human
***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: OBJECTIVE To determine the independent risk factors for  coronary artery disease ( CAD )  in type 1 diabetes by type of CAD at first presentation . RESEARCH DESIGN AND METHODS This is a historical prospect i ve cohort study of 603 patients with type 1 diabetes diagnosed before 18 years of age between 1950 and 1980 . The mean age and duration of diabetes at baseline were 28 ( range 8 - 47 ) and 19 years ( 7 - 37 ) , respectively , and patients were followed for 10 years . Patients with prevalent CAD were excluded from the study .  Electrocardiogram ( ECG ) ischemia  was defined by Minnesota Code ( MC ) 1.3 , 4.1 - 3 , 5.1 - 3 , or 7.1 ; angina was determined by Pittsburgh Epidemiology of Diabetes Complications ( EDC ) study physician diagnosis ; and hard CAD was determined by angiographic stenosis > or = 50 % , revascularization procedure , Q waves ( MC 1.1 - 1.2 ) , nonfatal myocardial infa rct ion ( MI ) , or CAD death . RESULTS A total of 108 incident CAD events occurred during the 10-year follow-up : 17 cases of ECG ischemia , 49 cases of angina , and 42 cases of hard CAD ( 5 CAD deaths , 25 nonfatal MI or major Q waves , and 12 revascularization or > or = 50 % stenosis ) . Blood pressure , lipid levels , inflammatory markers , renal disease , and peripheral vascular disease showed a positive gradient across the groups of no CAD , angina , and hard CAD ( P < 0.01 , trend analysis , all variables ) , although estimated glucose disposal rate ( eGDR ) and physical activity showed inverse associations ( P < 0.01 , trend analysis , both variables ) . In addition , depressive symptomatology predicted angina ( P = 0.016 ) , whereas HbA(1 ) showed no association with subsequent CAD . CONCLUSIONS These data suggest that although the st and ard CAD risk factors are still operative in type 1 diabetes , greater glycemia does not seem to predict future CAD events . In addition , depressive symptomatology predicts angina and insulin resistance ( eGDR ) predicts hard CAD end points Insulin resistance is a key pathogenic factor of type 2 diabetes ( T2DM ) ; in contrast , in type 1 diabetes ( T1DM ) it is considered a secondary alteration . Increased intramyocellular lipid ( IMCL ) content accumulation and reduced plasma adiponectin were suggested to be pathogenic events of insulin resistance in T2DM . This study was design ed to assess whether IMCL content and plasma adiponectin were also associated with the severity of insulin resistance in T1DM . We studied 18 patients with T1DM , 7 older and overweight/obese patients with T2DM , and 15 nondiabetic , insulin-resistant offspring of T2DM parents ( OFF ) and 15 healthy individuals ( NOR ) as appropriate control groups matched for anthropometric features with T1DM patients by means of the euglycemic hyperinsulinemic clamp combined with the infusion of [6,6 - 2H2]glucose and 1H magnetic resonance spectroscopy of the calf muscles . T1DM and T2DM patients showed reduced insulin-stimulated glucose metabolic clearance rate ( MCR : 5.1 + /- 0.6 and 3.2 + /- 0.8 ml x kg(-1 ) min(-1 ) ) similar to OFF ( 5.3 + /- 0.4 ml x kg(-1 ) x min(-1 ) ) compared with NOR ( 8.5 + /- 0.5 ml x kg(-1 ) min(-1 ) , P < 0.001 ) . Soleus IMCL content was increased in T1DM ( 112 + /- 15 AU ) , T2DM ( 108 + /- 10 AU ) and OFF ( 82 + /- 13 AU ) compared with NOR ( 52 + /- 7 AU , P < 0.05 ) and the result was inversely proportional to the MCR ( R2 = 0.27 , P < 0.001 ) ; an association between IMCL content and Hb A1c was found only in T1DM ( R2 = 0.57 , P < 0.001 ) . Fasting plasma adiponectin was reduced in T2DM ( 7 + /- 1 microg/ml , P = 0.01 ) and OFF ( 11 + /- 1 microg/ml , P = 0.03 ) but not in T1DM ( 25 + /- 6 microg/ml ) , whose plasma level was increased with respect to both OFF ( P = 0.03 ) and NOR ( 16 + /- 2 microg/ml , P = 0.05 ) . In conclusion , in T1DM , T2DM , and OFF , IMCL