***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 evaluate the efficacy and safety of combinations of empagliflozin/linagliptin as second-line therapy in subjects with type 2 diabetes inadequately controlled on metformin . RESEARCH DESIGN AND METHODS Subjects were r and omized to a combination of empagliflozin 25 mg/linagliptin 5 mg ( n = 137 ) , empagliflozin 10 mg/linagliptin 5 mg ( n = 136 ) , empagliflozin 25 mg ( n = 141 ) , empagliflozin 10 mg ( n = 140 ) , or linagliptin 5 mg ( n = 132 ) as add-on to metformin for 52 weeks . The primary end point was change from baseline in HbA1c at week 24 . RESULTS At week 24 , reductions in HbA1c ( mean baseline 7.90–8.02 % [ 62.8–64.1 mmol/mol ] ) with empagliflozin/linagliptin were superior to those with empagliflozin or linagliptin alone as add-on to metformin ; adjusted mean ( SE ) changes from baseline were −1.19 % ( 0.06 ) ( −13.1 mmol/mol [ 0.7 ] ) with empagliflozin 25 mg/linagliptin 5 mg , −1.08 % ( 0.06 ) ( −11.8 mmol/mol [ 0.7 ] ) with empagliflozin 10 mg/linagliptin 5 mg , −0.62 % ( 0.06 ) ( −6.8 mmol/mol [ 0.7 ] ) with empagliflozin 25 mg , −0.66 % ( 0.06 ) ( −7.2 mmol/mol [ 0.7 ] ) with empagliflozin 10 mg , and −0.70 % ( 0.06 ) ( −7.6 mmol/mol [ 0.7 ] ) with linagliptin 5 mg ( P < 0.001 for all comparisons ) . In these groups , respectively , 61.8 , 57.8 , 32.6 , 28.0 , and 36.1 % of subjects with baseline HbA1c ≥7 % ( ≥53 mmol/mol ) had HbA1c < 7 % ( < 53 mmol/mol ) at week 24 . Efficacy was maintained at week 52 . The proportion of subjects with adverse events ( AEs ) over 52 weeks was similar across treatment arms ( 68.6–73.0 % ) , with no hypoglycemic AEs requiring assistance . CONCLUSIONS Combinations of empagliflozin/linagliptin as second-line therapy for 52 weeks significantly reduced HbA1c compared with the individual components and were well tolerated INTRODUCTION Basal insulin dose requirements in patients with type 1 diabetes may be derived from the course of glucose concentrations in the fasting state ; i. e. by skipping meals . The present study examined whether fasting tests could be replaced by carbohydrate-free meals . MATERIAL AND METHODS 16 adult patients with type 1 diabetes ( 10 male ) on intensive insulin therapy participated in this prospect i ve intervention study . Mean age ( + /-SD ) was 44+/-12 years , BMI 24+/-3 kg/m ( 2 ) , mean HbA1c was 7.5+/-0.6 % and duration of diabetes 15+/-12 years . All participants skipped dinner and  plasma glucose concentrations were hourly monitored from 7 p.m. to 11 p.m. This blood glucose profile was compared with three test meals given at 7 p.m. at day 2 - 4 , consumed either in the hospital ( meal 1 ) or at home ( meal 2 and 3 ) . No insulin injection ( except to basal insulin ) was allowed . Test meals consisted of 2.5 g carbohydrate , 32.4 g protein , 52.0 g fat ( according to 612 kcal ) . RESULTS During 16 fasting tests plasma glucose concentration remained stable between 7.2+/-2.4 mmol/l at 7 p.m. and 6.8+/-2.8 mmol/l at 11 p.m. ( p=0.461 ) . Following the intake of near carbohydrate-free meals ( 48 tests ) , plasma glucose concentrations rose within 4 h from 6.7+/-2.0 at 7 p.m. to 9.8+/-3.4 mmol/l at 11 p.m. ( p<0.0001 ) . The increase in plasma glucose concentrations was similar in all three different meals tested . CONCLUSION Plasma glucose concentrations significantly increase in patients with type 1 diabetes following the intake of carbohydrate-free meals . Carbohydrate-free meal-tests can not replace skipping meal tests to determine the basal insulin requirement in patients with type 1 diabetes The effect of two isocaloric evening meals ( low protein-high fat vs. high protein-low fat content ) on plasma glucose regulation during the night were compared . Eight C-peptide-deficient type-I diabetic subjects without autonomic neuropathy were treated with fixed doses of continuous infusions of insulin during 2 nights . At 7 p.m. they received in r and om order either a low protein-high fat ( 5 % of total energy protein , 60 % fat , 35 % carbohydrate ) or a high protein-low fat ( 35 % protein , 30 % fat , 35 % carbohydrate ) evening meal . Venous plasma sample s were drawn hourly thereafter . Plasma glucose concentrations were similar postpr and ially during the 2 nights between 7 p.m. and 11 p.m. , but they were higher in the early morning hours after the high protein meal ( p < 0.02 vs. the low protein meal ) . Two subjects developed symptomatic hypoglycemia after the low protein meal . Plasma glucagon concentrations were higher ( p = 0.023 ) and serum free insulin lower ( p < 0.05 ) after the high protein-low fat meal .  Plasma cortisol and growth hormone were not significantly different between the two diets . Therefore , an increase in the protein content of the evening meal ( fat content diminished ) increases plasma glucose concentrations several hours later in the night , possibly due to protein-induced glucagon secretion and to lower plasma free insulin levels .  