***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: Repeated ingestion of insulin has been suggested as an immune tolerization therapy to prevent immune-mediated ( type 1 ) diabetes . We performed a placebo-controlled , two-dose , oral insulin tolerance trial in newly diagnosed ( < 2 years ) diabetic patients who had required insulin replacement for less than 4 weeks and were found to have cytoplasmic islet cell autoantibodies ( ICAs ) . No oral hypoglycemic agents were permitted during the trial . Endogenous insulin reserves were estimated at six-month intervals by plasma C-peptide responses to a mixed meal . Positive ICAs were found in 262 ( 31 % ) of the 846 patients screened . Of the 197 who agreed to participate , 187 could be followed for 6 to 36 months . Endogenous insulin retention was dependent upon initial stimulated C-peptide response , age at diabetes onset , and numbers of specific islet cell autoantibodies found . Oral insulin  improved plasma C-peptide responses in patients diagnosed at ages greater than 20 years , best seen at the low ( 1 mg/day ) over the high ( 10 mg/day ) insulin dose ( P = .003 and P = .01 , respectively ) . In patients diagnosed before age 20 years , the 1 mg dose was ineffective , whereas the 10 mg dose actually accelerated C-peptide loss ( P = .003 ) . There were no adverse effects . If confirmed , these findings suggest that diabetic patients over age 20 years with ICA evidence of late-onset immune-mediated diabetes should be considered for oral insulin at 1 mg/day to better retain endogenous insulin secretion Aims /hypothesis . Induction of tolerance to insulin is achievable in animal models of Type I ( insulin-dependent ) Diabetes mellitus by oral treatment with this hormone , which can lead to prevention of the disease . In the Diabetes Prevention Trial of Type I diabetes ( DPT-1 ) , oral insulin is given with the aim of preventing disease insurgence . We investigated whether if given at diagnosis of Type I diabetes in humans , oral insulin can still act as a tolerogen and therefore preserve residual beta-cell function , which is known to be substantial at diagnosis . Methods . A double-blind trial was carried out in patients ( mean age ± SD : 14 ± 8 years ) with recent-onset Type I diabetes to whom oral insulin ( 5 mg daily ) or placebo was given for 12 months in addition to intensive subcutaneous insulin therapy . A total of 82 patients with clinical Type I diabetes ( < 4 weeks duration ) were studied . Basal C peptide and glycated haemoglobin were measured and the insulin requirement monitored every 3 months up to 1 year . Insulin antibodies were also measured in 27 patients treated with oral insulin and in 18 patients receiving placebo at the beginning of the trial and after 3 , 6 and 12 months of treatment . Results . The trial was completed by 80 patients . Overall and without distinction between age at diagnosis , at 3 , 6 , 9 and 12 months baseline mean C-peptide secretion in patients treated with oral insulin did not differ from that of those patients treated with placebo . In patients younger than 15 years a tendency for lower C-peptide values at 9 and 12 months was observed in the oral insulin group . Insulin requirement at 1 year was similar between the two groups as well as the percentage of glycated haemoglobin . Finally , IgG insulin antibodies were similar in the two groups at each time point . Conclusion /interpretation . The results of this study indicate that the addition of 5 mg of oral insulin does not modify the course of the disease in the first year after diagnosis and probably does not statistically affect the humoral immune response against insulin . [ Diabetologia ( 2000 ) 43 : 1000–1004 OBJECTIVE The objectives of this exploratory study were to assess the postpr and ial glucose-lowering effects and evaluate the safety and tolerability of single , escalating doses of an oral insulin product , hexyl-insulin monoconjugate 2 ( HIM2 ) , in patients with type 2 diabetes .  