we conducted a single - center , open - label , randomized clinical trial to evaluate the progression of -cell dysfunction over 3.5 years in patients with treatment - nave newly diagnosed type 2 diabetes .
all patients were treated for 3 months with insulin and metformin and then randomly assigned to treatment with either insulin plus metformin ( ins group ) or triple oral therapy ( tot group ) with metformin , pioglitazone , and glyburide .
the results of the first 3-month run - in period were published previously ( 14 ) as were results of the glycemic control , adverse effects , and quality of life up to 36 months ( 15 ) .
patients aged 2170 years with treatment - nave type 2 diabetes diagnosed within the previous 2 months were recruited from parkland hospital and the clinical diabetes research center at the university of texas southwestern medical center at dallas ( utsw ) .
exclusion criteria included type 1 diabetes  related antibodies , baseline hba1c level < 7% , elevated serum creatinine ( > 1.5 mg / dl in male and > 1.4 mg / dl in female subjects ) , liver enzymes higher than two times the upper limit of normal , severe coronary artery disease ( myocardial infarction within the past 6 months or active angina ) , heart failure stages iii  iv , pregnancy or lack of approved contraception , untreated proliferative diabetic retinopathy , any life - threatening conditions , use of more than two alcoholic drinks per day , or illicit drug use within the 6 months before enrollment .
the study was approved by the institutional review board at utsw , and written informed consent was obtained from all subjects preceding the start of the study . following enrollment ,
insulin and metformin were initiated in all patients for a 3-month lead - in treatment period to enable everyone to attain similar glycemic control prior to randomization .
this also removed any preexisting glucotoxicity and associated temporary -cell stunning that might have been present in different degrees at the time of diagnosis .
novolog mix 70/30 by flexpen and metformin were initiated and titrated based on a previously published algorithm ( 14 ) . all patients received diabetes education and nutritional and lifestyle counseling at enrollment with reinforcement throughout the study .
after 3 months of treatment , patients were randomly assigned to either continue insulin and metformin or begin triple oral therapy .
randomization strata were race ( african american or non  african american ) and bmi ( cutoff 35 kg / m ) , chosen to minimize possible baseline characteristic confounders on -cell function .
the participants were enrolled and assigned ( by i.l . ) to interventions according to the randomization schema generated by the study statistician ( b.a .- h . ) .
patients randomly assigned to the tot group discontinued insulin , continued metformin 1 g twice daily ( or maximum tolerated dose ) , and started 1.25 mg glyburide twice daily and 15 mg daily pioglitazone .
titration of insulin and glyburide ( up to the highest clinically effective dose of 10 mg daily ) was performed by the study physician throughout the study , based on home blood glucose  monitoring logs to attain a fasting blood glucose level of 70110 mg / dl and postprandial blood glucose level of < 140 mg / dl .
all patients were asked to monitor blood glucose at least twice daily regardless of the group assignment .
initiation and dose adjustment of antihypertensive and lipid - lowering agents were allowed if medically necessary .
patients were followed at the clinical diabetes research center at utsw monthly for the first 4 months , at 6 months after randomization , and every 3 months thereafter for a total of 42 months .
treatment failure was a predefined study end point defined as hba1c > 8% confirmed by a second reading and occurring after maximization of the glyburide dose or adequate insulin dose titration .
volunteers randomly assigned to the tot group who reached this end point were transitioned to insulin and metformin treatment , whereas those randomly assigned to insulin continued with the same treatment .
evaluation of -cell response was performed at 0 , 6 , 12 , 18 , 30 , and 42 months postrandomization .
patients fasted the evening before , and antidiabetes treatment was withheld for 24 h prior to testing . a mixed - meal challenge test ( mmct )
was performed using high - protein boost 1 g / kg carbohydrate equivalent ( or maximum of 90 g , equivalent to 480 cc ) ingested over 5 min .
glucose and c - peptide were collected at 0 , 15 , 30 , 60 , 90 , 120 , 150 , and 180 min from the time of ingestion .
