Impact of Insulin Deprivation and Hyperglycemia on Plasma Protein Synthesis in People With Type 1 Diabetes Mellitus
Impact of Insulin Deprivation and Hyperglycemia on Plasma Protein Synthesis in People With Type 1 Diabetes Mellitus and Diabetes After Total Pancreatectomy
Study Overview
Status
Conditions
Intervention / Treatment
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 Type
Phase
- Not Applicable
Contacts and Locations
Study Locations
-
-
Minnesota
-
Rochester, Minnesota, United States, 55905
- Mayo Clinic
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-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
- Adult
- Older Adult
Accepts Healthy Volunteers
Description
Inclusion Criteria - Type 1 Diabetes Group:
- Able to provide written consent.
Exclusion Criteria - Type 1 Diabetes Group::
- BMI < 20 or > 32 kg/m^2.
- Celiac disease.
- Pregnancy.
- Smoking.
- 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^2.
- Severe peripheral or autonomic neuropathy.
- Dementia or any other neurologic disease.
- Uncontrolled psychiatric disease.
- Any learning disability.
- Anemia.
- Thyroid-stimulating hormone (TSH) ≥ 7 or TSH ≤ 7 and free T4 ≤ 0.9.
- 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^2.
- Celiac disease.
- Pregnancy.
- Smoking.
- 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^2.
- Severe peripheral or autonomic neuropathy.
- Dementia or any other neurologic disease.
- Uncontrolled psychiatric disease.
- Any learning disability.
- Anemia.
- TSH ≥ 7 or TSH ≤ 7 and free T4 ≤ 0.9.
- T2DM, or impaired fasting glucose.
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Health Services Research
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
|---|---|
|
Experimental: 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.
|
Needle muscle biopsy of the outer thigh muscle
An amino acid mixture containing 13C6 Lysine isotope label
|
|
Experimental: 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.
|
Needle muscle biopsy of the outer thigh muscle
An amino acid mixture containing 13C6 Lysine isotope label
|
|
Experimental: 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.
|
Needle muscle biopsy of the outer thigh muscle
An amino acid mixture containing 13C6 Lysine isotope label
Intravenous form of sugar
|
|
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.
|
Needle muscle biopsy of the outer thigh muscle
An amino acid mixture containing 13C6 Lysine isotope label
|
|
Experimental: 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.
|
Needle muscle biopsy of the outer thigh muscle
An amino acid mixture containing 13C6 Lysine isotope label
|
|
Experimental: 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.
|
Needle muscle biopsy of the outer thigh muscle
An amino acid mixture containing 13C6 Lysine isotope label
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
|---|---|---|
|
Protein synthesis
Time Frame: Approximately 7 hours
|
Measurement of isotope abundance in peptides derived from the digested proteins
|
Approximately 7 hours
|
Collaborators and Investigators
Sponsor
Investigators
- Principal Investigator: K. Sreekumaran Nair, MD, Mayo Clinic
Publications and helpful links
Helpful Links
Study record dates
Study Major Dates
Study Start (Estimated)
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Endocrine System Diseases
- Metabolic Diseases
- Autoimmune Diseases
- Immune System Diseases
- Glucose Metabolism Disorders
- Diabetes Mellitus
- Nutritional and Metabolic Diseases
- Diabetes Mellitus, Type 1
- Amino Acids, Peptides, and Proteins
- Pharmaceutical Preparations
- Dosage Forms
- Carbohydrates
- Sugars
- Complex Mixtures
- Colloids
- Hexoses
- Monosaccharides
- Amino Acids
- Glucose
- Gels
Other Study ID Numbers
- 21-000001
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
product manufactured in and exported from the U.S.
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