Effect Of Oral Insulin Research Articles

Effect of Oral Insulin on Early Combined Glucose and C‐Peptide Endpoints in Individuals at High‐Risk for Type 1 Diabetes

Effect of Oral Insulin on Early Combined Glucose and C‐Peptide Endpoints in Individuals at High‐Risk for Type 1 Diabetes

589-P: Effect of Oral Insulin (OI) on Combined Glucose and C-Peptide Endpoints in Individuals at High-Risk for Type 1 Diabetes (T1D)

The TrialNet OI prevention trial (TN07) with T1D as an endpoint showed no effect. However, in a smaller trial run in parallel with TN07 (termed secondary stratum 1), in which all participants had low first-phase insulin release, a statistically significant delay in T1D onset was found. Since trials with T1D as an endpoint take years to complete, we aimed to determine if combination C-peptide and glucose markers could identify a therapeutic benefit after 12 months of OI in this high-risk population. All participants were at-risk relatives with multiple autoantibodies including mIAA and normal glucose tolerance (n=40 with full data). The Figure shows changes in glucose and C-peptide response curves and their centroids (central points). Glucose rose and C-peptide declined in the placebo group compared to a minimal glucose rise with an increase of C-peptide in the OI group. Change from baseline to 1 year in the centroid ratio (C-peptide/glucose) differed significantly between groups (p=0.037 after adjustments for age, BMI, and baseline C-peptide and glucose). The AUC C-peptide/AUC glucose ratio and Index60 did not differ (both p=0.108). In conclusion, the findings support a positive effect of OI on combined glucose and C-peptide endpoints in high-risk individuals. These measures appear to detect differences in a shorter time than the standard T1D endpoint. Disclosure L. M. Jacobsen: None. M. A. Atkinson: None. J. Krischer: None. D. Schatz: Advisory Panel; Self; Abbott, Medtronic. J. Sosenko: None. D. D. Cuthbertson: None. E. K. Sims: None. H. M. Ismail: None. L. Dimeglio: Advisory Panel; Self; MannKind Corporation. T. M. Triolo: None. M. J. Redondo: Advisory Panel; Self; Provention Bio, Inc. M. Lundgren: None. P. Gottlieb: Advisory Panel; Self; Janssen Research & Development, LLC, Tolerion, Inc., Viacyte, Inc., Other Relationship; Self; ImmunoMolecular Therapeutics, Inc., Research Support; Self; Caladrius Biosciences, Inc., Immune Tolerance Network, Mercia Pharma Inc., National Institute of Diabetes and Digestive and Kidney Diseases, Precigen, Inc., Tolerion, Inc.

115-LB: Oral Insulin–Induced Reduction in Liver Fat Content in T2DM Patients with Nonalcoholic Steatohepatitis

Nonalcoholic fatty liver disease (NAFLD) and subsequent nonalcoholic steatohepatitis are leading causes of chronic liver disease, with disease progression directly associated with insulin resistance and T2DM. In light of the common risk factors, pathogenesis and complications with T2DM, direct insulin intervention has been suggested for T2DM patients with NAFLD. Recently, salient metabolic effects of oral insulin have been suggested, owing to first pass metabolism and local insulin availability and concentration in liver fat cells. This pilot study assessed the safety, tolerability and early effects on liver fat content of an oral insulin formulation (ORMD-0801), preprandially administered once-daily (2x8 mg capsules) for 12 consecutive weeks, to 8 T2DM patients with NASH. The 12-week ORMD-0801 treatment proved safe and tolerable in all patients, with no serious or severe adverse events recorded throughout the study period. The 12-week treatment induced a mean -6.9±6.8% reduction in liver fat content (sign test p value: 0.035), as measured by magnetic resonance imaging proton density fat fraction (MRI-PDFF). In parallel, concentrations of gamma-glutamyltransferase (GGTP), a key marker of chronic hepatitis, were significantly lower after 12 weeks of treatment as compared to baseline (-14.6±13.1 U/L; sign test p value: 0.008), as were fasting insulin levels (-96.5±206.0 pmol/L; sign test p value: 0.035). Taken together, these preliminary observations suggest a palliative effect of oral insulin on NASH in T2DM patients, as shown by reductions in liver fat content and chronic hepatitis. These encouraging findings will require further validation in large-scale, randomized clinical trials. Disclosure M. Kidron: Employee; Self; Oramed Pharmaceuticals. Stock/Shareholder; Self; Oramed Pharmaceuticals. S. Perles: Employee; Spouse/Partner; Haddassah Medical Center. Employee; Self; Oramed Pharmaceuticals. R. Kaloti: None. R. Ghantous: None. S.F. Sandouka: None. Y. Malaabi: None. R. Safadi: None.