Subcutaneous insulin and oral placebo were also administered for comparison . RESEARCH DESIGN AND METHODS Eighteen patients with type 2 diabetes were enrolled in this r and omized , single-blind , placebo-controlled , three-way crossover , dose-escalation study . A single dose of each of the following study drugs was administered to each patient on 3 separate days : oral HIM2 ( at one of three dose levels : 0.375 , 0.5 , or 1.0 mg/kg ) , subcutaneous regular insulin ( 8 units Humulin R ) , and oral placebo . At 30 min after dosing , patients ingested a st and ardized test meal ( 16 oz/720 calories of Boost Plus ) . Serial blood sample s were collected for determination of plasma glucose and insulin concentrations during the 4-h postdose period . RESULTS The mean glucose area under the curve for 0 to 240 min ( AUC(0 - 240 ) ) values were lower following administration of 0.5 and 1.0 mg/kg HIM2 vs. placebo ( 1,097.1 vs. 1,196.9 and 801.1 vs. 992.1 mg x h(-1 ) x dl(-1 ) , respectively ) . This difference was statistically significant at the 1.0-mg/kg HIM2 dose level . Insulin exposure , as measured by insulin AUC(0 - 240 ) values , for the 0.375- , 0.5- , and 1.0-mg/kg dose levels of HIM2 were 169.9 , 193.1 , and 230.8 micro U x h(-1 ) x ml(-1 ) , respectively ; insulin AUC(0 - 240 ) values for placebo were 165.8 , 196.1 , and 169.2 micro U x h(-1 ) x ml(-1 ) , respectively . The mean glucose AUC(0 - 240 ) values were similar following administration of 0.5 and 1.0 mg/kg HIM2 vs. subcutaneous insulin ( 1,097.1 vs. 1,048.0 and 801.1 vs. 875.2 mg x h(-1 ) x dl(-1 ) , respectively ) . For pooled data from the 0.5- and 1.0-mg/kg dose groups , the HIM2/subcutaneous insulin ratios for the 2-h postpr and ial glucose concentration ( 0.97 , 95 % CI 0.90 - 1.06 ) , maximum postpr and ial glucose concentration ( 0.99 , 95 % CI 0.93 - 1.06 ) , and glucose AUC(0 - 240 ) ( 0.98 , 95 % CI 0.9 - 1.06 ) were within 10 % of unity , implying glucodynamic equivalence . Although HIM2 ( 0.5 and 1.0 mg/kg ) and subcutaneous insulin ( 8 units ) provided comparable control of postpr and ial plasma glucose concentrations , HIM2 result ed in peripheral insulin concentrations that were lower than subcutaneous insulin ( mean insulin AUC(0 - 240 ) of 193.1 vs. 233.6 and 230.8 vs. 270.3 micro U x h(-1 ) x ml(-1 ) , respectively ) . CONCLUSIONS Single , oral doses of HIM2 were safe and well tolerated . HIM2 ( 0.5 and 1.0 mg/kg ) was more effective than placebo and as effective as subcutaneous regular insulin ( 8 units ) at controlling postpr and ial glycemia with respect to the following parameters : 2-h postpr and ial glucose concentration , maximum glucose concentration , and glucose AUC(0 - 240 ) . This occurred even though peripheral insulin concentrations were lower following the administration of HIM2 ( 0.5 and 1.0 mg/kg ) than subcutaneous insulin . Thus , HIM2 therapy may control postpr and ial glycemia without causing peripheral hyperinsulinemia in patients with type 2 diabetes The unpredictable behavior of uncontrolled type 1 diabetes often involves frequent swings in blood glucose levels that impact maintenance of a daily routine . An intensified insulin regimen is often unsuccessful , while other therapeutic options , such as amylin analog injections , use of continuous glucose sensors , and islet or pancreas transplantation are of limited clinical use . In efforts to provide patients with a more compliable treatment method , Oramed Pharmaceuticals tested the capacity of its oral insulin capsule ( ORMD-0801 , 8 mg insulin ) in addressing this resistant clinical state . Eight Type I diabetes patients with uncontrolled diabetes ( HbA1c : 7.5–10 % ) were monitored throughout the 15-day study period by means of a blind continuous glucose monitoring device .  