from january 2009 until may 2011 , patients were included in this randomized controlled crossover trial ; the last follow - up visit was on 13 december 2011 . thirty - five patients with type 1 diabetes , aged 1860 years and with a bmi of 1835 kg / m , were included ; they were recruited from the outpatient clinic of the vu university medical center ( vumc ) and from neighboring hospitals . after giving written informed consent , all participants had a screening visit consisting of a medical history , physical examination , and fasting blood and urine analyses . exclusion criteria were diabetes duration < 1 year ; a1c > 8.5% ; proliferative retinopathy ; a history of recurrent severe hypoglycemia ( defined as an episode that requires external assistance for recovery ) ; a medical history of hypoglycemia unawareness ; history of cardiovascular , renal , or liver disease or severe head trauma ; any neurological or psychiatric disorder ; endocrine diseases not well controlled for the last 3 months ; inability to undergo magnetic resonance imaging ( mri ) scanning ; substance abuse ; and the use of anticoagulants , oral steroids , or any centrally acting agent . of all patients in analysis , one had microalbuminuria , four stable background retinopathy , and one peripheral neuropathy ( toronto score   of 9/19 and a vibration perception   threshold of > 25 v at 5 of 12 locations ) . three patients were treated with antihypertensive medication ( one used an angiotensin ii receptor antagonist [ arb ] , one an ace inhibitor and an arb , and one an ace inhibitor and arb , a diuretic , and a calcium antagonist ) . two patients had stable hypothyroidism treated with thyroxin , and one had stable ulcerative colitis treated with mesalazin . the study was approved by the medical ethics review committee of the vumc and the central committee on research involving human subjects . the study was conducted in a randomized crossover design and was part of a larger trial ( clinicaltrials.gov , clinical trial reg . primary outcomes were cbf and cmrglu after a 12-week treatment period , and change in body weight after this 12-week treatment was a secondary outcome measurement . after a run - in period of at least 4 weeks , during which the current insulin therapy was optimized , patients were randomly assigned to start with either insulin detemir or nph insulin in the evening , both in combination with insulin aspart at mealtimes . randomization ( block design ) was conducted by the trial pharmacy of the vumc , and the assigned treatments were concealed by envelopes ; a research physician ( l.w.v.g . ) enrolled patients in the study and assigned them to the intervention . after assignment , no blinding was applied , since nph insulin needs to be mixed and visually inspected before injection . weekly seven - point self - measured blood glucose curves were made , and all fasting blood glucose levels were reported . where appropriate , basal insulin dose was adjusted to maintain a fasting glucose level of < 7 mmol / l . after 12 weeks of treatment , patients switched from basal insulin . on the day prior to the scan session , patients refrained from food , alcohol , and coffee intake from 2200 h onward . they were carefully instructed not to forget their basal insulin injection and , if possible , not to use any insulin aspart after their dinnertime injection . telephone calls were made both on the night before and early in the morning of the day of the pet scan , i.e. , before traveling to the hospital . in addition , a similar protocol was followed at the day of mri scanning ( a week prior to the pet scan ) , when patients had to arrive at the hospital at the same time in a fasting state , using the same basal insulin the night before . if necessary , the insulin regimen was adjusted after the mri scan to improve fasting glucose levels on the day of the pet scan . patients arrived at the hospital at 0715 h in the fasting state and remained fasted during the entire imaging procedure . upon arrival , blood glucose levels were checked and corrected if necessary ( when glucose was < 4 mmol / l and falling or when glucose was > 15 mmol / l ) . to prevent further rising of glucose during the remaining duration of the test visit , after we check for collateral circulation and administration of local anesthesia using intradermal 1% lidocain , a radial artery was cannulated by an experienced anesthesiologist . both cannulas were kept patent by a 3 ie / ml 0.9% nacl heparin solution . before and immediately after scanning , patients completed a questionnaire , scoring their hunger (  how hungry are you right now ?  ) , fullness (  how full are you at this moment ?  ) , appetite (  how much do you feel like eating right now ?  ) , prospective consumption (  how much could you eat right now ?  ) , desire to eat (  how strong is your desire to eat right now ?  ) , and thoughts of eating (  how much do you think about food right now ?  ) on a 10-point likert scale . furthermore , patients scored their insulin treatment satisfaction using the diabetes treatment satisfaction questionnaire , which measures satisfaction with treatment regimen , perceived frequency of hyperglycemia , and perceived frequency of hypoglycemia over the past few weeks ( 20 ) . three - dimensional structural mri images were acquired on a 3.0 t ge signa hdxt scanner ( general electric , milwaukee , wi ) , using a t1-weighted fast spoiled gradient echo sequence . pet scans were acquired with a high resolution research tomograph ( hrrt ) ( siemens / cti , knoxville , tn ) pet scanner . the scanning protocol consisted of a [ o]h2o scan to measure cbf and an [ f]fdg scan to measure cmrglu . details on scan protocol have previously been published ( 21 ) . during both scans , arterial concentrations were monitored continuously , and in addition , manual samples were taken for cross - calibration of the measured input function . samples obtained during the [ f]fdg scan ( 15 , 35 , and 55 min postinjection ) were also used to measure arterial plasma glucose levels . list mode emission data were histogrammed into multiframe sinograms , which subsequently were normalized , and corrected for randoms , dead time , decay , scatter , and attenuation . fully corrected sinograms were reconstructed using the standard 3d ordinary poisson ordered - subsets expectation maximization ( op - osem ) reconstruction algorithm ( 22 ) , resulting in 207 image planes with 256  256 voxels and a voxel size of 1.22  1.22  1.22 mm ( 21 ) . pet images were rebinned , and pet and mri images were cropped into a 128  128  126 matrix ( 21 ) . regions of interest ( rois ) were delineated on the mri scan using the template defined in pvelab ( 24 ) . subsequently , all rois were projected onto the dynamic pet images , generating time activity curves ( tacs ) for the following 16 left and right regions : orbitofrontal cortex , anterior and posterior cingulate cortex , thalamus , insula , caudate nucleus , putamen , medial inferior frontal cortex , superior temporal cortex , parietal cortex , medial inferior temporal cortex , superior frontal cortex , occipital cortex , sensorimotor cortex , cerebellum , hippocampus , a single white matter region , a total gray matter region , and striatum ( putamen and caudate nucleus combined ) . of these rois , the first seven were of specific interest , as these are involved in appetite regulation and reward . with use of standard nonlinear regression ( nlr ) , appropriately weighted [ o]h2o tacs were fitted to the standard one - tissue compartment model ( 25 ) to obtain regional cbf values . in addition , parametric ( voxel - wise ) cbf images were generated from 6-mm full - width - at - half - maximum gaussian smoothed dynamic [ o]h2o images using a basis function method ( bfm ) implementation of the same model ( 26 ) . with use of a standard nlr algorithm , appropriately weighted [ f]fdg tacs were fitted to an irreversible two - tissue compartment model with three rate constants and blood volume as fit parameters . next , the net rate of influx ki was calculated as k1  k3/(k2+k3 ) , where k1 is the rate of transport from blood to brain , k2 the rate of transport from brain to blood , and k3 the rate of phosphorylation by hexokinase . finally , ki was multiplied with the plasma glucose concentration and divided by a lumped constant ( lc ) of 0.81 ( 27 ) to obtain regional cmrglu values . capillary blood glucose ( patient monitoring ) was measured using a blood glucose meter ( onetouch ultraeasy ; lifescan , milpitas , ca ) . arterial glucose samples ( to determine cmrglu ) were measured using the hexokinase method ( glucoquant ; roche diagnostics , mannheim , germany ) . a1c was measured by cation - exchange chromatography ( reference values 4.36.1% ; menarini diagnostics , florence , italy ) . serum insulin concentrations were quantified using immunometric assays ( centaur ; siemens diagnostics , deerfield , il ) ; insulin detemir levels were divided by four to compensate for the difference in molar dose ratio relative to nph insulin . urine microalbumin was quantified using immunonephelometry ( immage 800 ; beckman coulter , brea , ca ) . skewed data and ordinal values are expressed as median and interquartile ( iq ) range . differences between both insulin treatments were tested by repeated - measures analysis or the wilcoxon signed rank test ( insulin detemir vs. nph insulin ) . analyses were performed using spss for windows , version 20.0 ( spss , chicago , il ) . parametric images were analyzed using spm8 software ( wellcome trust centre for neuroimaging , london , u.k . ) . parametric images were smoothed using a 6-mm full - width - at - half - maximum gaussian kernel , coregistered to corresponding t1-weighted mri images and normalized to montreal neurological institute space . paired t tests were performed ( insulin detemir vs. nph insulin ) . with use of data of 18 paired h2o pet measurements and an expected difference in total gray matter cbf of 15% ( 0.046  0.05 ml  cm  min ) , our study had a power of 96% (  0.05 ) to detect differences between treatment with insulin detemir and nph insulin . with use of 24 paired fdg pet data