Effects of Insulin Detemir and NPH Insulin on Body Weight and Appetite-Regulating Brain Regions in Human Type 1 Diabetes: A Randomized Controlled Trial

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.ClinicalTrials.gov NCT00626080

Study design.

<p>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).</p

Participant flow diagram.

<p>ID, insulin detemir; NPH, Neutral Protamine Hagedorn insulin; QC, quality control.</p

fMRI data.

<p>Coordinates of peak cluster activity from the normalized brain based on the Montreal Neurological Institute (MNI) system; ROI, region of interest.</p

Patient characteristics at baseline and at 12 week of intervention.

<p>Patient characteristics at baseline and at 12 week of intervention.</p

Increased activation in bilateral insula when watching food versus non-food pictures after treatment with NPH versus ID.

<p>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 <i>t</i> value for paired Student's <i>t</i> 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.</p

Cerebrospinal fluid levels of Alzheimer's disease biomarkers in middle-aged patients with type 1 diabetes

Type 1 diabetes is associated with moderate cognitive decline and cerebral alterations and may lead to an increased risk of dementia, including Alzheimer's disease. This study aimed to investigate the levels of risk markers for Alzheimer's disease in middle-aged patients with type 1 diabetes and controls, and their potential associations with cognitive and cerebral measures. Levels of β-amyloid (Aβ) 42, Tau, phosphorylated Tau (pTau), the soluble form of low-density lipoprotein receptor-related protein 1 (sLRP1) and macrophage colony-stimulating factor (MCSF) were quantified by ELISA in serum and cerebrospinal fluid (CSF) collected from 37 patients with type 1 diabetes and 15 controls. Associations between biomarkers and determinants of cognitive function and white matter integrity were assessed using hierarchical regression analysis controlling for age, HbA1c and estimated intelligence quotient (IQ). CSF levels of pTau, Aβ42 and LRP1 were higher in patients with type 1 diabetes than in controls (all p <0.05). There was a trend towards increased Tau levels in patients with type 1 diabetes (p = 0.056), while CSF levels of MCSF were similar between patients with type 1 diabetes and controls. Regression analysis showed that elevated CSF sLRP1 levels were associated with better attention (β = 0.518; p = 0.002) and a better speed of information-processing (β = 0.368; p = 0.034), as well as increased integrity of the white matter of the right inferior fronto-occipital tract (β = 0.395; p = 0.022). Furthermore, elevated Tau levels were associated with decreased integrity of the white matter of right inferior fronto-occipital tract (β = -0.584; p = 0.002). CSF levels of biomarkers for Alzheimer's disease are altered in patients with type 1 diabetes compared with controls, but the observed profile does not match the profile characterising pre-Alzheimer's disease patient