content was associated with insulin resistance , demonstrating that IMCL accretion is a marker of insulin resistance common to both primary genetically determined and secondary metabolic ( chronic hyperglycemia ) alterations . The increased adiponectin levels in insulin-resistant patients with T1DM , in contrast to the reduced levels found in patients with T2DM and in OFF , demonstrated that the relationship of adiponectin to insulin resistance in humans is still unclear AIMS To quantify and compare associations between femoral-gluteal adiposity and insulin sensitivity in adults with Type 1 diabetes mellitus with adults with normal glucose tolerance . METHODS Individuals with Type 1 diabetes ( n = 28 ) were recruited from the Pittsburgh Epidemiology of Diabetes Complication study , a 24-year prospect i ve study of childhood-onset diabetes , and compared cross-sectionally with individuals with normal glucose tolerance ( n = 56 ) of similar age , sex and BMI . Insulin sensitivity was defined as whole-body glucose disposal measured by hyperinsulinaemic-euglycaemic clamps . Adiposity was quantified by dual energy X-ray absorptiometry . RESULTS Individuals with Type 1 diabetes exhibited lower insulin sensitivity ( 5.8 vs. 8.2 mg min(-1 ) kg fat-free mass(-1 ) , P < 0.01 ) , lower total fat mass ( 20.1 vs. 29.0 kg , P < 0.001 ) and lower proportional leg fat mass ( 36.0 vs.37.7 % , P = 0.03 ) , but similar proportional trunk fat ( % trunk fat mass ) compared with individuals with normal glucose tolerance . Overall , results from linear regression demonstrated that higher % leg fat mass ( P < 0.01 ) and lower % trunk fat mass ( P < 0.01 ) were independently associated with lower insulin sensitivity after adjustments for age , sex , height , total fat mass ( kg ) and diabetes status . Higher % leg fat mass was independently associated with higher insulin sensitivity in individuals with normal glucose tolerance ( P < 0.01 ) after similar adjustment ; significant associations were not observed in Type 1 diabetes . CONCLUSIONS Reduced insulin sensitivity is a prominent feature of Type 1 diabetes and is associated with total and abdominal adiposity . Compared with adults with normal glucose tolerance , leg fat mass does not show any positive association with insulin sensitivity in Type 1 diabetes OBJECTIVE To determine the incidence of retinopathy and the relative importance of its risk factors in type 1 diabetes . RESEARCH DESIGN AND METHODS This is a 7.3-year follow-up of 764 of 1,215 ( 63 % ) people with type 1 diabetes across Europe , aged 15 - 60 years at baseline with no retinopathy ( the EURODIAB Prospect i ve Complications Study ) .  Retinal photographs  were taken at baseline and follow-up and risk factors were assessed to a st and ard protocol . RESULTS Retinopathy incidence was 56 % ( 429/764 , 95 % CI 52 - 59 % ) . Key risk factors included diabetes duration and glycemic control . We found no evidence of a threshold effect for HbA1c on retinopathy incidence . Univariate associations were observed between incidence and albumin excretion rate , cholesterol , triglyceride , fibrinogen , von Willebr and factor , gamma-glutamyltransferase , waist-to-hip ratio , and insulin dose . No associations were observed for blood pressure , cardiovascular disease , or smoking . Independent risk factors , as assessed by st and ardized regression effects , were HbA1C ( 1.93 , P = 0.0001 ) , duration ( 1.32 , P = 0.008 ) , waist-to-hip ratio ( 1.32 , P = 0.01 ) , and fasting triglyceride ( 1.24 , P = 0.04 ) . CONCLUSIONS Retinopathy incidence in type 1 diabetes remains high . Key risk factors include diabetes duration and glycemic control , with no evidence of a threshold for the latter . Other independent risk factors , such as waist-to-hip ratio and triglyceride levels , both markers of insulin resistance , were strongly related to incidence Background Hypertensive patients