-cell function was assessed using calculated c - peptide area under the curve ( aucc ) and glucose auc ( aucg ) .
initial insulin release was calculated as c030 and c030/g030 , and maximal insulin production was calculated as c0-max and c0-max / g0-max .
the incremental aucc ( iaucc ) and incremental aucg ( iaucg ) were calculated as the auc above baseline ( fasting ) values .
c - peptide was measured using radioimmunoassay ( millipore ) , hba1c by high - performance liquid chromatography , and glucose with yellow springs instrument in the clinical diabetes laboratory at utsw . the laboratory is accredited by the national glycohemoglobin standardization program .
patients were instructed to return their unused medications at every visit for inventory and estimation of patient compliance .
mild hypoglycemic episodes were defined as symptoms indicative of low blood glucose accompanied by a documented capillary blood glucose value of < 70 mg / dl .
severe hypoglycemia was defined as symptoms of hypoglycemia that required assistance from another individual for treatment , regardless of capillary blood glucose level .
the sample size was estimated to detect differences between the ins and tot groups in aucc of 240 ng / ml / min , with an estimated sd of 225 ng / ml / min ( 16 ) . to detect this effect size ,
completion of 20 patients in each group was needed for power of 90% at  = 0.05 .
the intention - to - treat analysis is reported ( unless otherwise stated ) , which included all subjects according to their randomization treatment assignment , including those who reached the predefined treatment failure end point and were switched from the tot to ins group .
biochemical measurements and auc responses were assessed with mixed - model repeated - measures analysis .
the repeated - measures models consisted of a treatment group factor , study time ( month ) factor , and interaction between group and time , with subject modeled as a random effect .
auc responses and hypoglycemic event rates were log or rank transformed , respectively , prior to analysis .
statistical analysis was performed with sas version 9.2 ( sas institute , cary , nc ) .
patients aged 2170 years with treatment - nave type 2 diabetes diagnosed within the previous 2 months were recruited from parkland hospital and the clinical diabetes research center at the university of texas southwestern medical center at dallas ( utsw ) .
exclusion criteria included type 1 diabetes  related antibodies , baseline hba1c level < 7% , elevated serum creatinine ( > 1.5 mg / dl in male and > 1.4 mg / dl in female subjects ) , liver enzymes higher than two times the upper limit of normal , severe coronary artery disease ( myocardial infarction within the past 6 months or active angina ) , heart failure stages iii  iv , pregnancy or lack of approved contraception , untreated proliferative diabetic retinopathy , any life - threatening conditions , use of more than two alcoholic drinks per day , or illicit drug use within the 6 months before enrollment .
the study was approved by the institutional review board at utsw , and written informed consent was obtained from all subjects preceding the start of the study .
following enrollment , insulin and metformin were initiated in all patients for a 3-month lead - in treatment period to enable everyone to attain similar glycemic control prior to randomization .
this also removed any preexisting glucotoxicity and associated temporary -cell stunning that might have been present in different degrees at the time of diagnosis .
novolog mix 70/30 by flexpen and metformin were initiated and titrated based on a previously published algorithm ( 14 ) . all patients received diabetes education and nutritional and lifestyle counseling at enrollment with reinforcement throughout the study .
after 3 months of treatment , patients were randomly assigned to either continue insulin and metformin or begin triple oral therapy .
randomization strata were race ( african american or non  african american ) and bmi ( cutoff 35 kg / m ) , chosen to minimize possible baseline characteristic confounders on -cell function .
the participants were enrolled and assigned ( by i.l . ) to interventions according to the randomization schema generated by the study statistician ( b.a .- h . ) .
patients randomly assigned to the tot group discontinued insulin , continued metformin 1 g twice daily ( or maximum tolerated dose ) , and started 1.25 mg glyburide twice daily and 15 mg daily pioglitazone .
titration of insulin and glyburide ( up to the highest clinically effective dose of 10 mg daily ) was performed by the study physician throughout the study , based on home blood glucose  monitoring logs to attain a fasting blood glucose level of 70110 mg / dl and postprandial blood glucose level of < 140 mg / dl .
all patients were asked to monitor blood glucose at least twice daily regardless of the group assignment .
initiation and dose adjustment of antihypertensive and lipid - lowering agents were allowed if medically necessary .
patients were followed at the clinical diabetes research center at utsw monthly for the first 4 months , at 6 months after randomization , and every 3 months thereafter for a total of 42 months .
treatment failure was a predefined study end point defined as hba1c > 8% confirmed by a second reading and occurring after maximization of the glyburide dose or adequate insulin dose titration .
volunteers randomly assigned to the tot group who reached this end point were transitioned to insulin and metformin treatment , whereas those randomly assigned to insulin continued with the same treatment .
evaluation of -cell response was performed at 0 , 6 , 12 , 18 , 30 , and 42 months postrandomization .
patients fasted the evening before , and antidiabetes treatment was withheld for 24 h prior to testing . a mixed - meal challenge test ( mmct )
was performed using high - protein boost 1 g / kg carbohydrate equivalent ( or maximum of 90 g , equivalent to 480 cc ) ingested over 5 min .
glucose and c - peptide were collected at 0 , 15 , 30 , 60 , 90 , 120 , 150 , and 180 min from the time of ingestion .
