Lipid and Glycogen Metabolism in Patients With Impaired Glucose Tolerance and Calcium Sensing Receptor Mutations

NCT02023489 | Unknown DMC

• 1 other identifier: EK1128/2013
• Study Type: interventional
• Target: 90
• Locations: 1 country
• Sites: 1

Brief Summary

Background: Type 2 diabetes mellitus is a main risk factor for cardiovascular disease and heart failure, in part due to diabetic cardiomyopathy. However, the association between intracellular lipid accumulation and (myocardial) functional impairment is likely more complex than originally imagined. Recent studies suggest that not fat per se, but the content of saturated or unsaturated fatty acids might predict the development of cardiac steatosis and myocardial dysfunction. In addition skeletal muscle and hepatic glycogen metabolism is impaired in patients with diabetes mellitus. Data from animal experiments suggest a relevant role of myocardial glycogen stores in ischemic preconditioning. Due to methodological limitations so far data on myocardial glycogen stores and myocardial lipid composition in humans are missing. Hypothesis: In addition to total ectopic lipid deposition in the myocardium, myocardial lipid composition, i.e. the relative abundance of saturated and unsaturated fatty acids, and impaired myocardial glycogen metabolism may play an important role in the development cardiac lipotoxicity leading to diabetic cardiomyopathy. Pancreatic endocrine function and myocardial morphology and function is altered in patients with heterozygote inactivating mutations of the CaSR-gene / FHH. Aims:

• Metabolic virtual biopsy of the myocardium for identification of specific patterns of intracellular lipid composition and myocardial glycogen metabolism as possible critical determinants of metabolic cardiomyopathy
• Characterization of the metabolic interplay between the myocardium, skeletal muscle, liver and adipose tissues in different stages of development of type 2 diabetes compared to patients with calcium sensing receptor mutation Methods:
• 1H/13C and 31P magnetic resonance spectroscopy and imaging for measurements of myocardial, skeletal and liver lipid and glycogen content, abdominal adipose tissue distribution and composition, ATP synthesis and myocardial functional parameters
• Mixed meal tolerance tests to trace the postprandial partitioning of substrates between insulin sensitive tissues (myocardium, skeletal muscle, liver, adipose tissue).
• Hyperinsulinemic-hyperglycemic glucose clamp (HHC) with enrichment of the infused glucose with the stable isotope \[1-13C\]glucose to trace the incorporation of circulating glucose into myocardial glycogen in healthy insulin sensitive volunteers, prediabetic insulin resistant volunteers with impaired glucose tolerance, healthy subjects, patients suffering from type 2 diabetes mellitus, patients suffering from type 1 diabetes and patients with heterozygote mutation in calcium sensing receptor.

Conditions

Type 2 Diabetes Mellitus; Prediabetes (Insulin Resistance, Impaired Glucose Tolerance); Familiar Hypocalcuric Hypercalcemia; Healthy Volunteers; Type 1 Diabetes Mellitus

Outcome Measures

Primary Outcomes (1)

• change in myocardial glycogen content

  13C magnetic resonance spectroscopy for the assessment of myocardial glycogen content: Localized 13C NMR spectra will be obtained in a 7T Magnetom MR System (Siemens Healthcare, Erlangen Germany) with a dedicated butterfly-shaped 13C (15cm)/1H(21cm) transmitter/receiver coil (Stark Contrast, Erlangen, Germany) placed over or under the thorax. Recently introduced ISIS based or 1D CSI localization schemes will be applied. Absolute glycogen concentrations will be quantified by comparing the C1 glycogen peak (100.5 ppm) integral of tissue specific spectra with that of a glycogen standard taken under identical conditions. Corrections for loading of the coil and sensitive volume of the coil will be performed.

  at baseline and during the third hour of the hyperglycemic clamp/ in the morning and at 5 p.m. after a meal tolerance test

Secondary Outcomes (1)

• change in myocardial lipid composition

  at baseline and during the third hour of the hyperglycemic clamp/ in the morning and at 5 p.m. after a meal tolerance test

Other Outcomes (2)

• change in lipid content/composition in liver and skeletal muscle

  at baseline and during the third hour of a hyperglycemic clamp/ in the morning and at 5:00 p.m. after a meal tolerance test

• differences in hepatic energy metabolism/ATP synthesis

  baseline

Study Arms (5)

Type 2 Diabetes Mellitus

OTHER

Device: 1H/ 13C and 31P Magnetic Resonance Spectroscopy; Other: Hyperglycemic-hyperinsulinemic clamp