frequently show resistance to insulin-stimulated glucose uptake and hyperinsulinemia . Diuretics and β-adrenoceptor blocking agents have been found to decrease insulin sensitivity , whereas α1-blockers and angiotensin converting enzyme inhibitors seem to improve it . Objective To compare the effects of a 3 months ' antihypertensive treatment with carvedilol , a non-selective β-adrenoceptor blocker with α1-blocking properties , with the β1-selective receptor blocker metoprolol on insulin sensitivity in non-diabetic hypertensive patients . Design A multicenter double-blind r and omized study . Subjects and methods Seventy-two non-diabetic hypertensive patients were r and omly assigned to treatment with either carvedilol or metoprolol . An isoglycemic , hyperinsulinemic glucose clamp was conducted before and after 12 weeks of treatment ; the metabolic clearance rate for glucose was taken as an indicator of insulin sensitivity . Results The two groups did not differ in age , sex , body mass index , blood pressure or lipids , and treatment effectively lowered blood pressure . In both groups , insulin sensitivity was impaired at baseline . After metoprolol treatment , insulin sensitivity further decreased significantly by about 14 % , whereas it increased after carvedilol . There was also a decrease in high-density lipoprotein and an increase in triglycerides levels in patients in the metoprolol-treated group , whereas these parameters remained unchanged in patients in the carvedilol-treated group . Conclusion This study confirms previous findings of a reduction in insulin sensitivity after chronic metoprolol treatment . Carvedilol treatment , however , result ed in a slight increase in insulin resistance and a better lipid profile . We thus demonstrate that a β-blocker with α1-blocking properties has favorable effects on glucose metabolism , suggesting a potentially important role of peripheral blood flow in regulating glucose uptake . These findings imply that β-blocker treatment , when combined with α1-blocking activity has advantageous effects on insulin sensitivity and lipids and could therefore be suitable for patients with the metabolic syndrome OBJECTIVE in type 2 diabetic patients and their first-degree relatives , insulin resistance ( IR ) is associated with impairment of insulin-stimulated myocellular glucose-6-phosphate ( g6p ) and unidirectional flux through ATP synthase ( fATP ) , suggesting the presence of inherited abnormal mitochondrial oxidative fitness . We hypothesized that patients with long-st and ing type 1 diabetes may also exhibit insulin resistance as well as lower fATP . DESIGN this single-centre trial was registered at Clinical Trials.gov ( NCT00481598 ) . SUBJECTS we included eight nonobese type 1 diabetic patients ( mean diabetes duration : 17 years ) with near-target glycaemic control [ haemoglobin A1c ( HbA1c ) : 6.8 ± 0.4 % ] during treatment with continuous subcutaneous insulin infusion pumps and eight healthy volunteers ( HbA1c : 5.4 ± 0.2 % ) of comparable age , body mass and level of physical activity . OUTCOME MEASURES myocellular fATP , g6p and intramyocellular lipid content ( IMCL ) were measured with ( 1 ) H/(31 ) P magnetic resonance spectroscopy during fasting and hyperinsulinaemic-euglycaemic clamp tests . RESULTS fasting fATP , g6p and IMCL did not differ between groups . During stimulation by insulin , type 1 diabetic patients exhibited approximately 50 % ( P < 0.001 ) lower whole-body glucose disposal along with approximately 42 % ( P = 0.003 ) lower intramyocellular g6p and approximately25 % ( P = 0.024 ) lower fATP . Insulin-stimulated fATP correlated positively with whole-body insulin sensitivity ( R = 0.706 , P = 0.002 ) and negatively with HbA1c ( R = -0.675 , P = 0 
    Output:
    
agent
Insulin mediated inhibition of lipolysis was decreased in patients , reflected by increased non-esterified fatty acid levels .
