Pancreatic Islet Mass in Pregnancy in Type 1 Diabetes
Pancreatic Islet Mass in Pregnancy in Type 1 Diabetes
Type 1 diabetic women have a decrease in insulin requirements during early pregnancy.
 Preliminary evidence suggests this decrease may be secondary to the regeneration of
 pancreatic B-cells during pregnancy During the second and third trimesters, insulin
 requirements in Type 1 diabetic women progressively increase until approximately 36 weeks
 gestation at which time there is a plateau, and frequently, a drop in insulin requirements.
 We hypothesize that there is regeneration of pancreatic islet cell mass in Type 1 diabetic
 women during pregnancy. In a cross-sectional study, we will use the acute insulin c-peptide
 response to arginine to determine if pancreatic islet mass increases at 12 and 36 weeks
 gestation. Type 1 diabetic women who are not pregnant, who are at 12 and 36 weeks gestation,
 and who are 6 weeks post-partum will undergo an intravenous arginine tolerance test following
 an overnight fast. If we find that there is regeneration of beta cells it opens the
 possibility that therapy may be directed to the same end for people with Type 1 diabetes.
For the pilot phase of this study we will contact women with type 1 diabetes. The study will
 be explained and the subjects will be asked to sign an informed consent. Each subject will be
 asked to complete a brief medical history and lifestyle questionnaire.

 Subjects will have blood samples taken for glucose and C-peptide and an intravenous arginine
 stimulation test. For the study tests, subjects will be asked to come to the Clinical
 Investigations Unit at the University of Alberta Hospital after an overnight fast only once
 during the study. The intravenous arginine test is a 10 minute test and does not cause
 hyperglycemia, an advantage over glucose in the setting of pregnancy.

 Arginine infusion The intravenous arginine infusion test will be performed after an overnight
 fast greater than or equal to 8 hours. Subjects may drink water. For the Type 1 diabetic
 patients on insulin, long-acting insulin may be taken no less than 8 hours prior to the test;
 no food or short-acting insulin may be taken within 5 hours of the test. Lispro insulin
 should not be taken within 4 hours of the test.

 On the morning of the test, an intravenous catheter, using a 20 gauge IV intercath, will be
 placed in an antecubital vein in one arm both for sampling and for infusion. Veins will be
 kept patent with an infusion of NaCl (0.9%) at 25 mL/hr throughout the test. The arm from
 which samples are obtained will be warmed to 55 C with a heating blanket to assist in the
 arterialization of the venous samples.

 Baseline blood samples for glucose and C-peptide measurements will be drawn in a serum gel
 barrier tube at minus 10 and 0 minutes. An injection of 5 g of arginine (20 ml Sabex) diluted
 with 20 ml normal saline to equal 40 ml will be administered over 30 seconds, starting at
 time 0. The vein will immediately be flushed with 20mL normal saline. Blood samples for
 insulin and C-peptide will be drawn in barrier tubes at 2, 3, 4, 5, 7 and 10 minutes and
 serum will be separated and transferred into a cryogenic tube for analysis.

 The acute C-peptide response to arginine is defined as the mean of the three highest insulin
 or C-peptide values between 2 and 5 minutes after the start of the arginine infusion with the
 mean of the minus 10 and 0 values subtracted.

 Blood samples (basal and stimulated) will be analyzed for glucose and C-peptide. The insulin
 response will not be measured in these Type 1 subjects as it would be meaningless and the
 C-peptide response will be used.

 Blood glucose will be determined by the hexokinase method using the Hitachi 917 system (Roche
 Diagnostics, Indianapolis, IN).

 C-peptide assay An Ultrasensitive C-peptide ELISA method will be used to analyze for
 C-peptide. This test is specific for low concentrations of C-peptide in blood, specifically
 for patients with abnormal insulin secretion.

 Statistical Analysis/Power calculation

 Upon the significance test results for group differences, we will proceed with multiple
 comparisons of groups to locate the source of significance, while adjusting for multiple
 significance testing, using the method of Bonferroni.

 Expected Possible Findings/ Conclusion

 We hope to show that pancreatic islet mass may be present in women with Type 1 diabetes. Any
 demonstration of beta-cell recovery even in the unique setting of pregnancy would be
 exciting, as it would demonstrate progenitor beta cells present in the pancreas in type 1
 diabetes subjects.
Inclusion Criteria:

 -  Signed informed consent

 -  Females with Type 1 diabetes for at least 5 years

 -  Diabetes onset < 21 years

 -  Lean at diabetes onset

 -  Insulin required from diagnosis

 -  Willing to undergo intravenous arginine tolerance tests

 Exclusion Criteria:

 -  Inability to provide informed consent

 -  Any medical condition that would preclude safe conduct of the intravenous arginine

 -  A family history which includes three generations of family members with the diagnosis
 of diabetes mellitus

 -  Women with elevated serum creatinine as arginine is excreted by the kidneys.