Effect of oral insulin on prevention of diabetes in relatives of patients with T1DM: a randomized clinical trial

Insulin is one of the autoantigens involved in the pathogenesis of T1DM. Therefore several trials with insulin given orally, nasal or subcutaneous have been conducted to prevent the development of T1DM in genetically high risk populations. This trial design built on the results of DPT-1 and included further investigations related to first phase insulin release. A dose of 7.5 mg/d did not prevent T1DM in the high risk population of autoantibody positive T1DM relatives. Possibly ongoing trials with higher insulin doses might show better effects on beta cell autoimmunity and T1DM incidence. Knowledge of pre-diabetes staging has informed several prevention trials and epidemiological studies in high risk populations. Individuals with two or more beta cell antibodies are now classified as Stage 1. Without intervention, most of these will develop abnormal glucose tolerance (Stage 2) and then clinically manifest T1DM (Stage 3). The overall rate of progression from Stage 1 to 3 is ~9.5% per year.

Effect of Oral Insulin on Prevention of Diabetes in Relatives of Patients With Type 1 Diabetes

Type 1 diabetes requires major lifestyle changes and carries increased morbidity and mortality. Prevention or delay of diabetes would have major clinical effect. To determine whether oral insulin delays onset of type 1 diabetes in autoantibody-positive relatives of patients with type 1 diabetes. Between March 2, 2007, and December 21, 2015, relatives with at least 2 autoantibodies, including insulin autoantibodies and normal glucose tolerance, were enrolled in Canada, the United States, Australia, New Zealand, the United Kingdom, Italy, Sweden, Finland, and Germany. The main study group (n = 389) had first-phase insulin release on an intravenous glucose tolerance test that was higher than the threshold. The 55 patients in the secondary stratum 1 had an identical antibody profile as the main study group except they had first-phase insulin release that was lower than the threshold. Secondary strata 2 (n = 114) and strata 3 (n = 3) had different autoantibody profiles and first-phase insulin release threshold combinations. Follow-up continued through December 31, 2016. Randomization to receive 7.5 mg/d of oral insulin (n = 283) or placebo (n = 277), including participants in the main study group who received oral insulin (n = 203) or placebo (n = 186). The primary outcome was time to diabetes in the main study group. Significance was based on a 1-sided threshold of .05, and 1-sided 95% CIs are reported. Of a total of 560 randomized participants (median enrollment age, 8.2 years; interquartile range [IQR], 5.7-12.1 years; 170 boys [60%]; 90.7% white non-Hispanic; 57.6% with a sibling with type 1 diabetes), 550 completed the trial including 389 participants (median age, 8.4 years; 245 boys [63%]), 382 (96%) in the main study group. During a median follow-up of 2.7 years (IQR, 1.5-4.6 years) in the main study group, diabetes was diagnosed in 58 participants (28.5%) in the oral insulin group and 62 (33%) in the placebo group. Time to diabetes was not significantly different between the 2 groups (hazard ratio [HR], 0.87; 95% CI, 0-1.2; P = .21). In secondary stratum 1 (n = 55), diabetes was diagnosed in 13 participants (48.1%) in the oral insulin group and in 19 participants (70.3%) in the placebo group. The time to diabetes was significantly longer with oral insulin (HR, 0.45; 95% CI, 0-0.82; P = .006). The HR for time to diabetes for the between-group comparisons for the 116 participants in the other secondary stratum was 1.03 (95% CI, 0-2.11; P = .53) and for the entire cohort of 560 participants was 0.83 (95% CI, 0-1.07; P = .11), which were not significantly different. The most common adverse event was infection (n = 254), with 134 events in the oral insulin group and 120 events in the placebo group, but no significant study-related adverse events occurred. Among autoantibody-positive relatives of patients with type 1 diabetes, oral insulin at a dose of 7.5 mg/d, compared with placebo, did not delay or prevent the development of type 1 diabetes over 2.7 years. These findings do not support oral insulin as used in this study for diabetes prevention. clinicaltrials.gov Identifier: NCT00419562.

