Type1diabetes, Hypoglycemia, Hypoglycemia Unawareness, Islet Cell Transplantation
Conditions
Keywords
Islet Graft Function, Islet Cell transplantation, Auto-islet transplantation, Intra-hepatic islets, Extra-hepatic islets
Brief summary
To determine the effect of sympathetic neural and hormonal (epinephrine) input on islet cell hormonal responses to insulin-induced hypoglycemia in type 1 diabetic recipients of intrahepatic islet transplantation. We hypothesize that α-adrenergic (neural) blockage will abolish insulin-mediated suppression of C-peptide, attenuating α-cell glucagon secretion during hypoglycemia, and that β-adrenergic (hormonal) blockage will have no effect. Glucose counterregulatory responses will be measured during hyperinsulinemic euglycemic-hypoglycemic clamps on three occasions with randomized, double-blind administration of the α-adrenergic blocker phentolamine, the β-adrenergic blocker propranolol, or placebo. The demonstration of neural rather than hormonal regulation of the transplanted islet cell response to hypoglycemia is critical for understanding the mechanism for protection from hypoglycemia afforded by intrahepatically transplanted.
Detailed description
This study is designed to test the hypothesis that α-adrenergic (neural) blockade will abolish insulin-mediated suppression of C-peptide, attenuating α-cell glucagon secretion during hypoglycemia, and that β-adrenergic (hormonal) blockade will have no effect. Glucose counterregulatory responses will be measured during hyperinsulinemic euglycemic-hypoglycemic clamps on three occasions with randomized, double-blind administration of the α-adrenergic blocker phentolamine, the β-adrenergic blocker propranolol, or placebo. The demonstration of neural rather than hormonal regulation of the transplanted islet cell response to hypoglycemia is critical for understanding the mechanism for protection from hypoglycemia afforded by intrahepatically transplanted islets. Glucose counterregulation has not been studied in type 1 diabetic recipients of extrahepatic islet transplantation. Comparison of glucose counterregulatory responses measured during hyperinsulinemic euglycemic-hypoglycemic clamps will be compared to those obtained from type 1 diabetic recipients of intrahepatic islet transplantation studied under the placebo condition above. Glucose counterregulation has not been directly compared between recipients of intrahepatic auto- and allo-islet transplantation. Direct comparison of glucose counterregulatory responses under the same experimental conditions is required to understand whether mechanisms other than the glucagon response may be important to the reported hypoglycemia affecting pancreatectomized recipients of islet auto-transplantation.
Interventions
DRUGPhentolamine
Physiologic receptor blockade (α1-receptor).
DRUGPropranolol
Physiologic receptor blockade (β2-receptor).
DRUGPlacebo
100mL bag of Normal Saline Solution (NSS).
Sponsors
University of Pennsylvania
National Institutes of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Study design
Allocation
RANDOMIZED
Intervention model
FACTORIAL
Primary purpose
BASIC_SCIENCE
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Conditions of testing for "Group 1" (intra-hepatic islet recipients) will remain double-blind for each subject until their completion of all testing visits, unless for safety concerns, either the PI or Medical Monitor request an unblinding. Groups "2" and "3" will have no masking.
Intervention model description
This study is a within subject and across group mechanistic design. Islet cell hormonal responses to a hyperinsulinemic euglycemic-hypoglycemic clamp will be assessed in "Group 1" on three occasions with randomized, double-blind administration of the α-adrenergic blocker phentolamine, the β-adrenergic blocker propranolol, or placebo. Responses in "Group 1" under the placebo condition will be used for comparison to those obtained from hyperinsulinemic euglycemic-hypoglycemic clamp testing on one occasion in subjects in each of "Group 2" and "Group 3".
Eligibility
Sex/Gender
ALL
Age
21 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
GROUP 1 1. Male and female subjects age 21 to 65 years of age. 2. Subjects who are able to provide written informed consent and to comply with the procedures of the study protocol. 3. Clinical history compatible with type 1 diabetes with onset of disease at \< 40 years of age and insulin-dependent for \> 10 years at the time of islet transplantation \> 6 months before study. 4. Stable islet graft function defined by C-peptide \> 0.5 ng/ml and insulin-independent or insulin-dependent with daily insulin requirement \< 0.2 units/kg•d to maintain HbA1c \< 7.0%. 5. Use of standard immunosuppression consisting of tacrolimus with or without sirolimus or mycophenolic acid. Substitutions of tacrolimus with cyclosporine, and of sirolimus or mycophenolic acid with azathioprine are permissible if stable for over 3 months. Prednisone is allowable if no more than 5 mg daily.
