF) insulin levels were measured after both treatments. Brain responses to viewing food and non-food pictures were measured using functional Magnetic Resonance Imaging in 32 type 1 diabetic patients, after each of two 12-week treatment periods with insulin detemir and NPH insulin, respectively, both combined with prandial insulin aspart. CSF insulin levels were determined in a subgroup. Insulin detemir decreased body weight by 0.8 kg and NPH insulin increased weight by 0.5 kg (p = 0.02 for difference), while both treatments resulted in similar glycemic control. After treatment with insulin detemir, as compared to NPH insulin, brain activation was significantly lower in bilateral insula in response to visual food stimuli, compared to NPH (p = 0.02 for right and p = 0.05 for left insula). Also, CSF insulin levels were higher compared to those with NPH insulin treatment (p = 0.003). Our findings support the hypothesis that in type 1 diabetic patients, the weight sparing effect of insulin detemir may be mediated by its enhanced action on the central nervous system, resulting in blunted activation in bilateral insula, an appetite-regulating brain region, in response to food stimuli.Trial RegistrationClinicalTrials.gov NCT00626080.
Highlights
In addition to its blood glucose lowering peripheral effects, insulin acts within the central nervous system (CNS) to regulate eating behavior and energy balance [1]
Insulin detemir (ID) differs from human insulin in that threonine at position B30 has been removed and that lysine at B29 has been acylated with myristic acid, a 14carbon fatty acid
32 T1DM men were included in functional MRI (fMRI) analyses (Table 1)
Summary
In addition to its blood glucose lowering peripheral effects, insulin acts within the central nervous system (CNS) to regulate eating behavior and energy balance [1]. ID differs from human insulin in that threonine at position B30 has been removed and that lysine at B29 has been acylated with myristic acid, a 14carbon fatty acid This fatty-acid moiety stabilizes ID selfassociation and enables the binding to albumin, which gives ID its long-acting properties [8]. It has been hypothesized [9] that due to the fatty acid moiety, ID more enters the brain, thereby potentially promoting satiety in relevant CNS regions and reducing appetite, food intake and body weight. The effects of ID on appetite regulating brain regions during food stimuli have not been studied and no data are available regarding insulin concentrations in human cerebrospinal fluid (CSF) during insulin treatment and its relation to insulin’s central actions
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