NIH Research To Prevent Type 1 Diabetes: George Eisenbarth's Legacy

We remember George Eisenbarth for his many contributions to the scientific understanding of the pathogenesis of type 1 diabetes (T1D). In this article we frame our discussion of Dr. Eisenbarth's legacy, citing quotations from a noted scientific philosopher of the modern era, David Hume:

Effects of Camel’s Milk as a Vehicle for Insulin on Glycaemic Control and Lipid Profile in Type 1 Diabetics

Problem statement: To evaluate effects of oral insulin carried by camel’s milk on type 1 diabetes patient in comparison with both insulin injection requirements and camel’s milk alone. Approach: Total of fifty randomly selected type 1 diabetic subjects were divided into three groups; A, B and C (n = 15). All subjects received a usual care (diet, exercise and insulin injection) but group B subjects in addition received 500 mL day-1 of camel’s milk, while group C their subjects in addition received insulin mixed with 500 ml day-1 of camel’s milk. Blood samples were taken at beginning and at end of treatment to measure lipid profile and HbA1c % while blood glucose measured weekly. Results: Data shown significant improvements in FBG (205.3±2.16-47.26±1.89), PBG (339.86±3.18-161.26±2.89), HbA1c % (9.9±0.25±5.62±0.21) and significant reduction in insulin requirement (59.26±0.7-20±0.35) in group C receiving insulin mixed with camel’s milk in comparison with groups A and B. Conclusion: Camel’s milk mixed with insulin was indicated to be an effective supplementation, as adjunctive therapy in management of type 1 diabetes than camel milk or insulin injection.

Effect of Oral Insulin on Diabetes-Induced Intestinal Mucosal Growth in Rats

To evaluate the intestinal response to the induction of diabetes and to oral insulin (OI) administration in a rat. Male Sprague-Dawley rats were divided into four experimental groups: control rats, CONTR-INS rats that were treated with OI given in drinking water for 7 days, diabetic rats that were injected with one dose of streptozotocin, and diabetic rats treated with OI. Intestinal structural changes, enterocyte proliferation and enterocyte apoptosis, bax and bcl-2 mRNA and protein levels, insulin receptor expression and ERK protein levels were determined at sacrifice. A one-way ANOVA for comparison, followed by Tukey's test for pair-wise comparison, were used for statistical analysis. Induction of diabetes resulted in a significant increase in bowel and mucosal weight (P < 0.05), mucosal protein (P < 0.05), villus height and crypt depth in jejunum and ileum (P < 0.05), and mucosal DNA in ileum (P < 0.05) (vs. control animals). Diabetes also enhances ERK-induced cell proliferation (P < 0.05) and concomitant bax/bcl-2 induced cell apoptosis (P < 0.05). Treatment of diabetic rats with OI resulted in a significant decrease in jejunal protein content (P < 0.05), jejunal and ileal villus height (P < 0.05), and jejunal crypt depth (P < 0.05), as well as an inhibition of ERK-related cell proliferation in ileum (P < 0.05). Expression of insulin receptor was down-regulated following OI administration in both control and diabetic animals. Experimental STZ-induced diabetes causes intestinal mucosal growth and enhances enterocyte turnover in a rat model. OI administration diminishes diabetes-accelerated cell turnover and diabetes-induced mucosal hyperplasia.

Oral Insulin Enhances Intestinal Regrowth Following Massive Small Bowel Resection in Rat

Experimental studies have suggested that insulin (INS) plays an important role in small intestinal growth and development. In the present study we investigated the effect of oral INS on structural intestinal adaptation and enterocyte proliferation and loss via apoptosis in a rat model of short bowel syndrome (SBS). Male Sprague-Dawley rats were divided into three experimental groups: sham rats underwent bowel transection, SBS rats underwent 75% small bowel resection, and SBS-INS rats underwent bowel resection and were treated with oral INS given in the drinking water from the 3rd to the 15th postoperative day. Parameters of intestinal adaptation (bowel and mucosal weight, mucosal DNA and protein, villous height, and crypt depth), enterocyte proliferation, and apoptosis were determined on day 15. SBS-INS rats demonstrated a significant increase (vs SBS rats) in jejunal and ileal overall bowel and mucosal weight, ileal mucosal DNA and protein, ileal villous height, and crypt depth. SBS-INS rats also showed an increased cell proliferation index in jejunum and ileum and decreased apoptotic index in jejunum compared to SBS animals. In conclusion, in a rat model of SBS, oral INS strongly enhances intestinal adaptation. Possible mechanisms may include increased cell proliferation and decreased enterocyte loss via apoptosis.