-cell function was assessed using calculated c - peptide area under the curve ( aucc ) and glucose auc ( aucg ) .
initial insulin release was calculated as c030 and c030/g030 , and maximal insulin production was calculated as c0-max and c0-max / g0-max .
the incremental aucc ( iaucc ) and incremental aucg ( iaucg ) were calculated as the auc above baseline ( fasting ) values .
c - peptide was measured using radioimmunoassay ( millipore ) , hba1c by high - performance liquid chromatography , and glucose with yellow springs instrument in the clinical diabetes laboratory at utsw . the laboratory is accredited by the national glycohemoglobin standardization program .
patients were instructed to return their unused medications at every visit for inventory and estimation of patient compliance .
mild hypoglycemic episodes were defined as symptoms indicative of low blood glucose accompanied by a documented capillary blood glucose value of < 70 mg / dl .
severe hypoglycemia was defined as symptoms of hypoglycemia that required assistance from another individual for treatment , regardless of capillary blood glucose level .
the sample size was estimated to detect differences between the ins and tot groups in aucc of 240 ng / ml / min , with an estimated sd of 225 ng / ml / min ( 16 ) . to detect this effect size ,
completion of 20 patients in each group was needed for power of 90% at  = 0.05 .
the intention - to - treat analysis is reported ( unless otherwise stated ) , which included all subjects according to their randomization treatment assignment , including those who reached the predefined treatment failure end point and were switched from the tot to ins group .
biochemical measurements and auc responses were assessed with mixed - model repeated - measures analysis .
the repeated - measures models consisted of a treatment group factor , study time ( month ) factor , and interaction between group and time , with subject modeled as a random effect .
auc responses and hypoglycemic event rates were log or rank transformed , respectively , prior to analysis .
statistical analysis was performed with sas version 9.2 ( sas institute , cary , nc ) .
sixty - three patients were recruited from november 2003 to june 2005 , and 58 completed the 3-month run - in period ( 29 were randomly assigned to continue insulin plus metformin and 29 were changed to triple oral therapy ( fig .
completion rates at 3.5 years in the study were 24 of 29 ( 83% ) in the ins group and 21 of 29 ( 72% ) in the tot group .
treatment failure occurred in three ( 10.3% ) patients in the ins group and five ( 17.2% ) patients in the tot group ( p = 0.33 ) .
baseline and end of study ( 42-month ) data results of all the calculated -cell function indices are shown in table 1 .
there was no significant change over time in -cell function between or within groups , as calculated by aucg , aucc , and aucc / aucg ( fig .
there also was no significant change over time or between groups in the following : iaucc , iaucc / iaucg ( fig . 2d and f ) , baseline - maximum or baseline30 min c - peptide or c - peptide/glucose .
there was a significant over - time decrease in iaucg ( p < 0.001 ) in the tot group when compared with the ins group , which had no significant change ( p = 0.009 group - by - time interaction ) ( fig .
likewise , the baseline30 min and baseline - maximum glucose ( p = 0.004 ) were significantly reduced over time in the tot but not the ins group ( p = 0.002 and p = 0.03 , respectively , group - by - time interaction ) .
these findings suggest an overall postprandial glycemic benefit of triple oral therapy , yet the two groups had very similar glycemic control and -cell function .
hba1c was substantially improved in both groups during the 3-month lead - in period ( from 10.8  2.6% to 5.9  0.5% ) ( 14 ) . at 3.5 years after randomization hba1c was 6.35  0.84% ins versus 6.59  1.94% tot ( p = 0.54 group by time interaction ) , and 19/24 ( 79% ) in ins and 17/21 ( 81% ) in tot met ada guidelines of hba1c < 7% .
