***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 study the pharmacodynamic properties of the subcutaneously injected long-acting insulin analog HOE901 ( 30 microg/ml zinc ) in comparison with those of NPH insulin and placebo . RESEARCH DESIGN AND METHODS In this single-center double-blind euglycemic glucose clamp study , 15 healthy male volunteers ( aged 27 + /- 4 years , BMI 22.2 + /- 1.8 kg/m2 ) received single subcutaneous injections of 0.4 U/kg body wt of HOE901 , NPH insulin , or placebo on 3 study days in a r and omized order . The necessary glucose infusion rates ( GIRs ) to keep blood glucose concentrations constant at 5.0 mmol/l were determined over a 30-h period after administration . RESULTS The injection of HOE901 did not induce the pronounced peak in metabolic activity observed with NPH insulin ( GIRmax 5.3 + /- 1.1 vs. 7.7 + /- 1.3 mg x kg(-1 ) x min(-1 ) ) ( P < 0.05 ) ; after an initial rise , metabolic activity was rather constant over the study period . This lack of peak was confirmed by a lower glucose consumption in the first 4 h after injection ( area under the curve from 0 to 4 h [ AUC(0 - 4 h ) ] 1.02 + /- 0.34 vs. 1.48 + /- 0.34 g/kg ) ( P < 0.001 ) with HOE901 , as compared with NPH insulin . In this single-dose study , the metabolic effect measured over a period of 30 h was lower with HOE901 than with NPH insulin ( AUC(0 - 30 h ) 7.93 + /- 1.82 vs. 9.24 + /- 1.29 g/kg ) ( P < 0.05 ) . CONCLUSIONS This study shows that the soluble long-acting insulin analog HOE901 induces a smoother metabolic effect than NPH insulin , from which a better substitution of basal insulin requirements may follow Insulin glulisine is appealing in principle , but the advantages of this drug over the other rapid-acting insulin analogs are still relatively unknown . The frequency of hypoglycemia , convenience in the timing of administration , and improvements in terms of HbA1c seem similar among the rapid-acting insulin analogs , including insulin glulisine . Only properly r and omized long-term clinical studies with insulin glulisine will reveal the true value of this novel insulin analog AIMS The IMPROVE observational study evaluated the safety profile and effectiveness of biphasic insulin aspart 30/70 ( BIAsp 30 )  in patients with type 2 diabetes in routine practice in 11 countries . METHODS Patients who initiated insulin therapy with , or switched existing insulin therapy to , BIAsp 30 in routine care were eligible for this 26-week , non-interventional observational study . Data on adverse events , hypoglycaemia and glycaemic parameters were obtained from patients ' diaries and medical notes . Question naire-based patient treatment satisfaction was also measured . We report global results and , uniquely for a diabetes observational study , country-specific data . RESULTS A total of 52,419 patients were enrolled from three pre study treatment groups :  no pharmaceutical therapy ( n = 8966 , diabetes duration 2.0 years , baseline HbA1c 9.9 % ) , oral antidiabetic drugs ( OADs ) only ( n = 33,797 , diabetes duration 7.4 years , baseline HbA1c 9.2 % ) and insulin + /- OADs ( n = 9568 , diabetes duration 10.4 years , baseline HbA1c 9.3 % ) . At final visit , HbA1c , fasting and postpr and ial blood glucose were significantly reduced from baseline in all subgroups ( no pharmaceutical therapy : -3.1 % , -5.9 and -9.0 mmol/l , respectively ; OADs-only : -2.1 % , -4.1 and -6.1 mmol/l ; insulin + /- OADs : -2.0 % , -3.3 and -5.1 mmol/l ) . Major hypoglycaemia rates decreased in all subgroups ; minor hypoglycaemia increased in the insulin-naïve groups . There was no mean weight gain across subgroups . Across all countries , glycaemic parameters and major hypoglycaemia were reduced ; weight increases were seen in some countries . Treatment satisfaction increased in all subgroups and countries following BIAsp 30 therapy . CONCLUSIONS Initiating insulin with , or switching insulin therapy to , BIAsp 30 in routine care result ed in improved glycaemic control , reduced major hypoglycaemia and greater treatment satisfaction OBJECTIVE Insulin degludec ( IDeg ) is a basal insulin that forms soluble multihexamers after subcutaneous injection , result ing in an ultra-long action profile . We assessed the efficacy and safety of IDeg formulations administered once daily in combination with mealtime insulin aspart in people with type 1 diabetes . RESEARCH DESIGN AND METHODS In this 16-week , r and omized , open-label trial , participants ( mean : 45.8 years old , A1C 8.4 % , fasting plasma glucose [ FPG ] 9.9 mmol/L , BMI 26.9 kg/m2 ) received subcutaneous injections of IDeg(A ) ( 600 μmol/L ; n = 59 ) , IDeg(B ) ( 900 μmol/L ; n = 60 ) , or insulin glargine ( IGlar ; n = 59 ) , all given once daily in the evening . Insulin aspart was administered at mealtimes . RESULTS At 16 weeks , mean A1C was comparable for IDeg(A ) ( 7.8 ± 0.8 % ) , IDeg(B ) ( 8.0 ± 1.0 % ) , and IGlar ( 7.6 ± 0.8 % ) , as was FPG ( 8.3 ± 4.0 , 8.3 ± 2.8 , and 8.9 ± 3.5 mmol/L , respectively ) . Estimated mean rates of confirmed hypoglycemia were 28 % lower for IDeg(A ) compared with IGlar ( rate ratio [ RR ] : 0.72 [ 95 % CI 0.52–1.00 ] ) and 10 % lower for IDeg(B ) compared with IGlar ( RR : 0.90 [ 0.65–1.24 ] ) ; rates of nocturnal hypoglycemia were 58 % lower for IDeg(A ) ( RR : 0.42 [ 0.25–0.69 ] ) and 29 % lower for IDeg(B ) ( RR : 0.71 [ 0.44–1.16 ] ) . Mean total daily insulin dose was similar to baseline . The frequency and pattern of adverse events was similar between insulin treatments . CONCLUSIONS In this clinical exploratory phase 2 trial in people with type 1 diabetes  , IDeg is safe and well tolerated and provides comparable glycemic control to IGlar at similar doses , with reduced rates of hypoglycemia Aims /hypothesisThe aim of the trial was to compare the efficacy and tolerability of two types of basal-bolus therapy , using either the soluble long-acting basal insulin analogue , insulin detemir , in combination with the rapid-acting analogue , insulin aspart , or NPH insulin in combination with mealtime regular human insulin . Methods In this 18-week , 1:1 r and omised , open-labelled , parallel trial , 595 patients with Type 1 diabetes mellitus received insulin detemir or NPH insulin in the morning and at bedtime in combination with mealtime insulin aspart or regular human insulin respectively . Results Glycaemic control with insulin detemir/insulin aspart was improved in comparison with NPH insulin/regular human insulin ( HbA1c : 7.88 % vs 8.11 % ; mean difference : −0.22 % point [ 95 % CI : −0.34 to −0.10 ] ; p<0.001 ) . Self-measured 8-point plasma glucose profiles differed between the groups ( p<0.001 ) , with lower postpr and ial plasma glucose levels in the insulin detemir/insulin aspart group . Within-person day-to-day variation in plasma glucose was lower with insulin detemir/insulin aspart than with NPH insulin/regular human insulin ( SD : 2.88 vs 3.12 mmol/l ; p<0.001 ) . Risk of overall and nocturnal hypoglycaemia ( 23.00–06.00 hours ) was , respectively , 21 % ( p=0.036 ) and 55 % ( p<0.001 ) lower in the insulin detemir/insulin aspart group than in the NPH insulin/regular human insulin  group . Body weight ( adjusted for baseline and change in HbA1c ) was 1 kg lower with insulin detemir/insulin aspart than with NPH insulin/regular human insulin ( p<0.001 ) . Conclusions /interpretationBasal-bolus therapy using insulin detemir/insulin aspart offers a better balance of control and tolerability than with NPH insulin/regular human insulin . The low variability and more physiological action profiles generated with these insulin analogues result ed in improved glycaemic control with lower risk of hypoglycaemia and no concomitant body weight increase BACKGROUND The positive association between obesity and postmenopausal breast cancer has been attributed , in part , to the fact that estrogen , a risk factor for breast cancer , is synthesized in adipose tissue . Obesity is also associated with high levels of insulin , a known mitogen . However , no prospect i ve studies have directly assessed associations between circulating levels of insulin and /or insulin-like growth factor (IGF)-I , a related hormone , and the risk of breast cancer independent of estrogen level . METHODS We conducted a case-cohort study of incident breast cancer among nondiabetic women who were enrolled in the Women 's Health Initiative Observational Study ( WHI-OS ) , a prospect i ve cohort of 93,676 postmenopausal women .  