and an expected difference in total gray matter cmrglu of 7.5% ( 0.011  0.02 mol  cm  min ) , our study had a power of 73% to detect differences between treatments . three - dimensional structural mri images were acquired on a 3.0 t ge signa hdxt scanner ( general electric , milwaukee , wi ) , using a t1-weighted fast spoiled gradient echo sequence . pet scans were acquired with a high resolution research tomograph ( hrrt ) ( siemens / cti , knoxville , tn ) pet scanner . the scanning protocol consisted of a [ o]h2o scan to measure cbf and an [ f]fdg scan to measure cmrglu . details on scan protocol have previously been published ( 21 ) . during both scans , arterial concentrations were monitored continuously , and in addition , manual samples were taken for cross - calibration of the measured input function . samples obtained during the [ f]fdg scan ( 15 , 35 , and 55 min postinjection ) were also used to measure arterial plasma glucose levels . list mode emission data were histogrammed into multiframe sinograms , which subsequently were normalized , and corrected for randoms , dead time , decay , scatter , and attenuation . fully corrected sinograms were reconstructed using the standard 3d ordinary poisson ordered - subsets expectation maximization ( op - osem ) reconstruction algorithm ( 22 ) , resulting in 207 image planes with 256  256 voxels and a voxel size of 1.22  1.22  1.22 mm ( 21 ) . pet images were rebinned , and pet and mri images were cropped into a 128  128  126 matrix ( 21 ) . regions of interest ( rois ) were delineated on the mri scan using the template defined in pvelab ( 24 ) . subsequently , all rois were projected onto the dynamic pet images , generating time activity curves ( tacs ) for the following 16 left and right regions : orbitofrontal cortex , anterior and posterior cingulate cortex , thalamus , insula , caudate nucleus , putamen , medial inferior frontal cortex , superior temporal cortex , parietal cortex , medial inferior temporal cortex , superior frontal cortex , occipital cortex , sensorimotor cortex , cerebellum , hippocampus , a single white matter region , a total gray matter region , and striatum ( putamen and caudate nucleus combined ) . of these rois , the first seven were of specific interest , as these are involved in appetite regulation and reward . with use of standard nonlinear regression ( nlr ) , appropriately weighted [ o]h2o tacs were fitted to the standard one - tissue compartment model ( 25 ) to obtain regional cbf values . in addition , parametric ( voxel - wise ) cbf images were generated from 6-mm full - width - at - half - maximum gaussian smoothed dynamic [ o]h2o images using a basis function method ( bfm ) implementation of the same model ( 26 ) . with use of a standard nlr algorithm , appropriately weighted [ f]fdg tacs were fitted to an irreversible two - tissue compartment model with three rate constants and blood volume as fit parameters . next , the net rate of influx ki was calculated as k1  k3/(k2+k3 ) , where k1 is the rate of transport from blood to brain , k2 the rate of transport from brain to blood , and k3 the rate of phosphorylation by hexokinase . finally , ki was multiplied with the plasma glucose concentration and divided by a lumped constant ( lc ) of 0.81 ( 27 ) to obtain regional cmrglu values . in addition , parametric cmrglu images were generated using patlak linearization ( 28 ) . capillary blood glucose ( patient monitoring ) was measured using a blood glucose meter ( onetouch ultraeasy ; lifescan , milpitas , ca ) . arterial glucose samples ( to determine cmrglu ) were measured using the hexokinase method ( glucoquant ; roche diagnostics , mannheim , germany ) . a1c was measured by cation - exchange chromatography ( reference values 4.36.1% ; menarini diagnostics , florence , italy ) . serum insulin concentrations were quantified using immunometric assays ( centaur ; siemens diagnostics , deerfield , il ) ; insulin detemir levels were divided by four to compensate for the difference in molar dose ratio relative to nph insulin . urine microalbumin was quantified using immunonephelometry ( immage 800 ; beckman coulter , brea , ca ) . skewed data and ordinal values are expressed as median and interquartile ( iq ) range . differences between both insulin treatments were tested by repeated - measures analysis or the wilcoxon signed rank test ( insulin detemir vs. nph insulin ) . analyses were performed using spss for windows , version 20.0 ( spss , chicago , il ) . parametric images were analyzed using spm8 software ( wellcome trust centre for neuroimaging , london , u.k . ) . parametric images were smoothed using a 6-mm full - width - at - half - maximum gaussian kernel , coregistered to corresponding t1-weighted mri images and normalized to montreal neurological institute space . paired t tests were performed ( insulin detemir vs. nph insulin ) . with use of data of 18 paired h2o pet measurements and an expected difference in total gray matter cbf of 15% ( 0.046  0.05 ml  cm  min ) , our study had a power of 96% (  0.05 ) to detect differences between treatment