Exclusion criteria
GROUP 1 1. BMI ≥ 30 kg/m2. 2. Insulin requirement of ≥ 0.2 units/kg•day. 3. HbA1c ≥ 7.0%. 4. Uncontrolled hypertension: systolic blood pressure \> 160 mmHg or diastolic blood pressure \> 100 mmHg. 5. History of cardiovascular disease, including coronary artery, cerebrovascular or peripheral vascular disease, or current use of β-blocker therapy. 6. Bronchial asthma. 7. Abnormal kidney function: Estimated glomerular filtration rate (eGFR) \< 60 ml/min/1.73 m2. 8. Abnormal liver function: persistent elevation of liver function tests \> 1.5 times the upper limit of normal. 9. Untreated hypothyroidism, Addison's disease, or Celiac disease. 10. Anemia: baseline hemoglobin concentration \< 11 g/dl in women and \< 12 g/dl in men. 11. Presence of a seizure disorder not related to prior severe hypoglycemia. 12. Use of glucocorticoids greater than 5 mg of prednisone daily, or an equivalent physiologic dose of hydrocortisone. 13. For female participants of child-bearing potential: Positive pregnancy test, presently breast-feeding, or unwillingness to use effective contraceptive measures for the duration of study participation. Oral contraceptives, intra-uterine devices, Norplant®, Depo-Provera®, and barrier devices with spermicide are acceptable contraceptive methods; condoms used alone are not acceptable. 14. Treatment with any anti-diabetic medication other than insulin within 4 weeks of enrollment. 15. Use of any investigational agents within 4 weeks of enrollment. 16. Any medical condition that, in the opinion of the PI, will interfere with the safe completion of the study Inclusion Criteria GROUP 2 1. Male and female subjects age 21 to 65 years of age. 2. Subjects who are able to provide written informed consent and to comply with the procedures of the study protocol. 3. Clinical history compatible with type 1 diabetes with onset of disease at \< 40 years of age and insulin-dependent for \> 10 years at the time of islet transplantation \> 6 months before study. 4. Stable islet graft function defined by C-peptide \> 0.5 ng/ml and insulin-independent or insulin-dependent with daily insulin requirement \< 0.2 units/kg•d to maintain HbA1c \< 7.0%. 5. Use of standard immunosuppression consisting of tacrolimus with or without sirolimus or mycophenolic acid. Substitutions of tacrolimus with cyclosporine, and of sirolimus or mycophenolic acid with azathioprine are permissible if stable for over 3 months. Prednisone is allowable if no more than 5 mg daily.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| C-PEPTIDE Suppression During Hyperinsulinemia Euglycemia. | For C-peptide at the 60-90 minute time-point during the hyperinsulinemic euglycemic-hypoglycemic clamp. | The primary outcome measures will be the levels of C-peptide during hyperinsulinemia euglycemia. |
| GLUCAGON Activation During Hyperinsulinemia Hypoglycemia. | For Glucagon at the 150-180 minute time-point during the hyperinsulinemic euglycemic-hypoglycemic clamp. | The primary outcome measures will be the levels of glucagon during hyperinsulinemia hypoglycemia. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| EPINEPHRINE During Hyperinsulinemia Hypoglycemia. | During metabolic testing in the 150-180 minute time-point of the hyperinsulinemic euglycemic-hypoglycemic clamp. | Secondary outcome measures will include levels of epinephrine during hyperinsulinemia hypoglycemia. |
| Rates of ENDOGENOUS GLUCOSE PRODUCTION During Hyperinsulinemia Hypoglycemia. | During metabolic testing in the 150-180 minute time-point of the hyperinsulinemic euglycemic-hypoglycemic clamp. | Secondary outcome measures will include rates of endogenous glucose production during hyperinsulinemia hypoglycemia |
| AUTONOMIC SYMPTOMS During Hyperinsulinemia Hypoglycemia | The autonomic symptom score was calculated as the mean of scores at the two hypoglycemic time points during the clamp (165 and 180 minutes). | A questionnaire was administered every 15-30 min during the study to quantitate autonomic symptoms as the sum of scores ranging from 0 (none) to 5 (severe) for each of the following symptoms: anxiety, palpitations, sweating, tremor, hunger, and tingling. (6 symptoms) Total scores range 0 - 30, where higher scores indicate greater autonomic symptoms. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORMichael R Rickels, MD., MS
Division of Endocrinology, Diabetes & Metabolism, Perelman School of Medicine
Participant flow
Recruitment details
We anticipated enrolling in Group 2 and Group 3 but were unable to enroll any participants for these groups. No participants were enrolled in the "Group 2 - Extra-hepatic Islet" and "Group 3 - Intra-hepatic Auto Islet" Arms.
Pre-assignment details
Participants were assigned to all 3 conditions / clamp interventions in random order. 9 individuals enrolled. 8 completed propranolol condition. 7 completed phentolamine condition and all 9 completed placebo condition.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 50.6 years STANDARD_DEVIATION 10.5 |
| BMI (kg/m²) | 24.4 (kg/m²) STANDARD_DEVIATION 2.6 |
| C-peptide (ng/mL) | 1.21 ng/mL STANDARD_DEVIATION 0.3 |
| Diabetes Duration (years) | 34.0 years STANDARD_DEVIATION 11.6 |
| HbA1c (%) | 5.91 % STANDARD_DEVIATION 0.63 |
| Insulin Use (U/kg/day) | 0.038 U/kg/day STANDARD_DEVIATION 0.057 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 9 Participants |
| Region of Enrollment United States | 9 participants |
| Sex: Female, Male Female | 5 Participants |
| Sex: Female, Male Male | 4 Participants |
| Transplant Duration (years) | 5.89 years STANDARD_DEVIATION 2.04 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 7 | 0 / 8 | 0 / 9 | 0 / 0 | 0 / 0 |
| other Total, other adverse events | 0 / 7 | 1 / 8 | 0 / 9 | 0 / 0 | 0 / 0 |
| serious Total, serious adverse events | 0 / 7 | 0 / 8 | 0 / 9 | 0 / 0 | 0 / 0 |
Outcome results
None listed