Effects of insulin detemir and NPH insulin on body weight and appetite-regulating brain regions in human type 1 diabetes: a randomized controlled trial

Larissa W van Golen, Dick J Veltman, Richard G IJzerman, Jan Berend Deijen, Annemieke C Heijboer, Frederik Barkhof, Madeleine L Drent, Michaela Diamant, Larissa W van Golen, Dick J Veltman, Richard G IJzerman, Jan Berend Deijen, Annemieke C Heijboer, Frederik Barkhof, Madeleine L Drent, Michaela Diamant

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 registration: ClinicalTrials.gov NCT00626080.

Conflict of interest statement

Competing Interests: This work was supported by an Investigator Initiated Grant of Novo Nordisk A/S. Insulin preparations were supplied by Novo Nordisk. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. http://www.novonordisk.nl/documents/home_page/document/index.asp. This does not alter the authors' adherence to PLOS ONE policies on sharing data and materials. MD: member advisory board: Abbott, Eli Lilly, Merck Sharp & Dohme (MSD), Novo Nordisk, Poxel Pharma and Sanofi; Consultant: Astra-BMS; Speaker: Eli Lilly, MSD, Novo Nordisk and Sanofi; through MD, the VU University Medical Center, receives research grants from Amylin/Eli Lilly, MSD, Novo Nordisk and Sanofi; MD receives no personal payments in connection to the abovementioned activities, but all payments are directly transferred to the Institutional Research Foundation. The other authors declare no conflict of interest. This does not alter the authors' adherence to PLOS ONE policies on sharing data and materials.

Figures

Figure 1. Participant flow diagram.
Figure 1. Participant flow diagram.
ID, insulin detemir; NPH, Neutral Protamine Hagedorn insulin; QC, quality control.
Figure 2. Study design.
Figure 2. Study design.
After a run-in period, patients were randomly assigned to treatment with either insulin detemir or NPH insulin. After each treatment period an fMRI-scan was acquired. During the fMRI, pictures were shown of four categories in random order (HC, high calorie food; LC, low calorie food; N, non-food; A, arrow).
Figure 3. Increased activation in bilateral insula…
Figure 3. Increased activation in bilateral insula when watching food versus non-food pictures after treatment with NPH versus ID.
SPM images for illustrative purposes. Increased activation after NPH treatment compared to ID treatment is shown in right (upper panel) and left insula (lower panel) respectively (crosshair); colour bar represents t value for paired Student's t test. In the graphs on the right the BOLD signal intensity (effect size) for each group is plotted (arbitrary units), mean ± SEM; NPH, NPH insulin; ID, insulin detemir.

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Source: PubMed

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