with insulin detemir and nph insulin . with use of 24 paired fdg pet data and an expected difference in total gray matter cmrglu of 7.5% ( 0.011  0.02 mol  cm  min ) , our study had a power of 73% to detect differences between treatments . during the study , one patient dropped out during his first treatment period ( because of nph insulin schedule difficulties ) and one in the second period ( because of a hip fracture ) . owing to technical problems ( n = 2 ) and patient movement ( n = 2 ) , combined [ f]fdg and [ o]h2o data were discarded for these four subjects . [ o]h2o was not available for one patient on both occasions and for three patients on one occasion . after quality control of the remaining scans , paired cmrglu data were available in 24 patients and paired cbf measurements in 18 patients . subject characteristics of all 28 patients included in the analyses are listed in table 1 . of all patients included in the analyses ( n = 28 ) , 15 patients started with nph insulin and 13 with insulin detemir . of patients starting with nph insulin , 5 had used insulin detemir and 10 insulin glargine , while of those starting with insulin detemir , 4 had used insulin detemir , 1 nph insulin , and 8 insulin glargine before the trial . at the end of the treatment period , daily insulin doses and a1c did not differ between treatment ( table 2 ) . insulin detemir decreased body weight by 0.7 kg , whereas nph insulin increased weight by 0.6 kg ( between - treatment difference 1.3 kg , p = 0.02 ) ( table 2 ) . perceived hyperglycemia and hypoglycemia did not differ significantly between treatments ( diabetes treatment satisfaction questionnaire ) ; patient satisfaction was significantly greater when with use of insulin detemir than nph insulin ( p = 0.003 ) . irrespective of the treatment arm , patients scored five of six items ( hunger , appetite , prospective consumption , desire to eat , and thoughts of eating ) significantly higher after the scan than before the scan ( p < 0.01 for each item ) , indicating that appetite increased during the scanning period ( all were fasting ) . when treated with insulin detemir , patients scored higher on the sixth item , i.e. , fullness , after the pet scan than patients treated with nph insulin ( mean 4.0 [ iq range 3.05.0 ] vs. 3.0 [ 2.04.0 ] , p = 0.03 for between - group difference ) . patient characteristics clinical characteristics before and at the end of each treatment period for insulin detemir , on the day of the pet scan , three patients , of whom two were excluded afterward from the cbf analyses , required several dextrose tablets to prevent or resolve a mild hypoglycemia , whereas six patients , of whom one was excluded from the cbf analyses , received 20 ml i.v . one patient received insulin detemir ( 12 iu s.c . ) because glucose was rising upon arrival at the hospital . for nph insulin , three patients , of whom two were excluded from the cbf analyses , required dextrose tablets because of a low or falling blood glucose level , whereas two patients , who were afterward excluded from the cbf analyses , received 15 ml i.v . three patients , who all were included in the cbf analyses , required insulin nph insulin ( 14 , 10 , and 5 iu s.c . ) at arrival in the hospital as a result of hyperglycemia . in all patients , mmol / l during data acquisition . for checking whether acute glucose manipulations had affected pet measurements of cbf and cmrglu , a separate analysis was performed in which patients who had received glucose or insulin were excluded . results of this additional analysis , however , were similar to those of the original analysis ( data not shown ) . nlr analysis showed that , after treatment with insulin detemir compared with treatment with nph insulin , cbf was higher in all regions . this was statistically significant in most appetite - related brain regions  bilateral insula , bilateral putamen and right caudate nucleus , right thalamus , and bilateral anterior and right posterior cingulate cortices  when patients received insulin detemir versus nph insulin ( table 3 ) . in addition , higher cbf was observed in the right medial inferior frontal cortex , bilateral parietal cortex , and bilateral sensorimotor cortex ( all p < 0.05 ) after treatment with insulin detemir versus nph insulin . in all other brain regions results were similar after exclusion of patients using antihypertensive medication ( n = 3 ) and after exclusion of the one left - handed patient . after adjustment for a1c , glucose , and insulin levels , cbf differences in appetite - related regions remained unaltered ( data not shown ) . no significant correlation between changes in cbf and changes in glucose , insulin , and a1c levels or body weight was found . regional analyses of parametric images showed good correlation with regional nlr analyses ( slope = 0.99 , r = 0.93 , for n = 5 nph and n = 5 insulin detemir , data not shown ; similar to data obtained in healthy subjects ) . these parametric analyses ( voxel level ) did not provide additional findings relative to regional nlr analyses . regional pet - measured cmrglu and cbf at the end of each intervention period during the [ f]fdg scan , mean arterial plasma glucose levels did not differ between treatments ; serum insulin levels were similar as well ( table 2 ) . nlr analysis showed no significant differences in cmrglu in appetite - related predefined ( pvelab ) regions ( table 3 ) . no significant differences in transport parameters for total gray matter ( ki , k1 , k2 , and k3 ) , were observed ( data not shown ) , and total gray matter cmrglu did not differ significantly between treatments ( 0.15  0.02 mol  cm  min after treatment with nph insulin versus 0.16  0.02 mol  cm  min after treatment with insulin detemir ) . the main finding of this study was that a relative loss in body weight in type 1 diabetic patients treated with insulin detemir was accompanied by an increase in cbf in insula , thalamus , anterior and posterior cingulate cortex , and striatum  regions that are involved in appetite regulation and reward . some of these studies suggest that changes in cbf are causal in the development of obesity . cbf responses in appetite - related brain regions to a meal in formerly obese persons were similar to those in obese persons but different from those in lean subjects ( 29 ) , indicating a predisposition to obesity that may involve areas of the brain that control complex aspects of eating behavior . this is in line with the observed increase in cbf in appetite - regulating brain regions in response to meal consumption in successful dieters ( 30 ) . in minipigs , however , diet - induced obesity resulted in a decrease in cbf in several of these brain regions , suggesting that the changes in cbf were the result of weight gain ( 31 ) . from the current study , it is not possible to determine whether increases in cbf in patients treated with insulin detemir are cause or consequence of the observed weight loss . previous studies in mice and healthy humans , however , showed cortical brain activation upon acute insulin detemir versus human insulin infusion with concomitant decrease in food intake ( 911 ) . in addition , it was shown that insulin - induced glucose lowering in type 1 diabetic patients resulted in an increase in cbf ( 32,33 ) . however , whether this was caused by increasing insulin or by decreasing glucose levels could not be determined in those studies . still , a direct effect of insulin on the brain is supported by the acute effects of insulin on cerebrovascular responses in rats ( 17 ) . ( 13 ) in eight healthy volunteers and six individuals with impaired glucose tolerance , in which no between - group cbf differences were observed and no cbf effect of insulin . in their study , acute clamp - induced hyperinsulinemic ( insulin levels 56 times higher compared with the current study ) euglycemia was imposed , which is different from the insulin effect of two chronic 12-week treatment periods . in addition , fasted , elevated ( glucose level 11 mmol / l ) glucose levels during pet data acquisition were higher in the current study . in addition , hirvonen et al . investigated two different subject groups , whereas we investigated only one group of individuals with type 1 diabetes and studied the effects of a chronic treatment in a crossover study design . finally , hirvonen et al . may not have observed the 10% difference owing to a lack of power ( although insulin levels were higher , the number of subjects was much less than in the current study ) or the lower signal - to - noise ratio of the pet scanner used . in contrast to the differential effects on cbf , the two insulin treatments did not result in significant differences in cmrglu in any of the regions investigated . previous studies have shown an inverse association of cmrglu and bmi ( 34 ) and increases in cmrglu after stimulation with food pictures ( 35,36 ) . of note , the increase in cmrglu in appetite - related brain regions after insulin infusion was blunted in insulin - resistant men compared with insulin - sensitive men ( 14 ) , and it was associated with insulin resistance and overweight . previously , it was shown that in type 1 diabetes changes in k3 are observed compared with healthy volunteers ( 37 ) , without significant concomitant changes in cbf . under the assumption of absence of between - group differences in phosphorylation ( which were indeed absent in the present data ) , the relationship between cmrglu and cbf is nonlinear [ as cmrglu and k1 are linearly related via cmrglu = ki  glucose / lc , where ki = k1  k3/(k2 + k3 ) , and cmrglu is linearly related to e  cbf , where e = 1  exp(ps / cbf ) ( 38,39 ) ] , and , especially at higher flow values , an increase in cbf will induce a smaller increase in cmrglu ( 37 ) , which is what was observed in the current study , although the latter was nonsignificant . possible confounders that could have accounted for the differences in cbf include a1c or prevailing glucose and insulin levels . however , these parameters were not significantly different between treatments , and the insulin detemir  induced increase in cbf was similar after