Impact of Insulin Deprivation and Hyperglycemia on Plasma Protein Synthesis in People With Type 1 Diabetes Mellitus

Study Overview
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Brief Summary
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This research is being done to better understand how insulin effects muscle, blood, and the body in people with Type 1 Diabetes.

Detailed Description
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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.

Official Title
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Impact of Insulin Deprivation and Hyperglycemia on Plasma Protein Synthesis in People With Type 1 Diabetes Mellitus and Diabetes After Total Pancreatectomy

Conditions
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Type 1 Diabetes

Intervention / Treatment
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* Procedure: Muscle Biopsy
* Other: Jell-O with Amino acids
* Dietary Supplement: Dextrose


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Health Services Research
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Type 1 Diabetes Mellitus (T1DM) Insulin Deprived<br>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. | Procedure: Muscle Biopsy<br>* Needle muscle biopsy of the outer thigh muscle<br>Other: Jell-O with Amino acids<br>* An amino acid mixture containing 13C6 Lysine isotope label<br>|
| Experimental: Type 1 Diabetes Mellitus (T1DM) Insulin Treated<br>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. | Procedure: Muscle Biopsy<br>* Needle muscle biopsy of the outer thigh muscle<br>Other: Jell-O with Amino acids<br>* An amino acid mixture containing 13C6 Lysine isotope label<br>|
| Experimental: Type 1 Diabetes Mellitus (T1DM) Insulin-Treated with Hyperglycemia<br>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. | Procedure: Muscle Biopsy<br>* Needle muscle biopsy of the outer thigh muscle<br>Other: Jell-O with Amino acids<br>* An amino acid mixture containing 13C6 Lysine isotope label<br>Dietary Supplement: Dextrose<br>* Intravenous form of sugar<br>|
| Other: Non-Diabetic Controls<br>Subjects will have blood draws to monitor glucose levels along with a muscle biopsy following consumption of a Jell-O with Amino acids. | Procedure: Muscle Biopsy<br>* Needle muscle biopsy of the outer thigh muscle<br>Other: Jell-O with Amino acids<br>* An amino acid mixture containing 13C6 Lysine isotope label<br>|
| Experimental: Diabetes after Total Pancreatectomized (DATP) Insulin Treated<br>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. | Procedure: Muscle Biopsy<br>* Needle muscle biopsy of the outer thigh muscle<br>Other: Jell-O with Amino acids<br>* An amino acid mixture containing 13C6 Lysine isotope label<br>|
| Experimental: Diabetes after Total Pancreatectomized (DATP) Insulin Deprived<br>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. | Procedure: Muscle Biopsy<br>* Needle muscle biopsy of the outer thigh muscle<br>Other: Jell-O with Amino acids<br>* An amino acid mixture containing 13C6 Lysine isotope label<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Protein synthesis | Measurement of isotope abundance in peptides derived from the digested proteins | Approximately 7 hours | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Continuous subcutaneous insulin infusion, Multiple daily injections of insulin