Effects of Oral Insulin in Relatives of Patients With Type 1 Diabetes

This randomized, double-masked, placebo-controlled clinical trial tested whether oral insulin administration could delay or prevent type 1 diabetes in nondiabetic relatives at risk for diabetes. We screened 103,391 first- and second-degree relatives of patients with type 1 diabetes and analyzed 97,273 samples for islet cell antibodies. A total of 3,483 were antibody positive; 2,523 underwent genetic, immunological, and metabolic staging to quantify risk of developing diabetes; 388 had a 5-year risk projection of 26-50%; and 372 (median age 10.25 years) were randomly assigned to oral insulin (7.5 mg/day) or placebo. Oral glucose tolerance tests were performed every 6 months. The median follow-up was 4.3 years, and the primary end point was diagnosis of diabetes. Diabetes was diagnosed in 44 oral insulin and 53 placebo subjects. Annualized rate of diabetes was similar in both groups: 6.4% with oral insulin and 8.2% with placebo (hazard ratio 0.764, P = 0.189). In a hypothesis-generating analysis of a subgroup with insulin autoantibody (IAA) levels confirmed (on two occasions) > or =80 nU/ml (n = 263), there was the suggestion of benefit: annualized diabetes rate 6.2% with oral insulin and 10.4% with placebo (0.566, P = 0.015). It is possible to identify individuals at high risk for type 1 diabetes and to enroll them in a large, multisite, randomized, controlled clinical trial. However, oral insulin did not delay or prevent type 1 diabetes. Further studies are needed to explore the potential role of oral insulin in delaying diabetes in relatives similar to those in the subgroup with higher IAA levels.

Insulin in human milk: postpartum changes and effect of gestational age

Objective: To determine if human milk insulin (HMI) concentrations are affected by gestational age and postnatal age. Design and setting: An observational study carried out in a level III neonatal...

Hypoglycemic Effect of Oral Insulin in Diabetic Rabbits Using pH-Dependent Coated Capsules Containing Sodium Salicylate Without and with Sodium Cholate

The hypoglycemic effect of oral insulin (20 U and 40 U) capsules coated with a pH-dependent soluble polymer (Eudragit S100) and containing sodium salicylate (50 mg) without and with sodium cholate (50 mg) was studied in alloxan-hyperglycemic rabbits and compared with that of s.c. insulin injection (20 U). The capsules containing 20 U insulin + sodium salicylate (50 mg) produced a significant reduction in plasma glucose level to 82 and 73% of initial values at 2 and 3 hr after administration, respectively. The blood glucose level slowly returned to normal values at 5 hr. The AUC0–5 hr was 73.7 ± 43.5 mg. hr/dl compared to 242 ± 70.5 mg. hr/dl for insulin (20 U, s.c.) with a relative hypoglycemia of 30.4%. A higher dose of oral insulin (40 U) + sodium salicylate (50 mg) was more effective in reducing plasma glucose level which steadily decreased and reached 56% of the initial value by 5 hr (AUC0–5 hr = 132 ± 41.5 mg. hr/dl and relative hypoglycemia = 27.3%). Sodium cholate (50 mg), however, slightly improved sodium salicylate effect producing an AUC0–5 hr of 139 ± 37.3 mg. hr/dl with relative hypoglycemia of 28.7%. The relative hypoglycemia of pH-dependent coated capsules reached in the present experiment is the highest found so far.

Effect of Oral Insulin on Lactase Activity, mRNA, and Posttranscriptional Processing in the Newborn Pig

SummaryInsulin, found in human and pig colostrum and mature milk, appears to influence small intestinal growth and development. Ileal lactase activity is increased when porcine insulin is added to feedings administered to newborn piglets. We studied 2‐day‐old miniature piglets to determine whether the increase in lactase activity is accompanied by changes in enterocyte expression of lactase activity, steady‐state levels of lactase mRNA, and/or posttranscriptional changes in lactase processing. We randomized the piglets to receive bottle feedings of a swine‐weaning milk formula with (group F + I) or without (group F) the addition of 85 mU/ml of regular porcine insulin. The piglets were fed for 6 days (to 8 days of age), after which they were killed and the small intestine removed for analysis. Despite large differences between groups in enterocyte expression of lactase activity in the ileum, no differences were noted in the level of ileal lactase mRNA. The relative proportions of the 207, 210, and 230 kDa precursors of the 160 kDa mature lactase protein were similar between groups. These data indicate that the insulin‐induced increased expression of ileal lactase activity is not regulated at the level of its mRNA or at the level of processing of the polypeptide.