Fasting serum sample s obtained at study entry from 835 incident breast cancer case subjects and from a subcohort of 816 r and omly chosen WHI-OS subjects were tested for levels of insulin , glucose , total IGF-I , free IGF-I , insulin-like growth factor binding protein-3 , and estradiol .  Multivariable Cox proportional hazards models were used to estimate associations between levels of the serologic factors and baseline characteristics ( including body mass index [ BMI ] ) and the risk of breast cancer . All statistical tests were two-sided . Results Insulin levels were positively associated with the risk of breast cancer ( hazard ratio [ HR ] for highest vs lowest quartile of insulin level = 1.46 , 95 % confidence interval [ CI ] = 1.00 to 2.13 , P(trend ) = .02 ) ; however , the association with insulin level varied by hormone therapy ( HT ) use ( P(interaction ) = .01 ) . In a model that controlled for multiple breast cancer risk factors including estradiol , insulin level was associated with breast cancer only among nonusers of HT ( HR for highest vs lowest quartile of insulin level = 2.40 , 95 % CI = 1.30 to 4.41 , P(trend ) < .001 ) . Obesity ( BMI > or=30 kg/m(2 ) ) was also associated with the risk of breast cancer among nonusers of HT ( HR for BMI > or=30 kg/m(2 ) vs 18.5 to < 25 kg/m(2 ) = 2.12 , 95 % CI = 1.26 to 3.58 , P(trend ) = .003 ) ; however , this association was attenuated by adjustment for insulin ( P(trend ) = .40 ) . CONCLUSION These data suggest that hyperinsulinemia is an independent risk factor for breast cancer and may have a substantial role in explaining the obesity-breast cancer relationship Insulin detemir is an analog of human insulin design ed to provide a long duration of basal insulin action . This is achieved by protracted absorption from the injection depot , which results in part from increased self-association of insulin detemir molecules and in part from reversible albumin binding . Subsequent albumin binding in the circulation is thought to buffer changes in the effects at target tissues that could otherwise arise from variability in absorption rate . In consequence , insulin detemir has shown a less variable pharmacodynamic profile than alternative basal insulins ; this manifests as more consistent temporal glucose reduction profiles in repeat-clamp studies . In clinical trials , insulin detemir has been characterized by consistent risk reductions in hypoglycemia , as well as reduced weight gain in comparison with other basal insulins . Given some recent associations that have been made in 
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Results While the discovery of animal insulin significantly decreased mortality rates from diabetes , issues with availability and large variability between batches led to difficulty in determining proper doses and , subsequently , challenges in achieving glycemic control and avoiding hypoglycemia .
The development of synthetic insulin created a more readily available supply , but hypoglycemia still persisted .
Recombinant DNA technology solved insulin production problems and allowed for the development of better retarding agents , but pharmacokinetic/pharmacodynamic profiles still did not mimic natural insulin .
Insulin premixes offered improved glycemic control , decreased intrapatient variability versus self-mixing , and required fewer injections per day ; however , patient adherence remained a problem due to the need to inject 30–60 minutes before a meal for optimal control .
This prompted the development of rapid-acting insulin analogs that could be injected right before a meal and long-acting insulin analogs with flatter time-action profiles .
Newer insulin analogs and more convenient routes of insulin delivery have shown promising safety and efficacy results .