Impact of Insulin Deprivation and Hyperglycemia on Plasma Protein Synthesis in People With Type 1 Diabetes Mellitus and Diabetes After Total Pancreatectomy
Trial Snapshot
- Phase
- Not Applicable
- Status
- Withdrawn
- Sponsor
- Mayo Clinic
- Enrollment
- 70
- Locations
- 1
- Primary Endpoint
- Protein synthesis
Study Overview
Brief Summary
This research is being done to better understand how insulin effects muscle, blood, and the body in people with Type 1 Diabetes.
Detailed Description
Insulin's contribution in controlling glucose homeostasis has been well appreciated but, its role in maintaining proteome homeostasis is less understood. Some animal and human studies have demonstrated that insulin signaling regulates protein synthesis and degradation as well as posttranslational modifications at the tissue level. Insulin's effect on the muscle's mitochondrial proteo-stasis has also been elucidated. Insulin deprivation increases global synthesis of splanchnic proteins based on isotope dilution studies across splanchnic bed. Most plasma proteins are derived from liver and preliminary studies suggest that synthesis rates of some plasma proteins increase while others decrease. Fractional rates of synthesis of various plasma proteins from the liver have been demonstrated in insulin deprivation state. These proteins might be implicated in the development of some of the complications from diabetes mellitus type 1. (T1DM) especially of macrovascular. Researchers have recently developed an isotope-based methodology to simultaneously measure in vivo synthesis rates of multiple plasma proteins in human.
In order to further investigate the effects of insulin deprivation researchers will apply the novel non-radioactive stable isotope-based approach on the rate of different plasma protein synthesis in T1DM and Diabetes after total pancreatectomy (DATP) in comparison with non-diabetic controls. Researchers will study pancreatectomized people because like T1DM they also are insulin deficient but unlike pancreatectomized people also are deficient in glucagon. Some tantalizing data from many studies indicate that glucagon also have catabolic effect not only on liver derived proteins but also on skeletal muscle-based proteins. Since skeletal muscle has no glucagon receptors, researchers hypothesize that unknown factors are released to the circulation that act on skeletal muscle to release amino acids for consumption in liver. Researchers will measure amino metabolites, acyl carnitines, organic acids, and ceramides in plasma and determine the blood exosome cargo by mass spectrometry-proteins and lipids and miRNA by PCR.
Researchers have previously shown reduced muscle mitochondrial ATP production during insulin deprivation in both T1D humans and diabetic mice and here researchers will measure mitochondrial energy dynamics in all study participants by the established techniques available in our lab.
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Health Services Research
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to 70 Years (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- Yes
Inclusion Criteria
- •Type 1 Diabetes Group:
- •- Able to provide written consent.
Exclusion Criteria
- •Type 1 Diabetes Group::
- •BMI < 20 or > 32 kg/m^
- •Celiac disease.
- •Pregnancy.
- •Reported history of illicit substance use.
- •History of active cardiovascular, cerebrovascular, or peripheral vascular disease.
- •Active renal disease evidenced by estimated glomerular filtration rate (GFR) < 50 mL/min/1.73 m^
- •Severe peripheral or autonomic neuropathy.
- •Dementia or any other neurologic disease.
- •Uncontrolled psychiatric disease.
- •Any learning disability.
- •Thyroid-stimulating hormone (TSH) ≥ 7 or TSH ≤ 7 and free T4 ≤ 0.
- •Hemoglobin A1c > 9.0%.
- •Type 2 Diabetes Mellitus (T2DM), or impaired fasting glucose.
- •Detectable C peptide.
- •Inclusion Criteria - Control Group:
- •Able to provide written consent.
- •T1DM treated with continuous subcutaneous insulin infusion (CSII) or multiple daily injections (MDI) (not Degludec).
- •Exclusion Criteria - Control Group:
- •BMI < 20 or > 32 kg/m^
- •Celiac disease.
- •Pregnancy.
- •Reported history of illicit substance use.
- •History of active cardiovascular, cerebrovascular, or peripheral vascular disease.
- •Active renal disease evidenced by estimated GFR < 50 mL/min/1.73 m^
- •Severe peripheral or autonomic neuropathy.
- •Dementia or any other neurologic disease.
- •Uncontrolled psychiatric disease.
- •Any learning disability.
- •TSH ≥ 7 or TSH ≤ 7 and free T4 ≤ 0.
- •T2DM, or impaired fasting glucose.