Effect of oral insulin on lactase activity, mRNA, and posttranscriptional processing in the newborn pig.

Insulin, found in human and pig colostrum and mature milk, appears to influence small intestinal growth and development. Ileal lactase activity is increased when porcine insulin is added to feedings administered to newborn piglets. We studied 2-day-old miniature piglets to determine whether the increase in lactase activity is accompanied by changes in enterocyte expression of lactase activity, steady-state levels of lactase mRNA, and/or posttranscriptional changes in lactase processing. We randomized the piglets to receive bottle feedings of a swine-weaning milk formula with (group F + I) or without (group F) the addition of 85 mU/ml of regular porcine insulin. The piglets were fed for 6 days (to 8 days of age), after which they were killed and the small intestine removed for analysis. Despite large differences between groups in enterocyte expression of lactase activity in the ileum, no differences were noted in the level of ileal lactase mRNA. The relative proportions of the 207, 210, and 230 kDa precursors of the 160 kDa mature lactase protein were similar between groups. These data indicate that the insulin-induced increased expression of ileal lactase activity is not regulated at the level of its mRNA or at the level of processing of the polypeptide.

Oral Insulin Increases Small Intestinal Mass and Disaccharidase Activity in the Newborn Miniature Pig

ABSTRACT: Factors, such as insulin, found in human and pig colostrum and mature milk likely influence small intestinal growth and development. Although pharmacologic doses of insulin injected parenterally may accelerate small intestinal development in altricial animals such as the rodent, the effects of oral insulin on intestinal development have not been studied. In the first of two studies, we randomized 2-d-old miniature piglets to receive bottlefeedings of a swine weaning milk formula with (group F + I) or without (group F) the addition of insulin. Serum glucose, insulin, and cortisol were measured before and 1 h after the first feeding the piglets received at our facility. In the second study, piglets were randomized (groups F and F + I) and fed for 6 d, after which blood samples were obtained as in the first experiment. The piglets were then killed and the small intestine removed for analysis. We found no differences between groups in serum glucose, insulin, and cortisol at both 2 and 8 d of age, both before and after feeding. In the second experiment, small intestinal weight was greater in the F + I than in the F group. Although no differences were noted between groups in the jejunum, values were greater for group F + I versus group F for ileal mucosal weight, protein, RNA, lactase, and maltase activities. No differences were found between groups in ileal DNA or sucrase activity. We conclude that the administration of oral insulin stimulated an increase in ileal mass and disaccharidase activity in the newborn miniature pig without apparent concomitant changes in serum glucose, insulin, or cortisol.

Oral Insulin Increases Small Intestinal Mass and Disaccharidase Activity in the Newborn Miniature Pig

Factors, such as insulin, found in human and pig colostrum and mature milk likely influence small intestinal growth and development. Although pharmacologic doses of insulin injected parenterally may accelerate small intestinal development in altricial animals such as the rodent, the effects of oral insulin on intestinal development have not been studied. In the first of two studies, we randomized 2-d-old miniature piglets to receive bottle-feedings of a swine weaning milk formula with (group F + I) or without (group F) the addition of insulin. Serum glucose, insulin, and cortisol were measured before and 1 h after the first feeding the piglets received at our facility. In the second study, piglets were randomized (groups F and F + I) and fed for 6 d, after which blood samples were obtained as in the first experiment. The piglets were then killed and the small intestine removed for analysis. We found no differences between groups in serum glucose, insulin, and cortisol at both 2 and 8 d of age, both before and after feeding. In the second experiment, small intestinal weight was greater in the F + I than in the F group. Although no differences were noted between groups in the jejunum, values were greater for group F + I versus group F for ileal mucosal weight, protein, RNA, lactase, and maltase activities. No differences were found between groups in ileal DNA or sucrase activity. We conclude that the administration of oral insulin stimulated an increase in ileal mass and disaccharidase activity in the newborn miniature pig without apparent concomitant changes in serum glucose, insulin, or cortisol.