adjustment for a1c , glucose , and insulin levels . nph insulin is a cloudy suspension that needs to be thoroughly stirred before injection , whereas insulin detemir is a clear , colorless solution that does not require stirring . worldwide , however , nph insulin is the standard ( intermediate ) long - acting human insulin and , therefore , the best active comparator . moreover , even if patients were aware of the type of insulin treatment , it is unlikely that this will have had an effect on the present findings . it should be noted that not all patients in the study were insulin detemir nave , i.e. , five and six patients starting with nph insulin and insulin detemir , respectively , already used insulin detemir before the start of the study . as insulin detemir  nave patients and insulin detemir users were equally distributed between treatment groups , it is unlikely that medication prior to the study has affected the results , especially since pet scans were performed after 12 weeks of exposure to the test insulin . data in the current study were obtained during a resting and fasting condition . in future studies , it may be of interest to investigate responses to ( visual ) food stimuli in appetite regulating brain regions after both treatments . however , due to radiation exposure and practical reasons ( small inner diameter of the hrrt scanner , making it difficult to present visual stimuli ) , this was not possible in the current study . in addition , for detection of changes in brain activation using [ f]fdg pet , two separate sessions are required to test stimulated versus nonstimulated conditions ( 35,36 ) . some patients required glucose or ( basal ) insulin to prevent emerging hypo- or hyperglycemia , respectively . in six patients on insulin detemir versus one on nph insulin , glucose was necessary to prevent low or falling blood glucose levels , which could have biased results , as hypoglycemia increases cbf ( 32,33 ) . as three patients in the insulin detemir versus only one in the nph insulin group required additional basal insulin to avoid hyperglycemia , one could argue that if acute injection of basal insulin would have affected cbf , this would have attenuated the difference in cbf between the groups . more importantly , the increase in cbf in the detemir versus nph group remained unchanged after exclusion of patients who had received insulin or glucose . although weight gain associated with insulin treatment is relevant for type 1 diabetic patients , it is especially important for patients with type 2 diabetes . it is tempting to generalize the present findings to type 2 diabetes , but further studies in these patients are needed , especially since central insulin resistance possibly plays a role in type 2 diabetes . it should be noted , however , that other mechanisms have been proposed to explain its weight - reducing effect . these include less defensive eating due to less hypoglycemia , increased energy expenditure , and higher insulin levels in the liver compared with peripheral tissue , although none of these could be firmly established ( 4043 ) . in the current study , no significant differences in perceived hypoglycemia frequency were found between treatments . in conclusion , the present findings support the hypothesis that a differential effect on cbf , measured during a resting , fasting condition , may contribute to the consistently observed weight - sparing effect of insulin detemir treatment .
objectiveto test the hypothesis that insulin detemir , which is associated with less weight gain than other basal insulin formulations , exerts its weight - modulating effects by acting on brain regions involved in appetite regulation , as represented by altered cerebral blood flow ( cbf ) or cerebral glucose metabolism ( cmrglu).research design and methodstwenty - eight male type 1 diabetic patients ( age 36.9  9.7 years , bmi 24.9  2.7 kg / m2 , a1c 7.5  0.6% ) successfully completed a randomized crossover study , consisting of two periods of 12-week treatment with either insulin detemir or nph insulin , both in combination with prandial insulin aspart . 
 after each treatment period , patients underwent positron emission tomography scans to measure regional cbf and cmrglu.resultsafter 12 weeks , a1c , daily insulin doses , fasting insulin , and blood glucose levels were similar between treatments . 
 insulin detemir resulted in body weight loss , whereas nph insulin induced weight gain ( between - treatment difference 1.3 kg ; p = 0.02 ) . 
 after treatment with insulin detemir relative to nph insulin , cbf was higher in brain regions involved in appetite regulation , whereas no significant difference in cmrglu was observed.conclusionstreatment with insulin detemir versus nph insulin resulted in weight loss , paralleled by increased cbf in appetite - related brain regions in the resting state , in men with well - controlled type 1 diabetes . 
 these findings lend support to the hypothesis that a differential effect on the brain may contribute to the consistently observed weight - sparing effect of insulin detemir .