Arms & Interventions
Type 1 Diabetes Mellitus (T1DM) Insulin Deprived
Subjects will have their insulin infusions replaced with saline and have blood draws to monitor glucose levels along with a muscle biopsy following consumption of a Jell-O with Amino acids.
Intervention: Jell-O with Amino acids (Other)
Type 1 Diabetes Mellitus (T1DM) Insulin Treated
Subjects will continue their baseline insulin infusion while maintaining a target blood glucose range. Blood draws will be obtained to monitor glucose levels along with a muscle biopsy following consumption of a Jell-O with Amino acids.
Intervention: Muscle Biopsy (Procedure)
Type 1 Diabetes Mellitus (T1DM) Insulin Treated
Subjects will continue their baseline insulin infusion while maintaining a target blood glucose range. Blood draws will be obtained to monitor glucose levels along with a muscle biopsy following consumption of a Jell-O with Amino acids.
Intervention: Jell-O with Amino acids (Other)
Type 1 Diabetes Mellitus (T1DM) Insulin-Treated with Hyperglycemia
Subjects will be continue their baseline insulin infusion for 2 hours and then receive an intravenous dextrose infusion to maintain elevated blood sugar levels. Blood draws will be obtained to monitor glucose levels along with a muscle biopsy following consumption of a Jell-O with Amino acids.
Intervention: Muscle Biopsy (Procedure)
Diabetes after Total Pancreatectomized (DATP) Insulin Deprived
Subjects will have their insulin infusions replaced with saline and have blood draws to monitor glucose levels along with a muscle biopsy following consumption of a Jell-O with Amino acids.
Intervention: Jell-O with Amino acids (Other)
Type 1 Diabetes Mellitus (T1DM) Insulin Deprived
Subjects will have their insulin infusions replaced with saline and have blood draws to monitor glucose levels along with a muscle biopsy following consumption of a Jell-O with Amino acids.
Intervention: Muscle Biopsy (Procedure)
Type 1 Diabetes Mellitus (T1DM) Insulin-Treated with Hyperglycemia
Subjects will be continue their baseline insulin infusion for 2 hours and then receive an intravenous dextrose infusion to maintain elevated blood sugar levels. Blood draws will be obtained to monitor glucose levels along with a muscle biopsy following consumption of a Jell-O with Amino acids.
Intervention: Jell-O with Amino acids (Other)
Non-Diabetic Controls
Subjects will have blood draws to monitor glucose levels along with a muscle biopsy following consumption of a Jell-O with Amino acids.
Intervention: Muscle Biopsy (Procedure)
Non-Diabetic Controls
Subjects will have blood draws to monitor glucose levels along with a muscle biopsy following consumption of a Jell-O with Amino acids.
Intervention: Jell-O with Amino acids (Other)
Diabetes after Total Pancreatectomized (DATP) Insulin Treated
Subjects will continue their baseline insulin infusion while maintaining a target blood glucose range. Blood draws will be obtained to monitor glucose levels along with a muscle biopsy following consumption of a Jell-O with Amino acids.
Intervention: Muscle Biopsy (Procedure)
Diabetes after Total Pancreatectomized (DATP) Insulin Treated
Subjects will continue their baseline insulin infusion while maintaining a target blood glucose range. Blood draws will be obtained to monitor glucose levels along with a muscle biopsy following consumption of a Jell-O with Amino acids.
Intervention: Jell-O with Amino acids (Other)
Diabetes after Total Pancreatectomized (DATP) Insulin Deprived
Subjects will have their insulin infusions replaced with saline and have blood draws to monitor glucose levels along with a muscle biopsy following consumption of a Jell-O with Amino acids.
Intervention: Muscle Biopsy (Procedure)
Type 1 Diabetes Mellitus (T1DM) Insulin-Treated with Hyperglycemia
Subjects will be continue their baseline insulin infusion for 2 hours and then receive an intravenous dextrose infusion to maintain elevated blood sugar levels. Blood draws will be obtained to monitor glucose levels along with a muscle biopsy following consumption of a Jell-O with Amino acids.
Intervention: Dextrose (Dietary Supplement)
Outcomes
Primary Outcomes
Protein synthesis
Time Frame: Approximately 7 hours
Measurement of isotope abundance in peptides derived from the digested proteins
Secondary Outcomes
No secondary outcomes reported
Investigators
K. Sreekumaran Nair
Principal Investigator
Mayo Clinic