Insulin resistance is a prominent feature of patients with type 1 diabetes mellitus and involves hepatic , peripheral and adipose tissues
***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: OBJECTIVE To determine the independent risk factors for  coronary artery disease ( CAD )  in type 1 diabetes by type of CAD at first presentation . RESEARCH DESIGN AND METHODS This is a historical prospect i ve cohort study of 603 patients with type 1 diabetes diagnosed before 18 years of age between 1950 and 1980 . The mean age and duration of diabetes at baseline were 28 ( range 8 - 47 ) and 19 years ( 7 - 37 ) , respectively , and patients were followed for 10 years . Patients with prevalent CAD were excluded from the study .  Electrocardiogram ( ECG ) ischemia  was defined by Minnesota Code ( MC ) 1.3 , 4.1 - 3 , 5.1 - 3 , or 7.1 ; angina was determined by Pittsburgh Epidemiology of Diabetes Complications ( EDC ) study physician diagnosis ; and hard CAD was determined by angiographic stenosis > or = 50 % , revascularization procedure , Q waves ( MC 1.1 - 1.2 ) , nonfatal myocardial infa rct ion ( MI ) , or CAD death . RESULTS A total of 108 incident CAD events occurred during the 10-year follow-up : 17 cases of ECG ischemia , 49 cases of angina , and 42 cases of hard CAD ( 5 CAD deaths , 25 nonfatal MI or major Q waves , and 12 revascularization or > or = 50 % stenosis ) . Blood pressure , lipid levels , inflammatory markers , renal disease , and peripheral vascular disease showed a positive gradient across the groups of no CAD , angina , and hard CAD ( P < 0.01 , trend analysis , all variables ) , although estimated glucose disposal rate ( eGDR ) and physical activity showed inverse associations ( P < 0.01 , trend analysis , both variables ) . In addition , depressive symptomatology predicted angina ( P = 0.016 ) , whereas HbA(1 ) showed no association with subsequent CAD . CONCLUSIONS These data suggest that although the st and ard CAD risk factors are still operative in type 1 diabetes , greater glycemia does not seem to predict future CAD events . In addition , depressive symptomatology predicts angina and insulin resistance ( eGDR ) predicts hard CAD end points Insulin resistance is a key pathogenic factor of type 2 diabetes ( T2DM ) ; in contrast , in type 1 diabetes ( T1DM ) it is considered a secondary alteration . Increased intramyocellular lipid ( IMCL ) content accumulation and reduced plasma adiponectin were suggested to be pathogenic events of insulin resistance in T2DM . This study was design ed to assess whether IMCL content and plasma adiponectin were also associated with the severity of insulin resistance in T1DM . We studied 18 patients with T1DM , 7 older and overweight/obese patients with T2DM , and 15 nondiabetic , insulin-resistant offspring of T2DM parents ( OFF ) and 15 healthy individuals ( NOR ) as appropriate control groups matched for anthropometric features with T1DM patients by means of the euglycemic hyperinsulinemic clamp combined with the infusion of [6,6 - 2H2]glucose and 1H magnetic resonance spectroscopy of the calf muscles . T1DM and T2DM patients showed reduced insulin-stimulated glucose metabolic clearance rate ( MCR : 5.1 + /- 0.6 and 3.2 + /- 0.8 ml x kg(-1 ) min(-1 ) ) similar to OFF ( 5.3 + /- 0.4 ml x kg(-1 ) x min(-1 ) ) compared with NOR ( 8.5 + /- 0.5 ml x kg(-1 ) min(-1 ) , P < 0.001 ) . Soleus IMCL content was increased in T1DM ( 112 + /- 15 AU ) , T2DM ( 108 + /- 10 AU ) and OFF ( 82 + /- 13 AU ) compared with NOR ( 52 + /- 7 AU , P < 0.05 ) and the result was inversely proportional to the MCR ( R2 = 0.27 , P < 0.001 ) ; an association between IMCL content and Hb A1c was found only in T1DM ( R2 = 0.57 , P < 0.001 ) . Fasting plasma adiponectin was reduced in T2DM ( 7 + /- 1 microg/ml , P = 0.01 ) and OFF ( 11 + /- 1 microg/ml , P = 0.03 ) but not in T1DM ( 25 + /- 6 microg/ml ) , whose plasma level was increased