the average insulin dose at the time of randomization was 0.63  0.29 units / kg / day while after 42 months it increased to 0.82 
weight increased in both groups over time ( from 102.2  24.9 to 106.2  31.7 kg in the ins group and from 100.9  23.0 to 110.5  31.8 kg in the tot group ) , with no significant difference between groups ( p = 0.35 ) ( fig .
b : mild hypoglycemic episodes , defined as any symptoms associated with a capillary glucose level of < 70 mg / dl .
there was a low rate of mild hypoglycemia overall , defined conservatively as any symptoms with a glucose reading < 70 mg / dl .
mild hypoglycemia decreased significantly over time ( p = 0.01 ) but did not differ significantly between groups ( p = 0.5 ) .
both groups had on average 1.3  1.5 events in the month after randomization , but this fell rapidly and leveled off by month 9 . at the end of the study , there were 0.5  0.8 events per month in the ins group and 0.4  0.5 events per month in the tot group ( fig .
the proportion of patients having any hypoglycemic events remained stable throughout the study ( 48.5% in the ins group and 52.9% in the tot group ) , but the number of events per person decreased over time .
two participants in the ins group had three events of severe hypoglycemia ( all within the first month postrandomization ) , whereas four participants in the tot group had six such events ( four in the first 2 months postrandomization ) .
compliance with all medications at 3.5 years was 87  20% in the ins group and 90  15% in the tot group .
there was no significant change over time in -cell function between or within groups , as calculated by aucg , aucc , and aucc / aucg ( fig .
there also was no significant change over time or between groups in the following : iaucc , iaucc / iaucg ( fig . 2d and f ) , baseline - maximum or baseline30 min c - peptide or c - peptide/glucose .
there was a significant over - time decrease in iaucg ( p < 0.001 ) in the tot group when compared with the ins group , which had no significant change ( p = 0.009 group - by - time interaction ) ( fig .
likewise , the baseline30 min and baseline - maximum glucose ( p = 0.004 ) were significantly reduced over time in the tot but not the ins group ( p = 0.002 and p = 0.03 , respectively , group - by - time interaction ) .
these findings suggest an overall postprandial glycemic benefit of triple oral therapy , yet the two groups had very similar glycemic control and -cell function .
hba1c was substantially improved in both groups during the 3-month lead - in period ( from 10.8  2.6% to 5.9  0.5% ) ( 14 ) . at 3.5 years after randomization hba1c was 6.35  0.84% ins versus 6.59  1.94% tot ( p = 0.54 group by time interaction ) , and 19/24 ( 79% ) in ins and 17/21 ( 81% ) in tot met ada guidelines of hba1c < 7% .
the average insulin dose at the time of randomization was 0.63  0.29 units / kg / day while after 42 months it increased to 0.82 
weight increased in both groups over time ( from 102.2  24.9 to 106.2  31.7 kg in the ins group and from 100.9  23.0 to 110.5  31.8 kg in the tot group ) , with no significant difference between groups ( p = 0.35 ) ( fig .
b : mild hypoglycemic episodes , defined as any symptoms associated with a capillary glucose level of < 70 mg / dl .
there was a low rate of mild hypoglycemia overall , defined conservatively as any symptoms with a glucose reading < 70 mg / dl .
mild hypoglycemia decreased significantly over time ( p = 0.01 ) but did not differ significantly between groups ( p = 0.5 ) .
both groups had on average 1.3  1.5 events in the month after randomization , but this fell rapidly and leveled off by month 9 . at the end of the study , there were 0.5  0.8 events per month in the ins group and 0.4  0.5 events per month in the tot group ( fig .
3b ) . of interest , the proportion of patients having any hypoglycemic events remained stable throughout the study ( 48.5% in the ins group and 52.9% in the tot group ) , but the number of events per person decreased over time .
two participants in the ins group had three events of severe hypoglycemia ( all within the first month postrandomization ) , whereas four participants in the tot group had six such events ( four in the first 2 months postrandomization ) .
compliance with all medications at 3.5 years was 87  20% in the ins group and 90  15% in the tot group .
our data show that -cell function can be preserved for at least 3.5 years after diagnosis of type 2 diabetes when intensive therapy is initiated early in the disease process .
this was true regardless of the method used to attain intensive control ( insulin - based regimen or a triple combination of oral agents , both after an initial 3-month insulin treatment period ) .
both treatments led to excellent glycemic control , were well tolerated , safe , and had good compliance .