Baseline patient blood glucose behavior was monitored and recorded over a five-day pretreatment screening period . During the ensuing ten-day treatment phase , patients were asked to conduct themselves as usual and to self-administer an oral insulin capsule three times daily , just prior to meal intake . CGM data sufficient for pharmacodynamics analyses were obtained from 6 of the 8 subjects . Treatment with ORMD-0801 was associated with a significant 24.4 % reduction in the frequencies of glucose readings > 200 mg/dL ( 60.1±7.9 % pretreatment vs. 45.4±4.9 % during ORMD-0801 treatment ; p = 0.023 ) and a significant mean 16.6 % decrease in glucose area under the curve ( AUC ) ( 66055±5547 mg/dL/24 hours vs. 55060±3068 mg/dL/24 hours , p = 0.023 ) , with a greater decrease during the early evening hours . In conclusion , ORMD-0801 oral insulin capsules in conjunction with subcutaneous insulin injections , well tolerated and effectively reduced glycemia throughout the day . Trial Registration Clinical trials.gov NCT00867594 An effective , orally administered insulin product would be of substantial benefit in the treatment of patients with diabetes mellitus . This phase I/II clinical trial was the first to investigate the safety and effectiveness of a single oral dose of a modified human insulin in controlling postpr and ial plasma glucose levels in patients with type 1 diabetes mellitus who were receiving basal continuous subcutaneous insulin infusion ( CSII ) therapy . Fourteen patients with type 1 diabetes mellitus were evaluated in an open-label , 2-center , dose-escalation , nonr and omized study of oral hexyl-insulin monoconjugate 2 ( HIM2 ) . After an overnight fast and prior to receiving a st and ardized meal ( 50 % carbohydrates , 30 % fat , 20 % proteins ; 650 calories ) , the patients received either no additional insulin ( day 1 ) , or 0.5 to 1.0 mg/kg of HIM2 ( day 2 ) . All patients received a basal insulin regimen by CSII throughout the study . Blood sample s were collected for determination of glucose and insulin levels for 240 minutes post-dose . The postpr and ial glucose excursion versus time curves showed clear reductions in glucose values after both HIM2 doses ( day 2 ) relative to no treatment ( day 1 ) , although the differences in the reductions were not statistically significant . When the data for both HIM2 doses were pooled , a statistically significant effect of HIM2 on glucose excursion ( as measured by AUCex(30 - 240 ) ) was observed . Mean + /- SD values for AUCex(30 - 240 ) were 501.35 + /- 124.1 mg . h/dL after no treatment and 375.81 + /- 215.5 mg . h/dL after HIM2 ( Wilcoxon signed-rank test , P = .042 ) . The results of this study suggest that oral HIM2 , when added to a basal insulin regimen , was safe and may prove effective in controlling postpr and ial hyperglycemia in patients with type 1 diabetes mellitus . Further clinical investigation is necessary AIM The objective of the study was to establish the dose response of IN-105 tablets and explore a possible therapeutic window in type 2 diabetes subjects poorly controlled on metformin . METHODS The primary objective was to examine the effect of sequential single ascending doses of IN-105 on the plasma glucose concentration under fed conditions . All subjects received , sequentially , matching placebo , 10 , 15 , 20 and 30 mg IN-105 tablets in five consecutive periods . Tablets were administered 20 min prior to meal in all the periods . Plasma levels of immun 
    Output:
    
Meta-analyses showed that there is no significant difference between oral and SC insulin in controlling HbA1c , FBG , 1 and 2 h postpr and ial blood glucose and producing Cmax of insulin ( P > 0.05 ) ; however oral insulin had faster action as indicated by the shorter Tmax , compared to SC insulin ( P < 0.05 ) .
Conclusion This systematic review and meta- analysis showed that oral insulin is comparable to SC insulin with regard to glycemic efficacy and safety .