with respect to both OFF ( P = 0.03 ) and NOR ( 16 + /- 2 microg/ml , P = 0.05 ) . In conclusion , in T1DM , T2DM , and OFF , IMCL content was associated with insulin resistance , demonstrating that IMCL accretion is a marker of insulin resistance common to both primary genetically determined and secondary metabolic ( chronic hyperglycemia ) alterations . The increased adiponectin levels in insulin-resistant patients with T1DM , in contrast to the reduced levels found in patients with T2DM and in OFF , demonstrated that the relationship of adiponectin to insulin resistance in humans is still unclear AIMS To quantify and compare associations between femoral-gluteal adiposity and insulin sensitivity in adults with Type 1 diabetes mellitus with adults with normal glucose tolerance . METHODS Individuals with Type 1 diabetes ( n = 28 ) were recruited from the Pittsburgh Epidemiology of Diabetes Complication study , a 24-year prospect i ve study of childhood-onset diabetes , and compared cross-sectionally with individuals with normal glucose tolerance ( n = 56 ) of similar age , sex and BMI . Insulin sensitivity was defined as whole-body glucose disposal measured by hyperinsulinaemic-euglycaemic clamps . Adiposity was quantified by dual energy X-ray absorptiometry . RESULTS Individuals with Type 1 diabetes exhibited lower insulin sensitivity ( 5.8 vs. 8.2 mg min(-1 ) kg fat-free mass(-1 ) , P < 0.01 ) , lower total fat mass ( 20.1 vs. 29.0 kg , P < 0.001 ) and lower proportional leg fat mass ( 36.0 vs.37.7 % , P = 0.03 ) , but similar proportional trunk fat ( % trunk fat mass ) compared with individuals with normal glucose tolerance . Overall , results from linear regression demonstrated that higher % leg fat mass ( P < 0.01 ) and lower % trunk fat mass ( P < 0.01 ) were independently associated with lower insulin sensitivity after adjustments for age , sex , height , total fat mass ( kg ) and diabetes status . Higher % leg fat mass was independently associated with higher insulin sensitivity in individuals with normal glucose tolerance ( P < 0.01 ) after similar adjustment ; significant associations were not observed in Type 1 diabetes . CONCLUSIONS Reduced insulin sensitivity is a prominent feature of Type 1 diabetes and is associated with total and abdominal adiposity . Compared with adults with normal glucose tolerance , leg fat mass does not show any positive association with insulin sensitivity in Type 1 diabetes OBJECTIVE To determine the incidence of retinopathy and the relative importance of its risk factors in type 1 diabetes . RESEARCH DESIGN AND METHODS This is a 7.3-year follow-up of 764 of 1,215 ( 63 % ) people with type 1 diabetes across Europe , aged 15 - 60 years at baseline with no retinopathy ( the EURODIAB Prospect i ve Complications Study ) .  Retinal photographs  were taken at baseline and follow-up and risk factors were assessed to a st and ard protocol . RESULTS Retinopathy incidence was 56 % ( 429/764 , 95 % CI 52 - 59 % ) . Key risk factors included diabetes duration and glycemic control . We found no evidence of a threshold effect for HbA1c on retinopathy incidence . Univariate associations were observed between incidence and albumin excretion rate , cholesterol , triglyceride , fibrinogen , von Willebr and factor , gamma-glutamyltransferase , waist-to-hip ratio , and insulin dose . No associations were observed for blood pressure , cardiovascular disease , or smoking . Independent risk factors , as assessed by st and ardized regression effects , were HbA1C ( 1.93 , P = 0.0001 ) , duration ( 1.32 , P = 0.008 ) , waist-to-hip ratio ( 1.32 , P = 0.01 ) , and fasting triglyceride ( 1.24 , P = 0.04 ) . CONCLUSIONS Retinopathy incidence in type 1 diabetes remains high . Key risk factors include diabetes duration and glycemic control , with no evidence of a threshold for the latter . Other independent risk factors , such as waist-to-hip ratio