this confirms previous studies that showed -cell preservation with short - term intensive insulin therapy or oral monotherapy , but most importantly our study shows that an insulin - based regimen or a combination of oral hypoglycemic agents has the potential to change the course of the disease for a more meaningful period of time .
chen et al . ( 12 ) performed a similar study in which 50 patients with newly diagnosed type 2 diabetes were treated in - house with intensive insulin therapy for 1014 days and then randomly assigned to continue insulin therapy ( nph only ) or change to a single oral medication ( metformin or a sulfonylurea based on bmi ) for 6 months .
the oral drugs were titrated up at clinic visits ( every 24 weeks ) , and after maximum titration the other drug was added .
the study showed that hba1c was significantly higher in the oral treatment group at 6 months postrandomization ( 7.5  1.5 vs. 6.33  0.70% ) .
both groups had improved -cell function using oral glucose tolerance testing , but significantly more improvement was seen in the insulin therapy group . unfortunately , the study only analyzed -cell function in patients with hba1c < 7% ( ~90% of the insulin group and 45% of the oral group ) , which likely excluded patients in whom -cell function actually declined below baseline , especially in the oral group .
our study showed comparable improvement in glycemic control and -cell function in both treatment groups .
this difference in results could be attributed to initial shorter treatment with insulin at diagnosis ( 1014 days vs. 3 months ) , possibly inducing less recovery of  stunned  -cells ( 17 ) , or the stepwise treatment strategy used in the oral group .
nph insulin was titrated up every 3 days based on fasting blood glucose readings , whereas the oral agent was only titrated up or an additional pill added at office visits .
this approach illustrates the pitfalls of the currently advocated stepwise titration strategy of oral medications leading to less and slower improvement in hyperglycemia and -cell recovery .
the adopt trial randomly assigned recently diagnosed ( <3 years ) treatment - nave patients with diabetes ( baseline hba1c 7.36  0.93% ) to monotherapy with either metformin , glyburide , or rosiglitazone for a median of 4 years ( 13 ) .
although glycemic control improved within the first 6 months , hba1c increased over the next 3.5 years , and at 4 years only 40% of rosiglitazone , 36% of metformin , and 26% of glyburide groups had hba1c < 7% .
this correlated with -cell function ( assessed by homeostasis model assessment ) , which also increased in all groups at 6 months but then declined steadily over the remainder of the study , with a greater fall in the group with the highest failure rate ( 6.1% annual decline in glyburide ) and lowest in the group with the lowest failure rate ( 2% annual decline in rosiglitazone ) .
these results further demonstrate the lack of durability ( conferred by -cell function stabilization or improvement ) of single - drug therapy even when initial glycemic control is not far from goal . of note , rosiglitazone , a peroxisome proliferator 
thiazolidinediones confer a protective effect on -cells through multiple mechanisms , as they 1 ) improve insulin sensitivity , leading to reduced glucotoxicity ; 2 ) increase insulin - sensitive adipocytes promoting fatty acid uptake and storage , leading to reduced lipotoxicity ( 18 ) ; and 3 ) directly prevent -cell apoptosis and increase proliferation in animal models ( 19 ) .
they have been shown to improve -cell function in several clinical trials ( 2022 ) and may have been a pivotal component in the tot group in our study . yet
it is clear that not even thiazolidinedione monotherapy is sufficient to alter the natural course of the disease , and a multidrug approach is most appropriate .
our study was 42 months but involved frequent clinic visits ( every 3 months ) with intensive medication titration , plenty of encouragement , and regular compliance checks .
this should not hinder applicability to outpatient clinical treatment as it is well known that type 2 diabetes is a progressive disease and does require frequent medication titration and a multidisciplinary approach with frequent visits .
we also acknowledge that the 3.5 year follow - up in this study , although a lot longer than any previous intervention that achieved -cell stabilization , is still short when the life - long burden of diabetes is considered .
we are continuing to follow - up our study volunteers to assess whether these results persist .
we assessed -cell function using oral mixed - meal testing , which gives a more comprehensive assessment of -cell function , taking into account intestinal incretin hormone interactions .
in addition , we measured c - peptide to avoid the drawbacks of using insulin concentration : 1 ) insulin measurement is not simply a function of pancreatic secretion but also depends on clearance , 2 ) insulin antibodies can develop and interfere with measurement , and 3 ) the insulin assays can cross - react with the exogenous insulin patients were receiving .