Patients with type-I diabetes with a tendency to develop hypoglycemia during the night may avoid this problem by increasing the protein content of the evening meal BACKGROUND We attempted to identify an optimal insulin pump meal bolus by comparing postpr and ial sensor glucose values following three methods of insulin pump meal bolusing for a consistent pizza meal . RESEARCH DESIGN AND METHODS Twenty-four patients with type 1 diabetes participated in a study to compare postpr and ial glucose values following three meal bolus regimens for a consistent evening pizza meal . Each participant utilized the following insulin lispro regimens on consecutive evenings , and glucose values were tracked by the Continuous Glucose Monitoring System ( CGMS , Medtronic MiniMed , Northridge , CA ) : ( a ) single-wave bolus ( 100 % of insulin given immediately ) ; ( b ) 4-h dual-wave bolus ( 50 % of insulin given immediately and 50 % given over a 4-h period ) ; and ( c ) 8-h dual-wave bolus ( 50 % of insulin given immediately and 50 % given over a 8-h period ) . Total insulin bolus amount was kept constant for each pizza meal . RESULTS Divergence in blood glucose among the regimens was greatest at 8 - 12 h. The 8-h dual-wave bolus provided the best glycemic control and lowest mean glucose values ( singlewave bolus , 133 mg/dL ; 4-h dual-wave bolus , 145 mg/dL ; 8-h dual-wave bolus , 104 mg/dL ) , leading to a difference in mean glucose of 29 mg/dL for the single-wave bolus versus the 8-h dual-wave bolus and 42 mg/dL for the 4-h dual-wave bolus versus the 8-h dual-wave bolus . The lower mean glucose in the 8-h dual-wave bolus was not associated with any increased incidence of hypoglycemia . CONCLUSIONS Use of a dual-wave bolus extended over an 8-h period following a pizza meal provided significantly less postpr and ial hyperglycemia in the late postpr and ial period ( 8 - 12 h ) with no increased risk of hypoglycemia BACKGROUND Concerning continuous subcutaneous insulin infusion ( CSII ) , there are controversial results related to changes in glycemic response according to the meal composition and bolus design . Our aim is to determine whether the presence of protein and fat in a meal could involve a different postpr and ial glycemic response than that obtained with only carbohydrates ( CHs ) . SUBJECTS AND METHODS This was a crossover , r and omized clinical trial . Seventeen type 1 diabetes ( T1D ) patients on CSII wore a blinded continuous glucose monitoring system sensor for 3 days . They ingested two meals ( meal 1 vs. meal 2 ) with the same CH content ( 50 g ) but different fat ( 8.9 g vs. 37.4 g ) and protein ( 3.3 g vs. 28.9 g ) contents . A single-wave insulin bolus was used , and the interstitial glucose values were measured every 30 min for 3 h. We evaluated the different postpr and ial glycemic response between meal 1 and meal 2 by using mixed-effects models . RESULTS The postmeal glucose increase was 22 mg/dL for meal 1 and 31 mg/dL for meal 2 . In univariate analysis , at different times not statistically significant differences in glucose levels between meals occurred . In mixed-model analysis , a time × meal interaction was found , indicating a different response between treatments along the time . However , most of the patients remained in the normoglycemic range ( 70 - 180 mg/dL ) during the 3-h postmeal period ( 84.4 % for meal 1 and 93.1 % for meal 2 ) . CONCLUSIONS The presence of balanced amounts of protein and fat determined a different glycemic response from that obtained with only CH up to 3 h after eating . The clinical relevance of this finding remains to be eluci date OBJECTIVE To assess the possibility of improving nocturnal glycemic control as well as meal glycemic response using closed-loop therapy in children aged < 7 years . RESEARCH DESIGN AND METHODS This was a r and omized controlled crossover trial comparing closed-loop with st and ard open-loop insulin pump therapy performed in an inpatient clinical research center . Ten subjects aged < 7 years with type 1 diabetes for > 6 months treated with insulin pump therapy  were studied . Closed-loop therapy and st and ard open-loop therapy were compared from 10:00 p.m. to 12:00 p.m. on 2 consecutive days . The primary outcome was plasma glucose time in range ( 110–200 mg/dL ) during the night ( 10:00 p.m.–8:00 a.m. ) . Secondary outcomes included peak postpr and ial glucose levels , incidence of hypoglycemia , degree of hyperglycemia , and prelunch glucose levels . RESULTS A trend toward a higher mean nocturnal time within target range was noted for closed- versus open-loop therapy , although not reaching statistical significance ( 5.3 vs. 3.2 h , P = 0.12 ) . There was no difference in peak postpr and ial glucose or number of episodes of hypoglycemia . There was significant improvement in time spent > 300 mg/dL overnight with closed-loop therapy ( 0.18 vs. 1.3 h , P = 0.035 ) and the total area under the curve of glucose > 200 mg/dL ( P = 0.049 ) . Closed-loop therapy returned prelunch blood glucose closer to target ( 189 vs. 273 mg/dL on open loop , P = 0.009 ) . CONCLUSIONS Closed-loop insulin delivery decreases the severity of overnight hyperglycemia without increasing the incidence of hypoglycemia . The therapy is better able to reestablish target glucose levels in advance of a subsequent meal . Younger children with type 1 diabetes may reap significant benefits from closed-loop therapy OBJECTIVE Although carbohydrate counting is routine practice in type 1 diabetes , hyperglycemic episodes are common . A food insulin index ( FII ) has been developed and vali date d for predicting the normal insulin dem and generated by mixed meals in healthy adults . We sought to compare a novel algorithm on the basis of the FII for estimating mealtime insulin dose with carbohydrate counting in adults with type 1 diabetes . RESEARCH 
    Output:
    
Because of method ological differences and limitations in experimental design , study findings were inconsistent regarding optimal bolus delivery pattern ; however , the studies indicated that high-fat/protein meals require more insulin than lower-fat/protein meals with identical carbohydrate content .