and triglyceride levels , both markers of insulin resistance , were strongly related to incidence Background Hypertensive patients frequently show resistance to insulin-stimulated glucose uptake and hyperinsulinemia . Diuretics and β-adrenoceptor blocking agents have been found to decrease insulin sensitivity , whereas α1-blockers and angiotensin converting enzyme inhibitors seem to improve it . Objective To compare the effects of a 3 months ' antihypertensive treatment with carvedilol , a non-selective β-adrenoceptor blocker with α1-blocking properties , with the β1-selective receptor blocker metoprolol on insulin sensitivity in non-diabetic hypertensive patients . Design A multicenter double-blind r and omized study . Subjects and methods Seventy-two non-diabetic hypertensive patients were r and omly assigned to treatment with either carvedilol or metoprolol . An isoglycemic , hyperinsulinemic glucose clamp was conducted before and after 12 weeks of treatment ; the metabolic clearance rate for glucose was taken as an indicator of insulin sensitivity . Results The two groups did not differ in age , sex , body mass index , blood pressure or lipids , and treatment effectively lowered blood pressure . In both groups , insulin sensitivity was impaired at baseline . After metoprolol treatment , insulin sensitivity further decreased significantly by about 14 % , whereas it increased after carvedilol . There was also a decrease in high-density lipoprotein and an increase in triglycerides levels in patients in the metoprolol-treated group , whereas these parameters remained unchanged in patients in the carvedilol-treated group . Conclusion This study confirms previous findings of a reduction in insulin sensitivity after chronic metoprolol treatment . Carvedilol treatment , however , result ed in a slight increase in insulin resistance and a better lipid profile . We thus demonstrate that a β-blocker with α1-blocking properties has favorable effects on glucose metabolism , suggesting a potentially important role of peripheral blood flow in regulating glucose uptake . These findings imply that β-blocker treatment , when combined with α1-blocking activity has advantageous effects on insulin sensitivity and lipids and could therefore be suitable for patients with the metabolic syndrome OBJECTIVE in type 2 diabetic patients and their first-degree relatives , insulin resistance ( IR ) is associated with impairment of insulin-stimulated myocellular glucose-6-phosphate ( g6p ) and unidirectional flux through ATP synthase ( fATP ) , suggesting the presence of inherited abnormal mitochondrial oxidative fitness . We hypothesized that patients with long-st and ing type 1 diabetes may also exhibit insulin resistance as well as lower fATP . DESIGN this single-centre trial was registered at Clinical Trials.gov ( NCT00481598 ) . SUBJECTS we included eight nonobese type 1 diabetic patients ( mean diabetes duration : 17 years ) with near-target glycaemic control [ haemoglobin A1c ( HbA1c ) : 6.8 ± 0.4 % ] during treatment with continuous subcutaneous insulin infusion pumps and eight healthy volunteers ( HbA1c : 5.4 ± 0.2 % ) of comparable age , body mass and level of physical activity . OUTCOME MEASURES myocellular fATP , g6p and intramyocellular lipid content ( IMCL ) were measured with ( 1 ) H/(31 ) P magnetic resonance spectroscopy during fasting and hyperinsulinaemic-euglycaemic clamp tests . RESULTS fasting fATP , g6p and IMCL did not differ between groups . During stimulation by insulin , type 1 diabetic patients exhibited approximately 50 % ( P < 0.001 ) lower whole-body glucose disposal along with approximately 42 % ( P = 0.003 ) lower intramyocellular g6p and approximately25 % ( P = 0.024 ) lower fATP . Insulin-stimulated fATP correlated positively with whole-body insulin sensitivity ( R = 0.706 , P = 0.002 ) and negatively with HbA1c ( R = -0.675 , P = 0 
    Output:
    