given the design of the study , we are unable to differentiate whether the -cell preservation effect was attributed to the initial insulin - based therapy that all patients received in the run - in phase or attributed to ongoing therapy received after randomization .
several studies have shown that short - term insulin treatment in patients with newly diagnosed type 2 diabetes can lead to rapid improvement in -cell function ( 811 ) and even -cell preservation up to 1 year ( 10,11 ) .
although we have certainly noted a very rapid and impressive improvement in glycemia with this initial insulin treatment ( 14 ) , we believe that in the absence of continuous intensive therapy this would not have been sustained .
conversely , we believe that the results of the study might have been quite different in the absence of the run - in period , where all patients were treated with an insulin - based regimen . this study was designed to compare the progression of -cell dysfunction in patients treated with intensive insulin - based therapy versus intensive oral therapy and had no control group receiving stepwise initiation of either therapy . however , we believe there is well - established evidence that there is progressive loss of -cell function in patients with type 2 diabetes treated in this manner
this certainly limited our power to detect a between - group as well as an over - time difference in the primary outcome .
nevertheless aucc seems to have slightly increased overtime , especially in the ins group ( fig .
2c ) ; therefore , our conclusions are conservative and well supported by the data .
the population in our trial is representative of minorities ( 43% african american and 38% hispanic ) , mostly recruited from the county hospital system .
this lends additional strength to these findings , as these therapeutic interventions were successfully administered and results attained in a patient population most challenging to treat .
our study shows that it is possible to preserve -cell function long after the initial diagnosis of type 2 diabetes if therapy is initiated in a timely and intensive manner . instead of starting with diet and/or monotherapy followed by stepwise treatment escalation when failure is achieved ,
patients should be treated with an initial period of intensive insulin therapy to maximize -cell recovery and then either continued on an insulin - based regimen or switched to multiple hypoglycemic medications with complementary mechanisms of action
. either of these strategies will stabilize -cell function and maintain excellent long - term glucose control , a desirable disease - modifying effect .
in addition , this can be achieved safely , and we have previously shown ( 15 ) that both treatment strategies have high patient satisfaction ratings with improved quality of life . in conclusion , intensive insulin therapy at the time of diagnosis of type 2 diabetes followed by either an insulin - based regimen or multiple oral hypoglycemic agents preserves both glycemic control and -cell function for at least 3.5 years with no significant difference in the adverse - effect profile .
 objectiveto assess -cell function preservation after 3.5 years of intensive therapy with insulin plus metformin ( ins group ) versus triple oral therapy ( tot group ) with metformin , glyburide , and pioglitazone.research design and methodsthis was a randomized trial of 58 patients with treatment - nave newly diagnosed type 2 diabetes . 
 all patients were treated with insulin and metformin for a 3-month lead - in period followed by random assignment to the ins or tot group . 
 -cell function was assessed using a mixed - meal challenge test at randomization and 6 , 12 , 18 , 30 , and 42 months . 
 analyses were intention to treat and performed with repeated - measures models.resultscompletion rates at 3.5 years were 83% in the insulin group and 72% in the tot group , with good compliance in both groups ( 87  20% in the ins group vs. 90  15% in the tot group ) . 
 -cell function was preserved at 3.5 years after diagnosis , with no significant change from baseline or difference between the two groups as measured by area under the curve ( auc ) of c - peptide ( p = 0.14 ) or the ratio of c - peptide to glucose auc ( p = 0.7 ) . 
 excellent glycemic control was maintained in both groups ( end - of - study hba1c 6.35  0.84% in the ins group vs. 6.59  1.94% in the tot group ) . 
 weight increased in both groups over time ( from 102.2  24.9 kg to 106.2  31.7 kg in the ins group and from 100.9  23.0 kg to 110.5  31.8 kg in the tot group ) , with no significant difference between groups ( p = 0.35 ) . 
 hypoglycemic events decreased significantly over time ( p = 0.01 ) but did not differ between groups ( p = 0.83).conclusions-cell function can be preserved for at least 3.5 years with early and intensive therapy for type 2 diabetes with either insulin plus metformin or triple oral therapy after an initial 3-month insulin - based treatment period . 
RESEARCH DESIGN AND METHODS
Participants and eligibility
Randomization and interventions
Measurements
Statistical analysis
RESULTS
-Cell function
Glycemic control
Safety and compliance
CONCLUSIONS