Insulin sensitive volunteers

OTHER

Device: 1H/ 13C and 31P Magnetic Resonance Spectroscopy; Other: Meal Tolerance Test; Other: Hyperglycemic-hyperinsulinemic clamp

prediabetic subjects

OTHER

Device: 1H/ 13C and 31P Magnetic Resonance Spectroscopy; Other: Meal Tolerance Test; Other: Hyperglycemic-hyperinsulinemic clamp

familiar hypocalciuric hypercalcemic patients

OTHER

Device: 1H/ 13C and 31P Magnetic Resonance Spectroscopy; Other: Meal Tolerance Test

Type 1 diabetes mellitus

OTHER

Device: 1H/ 13C and 31P Magnetic Resonance Spectroscopy

Interventions

1H/ 13C and 31P Magnetic Resonance Spectroscopy DEVICE

Study participants will be studied in the fasting state after an overnight fast of at least 10 h. Participants will arrive at the MR-Centre in the morning of the study. Between 6:30 and 10:00 a.m., 1H MRI (3T) will be performed for the assessment abdominal adipose tissue distribution and composition as well as myocardial functional parameters. 1H/13C MRS examinations (7T) will be performed for measurements of myocardial, skeletal muscle and liver lipid content and composition as well as glycogen content. Additionally, ATP synthesis and energy metabolism will be assessed.

Insulin sensitive volunteers; Type 1 diabetes mellitus; Type 2 Diabetes Mellitus; familiar hypocalciuric hypercalcemic patients; prediabetic subjects

Meal Tolerance Test OTHER

A meal tolerance test meal tolerance test according to Petersen et al. (PNAS, Vol 104, 2007) will be performed. After MRI and MRS examinations subjects will be returned at our outpatients clinic, where small polyethylene catheter will be inserted in an antecubital vein for hourly blood sampling. At 10:30 a.m. and 1:30 p.m. two liquid high carbohydrate meals of equal size containing all the required daily energy (30 kcal/kg of body weight; 55% carbohydrate, 10% protein, and 35% fat) with an additional 25% of the daily energy requirements added in the form of sucrose will be served. At 5 p.m. subjects will be returned at the MR - Centre for postprandial 1H / 13C MRS (7T) of muscle, liver and myocardial lipid and glycogen contents. Myocardial function parameters and abdominal fat distribution will be assessed again by 1H MRI (3T).

Insulin sensitive volunteers; familiar hypocalciuric hypercalcemic patients; prediabetic subjects

Hyperglycemic-hyperinsulinemic clamp OTHER

All volunteers will be admitted in the morning and basal 13C tracer enrichment will be assessed. At 8:00a.m. (0 min) a hyperglycemic-hyperinsulinemic-pancreatic clamp test will be initiated by somatostatin (-5-300 min: 0.1 µg·kg-1·min-1, UCB Pharma, Vienna, Austria) and insulin (0 - 8 min: 80 mU·min-1·m-2 body surface area; 8 -300 min: 40 mU·min-1·m-2 body surface area) infusion. Plasma glucose will be raised and maintained at \~180 mg·dL-1 by primed (0.2 g·kg-1)-variable dextrose infusion (20%w/v) enriched with \[1-13C\]glucose (40%w/w). A second catheter will be placed into an antecubital vein of the other arm and blood samples for the measurement of glucose, insulin and c-peptide. Glucose concentrations will be analysed immediately every 5 minutes, employing a glucose analyser. Myocardial glycogen concentrations will be measured before the clamp (-60 - 0 min) and from 90 min to 180 min during the clamp employing 13C MRS.

Insulin sensitive volunteers; Type 2 Diabetes Mellitus; prediabetic subjects

Eligibility Criteria

• Age: 18 Years - 90 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• HbA1c: 7.0-8.0 %,
• m/f,
• age \<90,
• no insulin therapy,
• normal liver function (transaminase \<2 x than normal),
• no late diabetic complication (prolif. retinopathy, neuropathy, creatinin \<1.5 mg/dl),
• female premenopausal patients: follicular = 1. phase of menstrual cycle,
• no evidence of coronary artery disease (ECG, patient history, symptoms).

You may not qualify if:

• age \<18 / \>90a,
• dyslipidaemia (serum total cholesterol \> 220 mg/dl, triglycerides \> 150 mg/dl, LDL cholesterol \> 130 mg/dl),
• arterial hypertension,
• cardiovascular diseases,
• thyroid disorders,
• bleeding disorders,
• medication potentially affecting glucose or lipid metabolism.
• genetically characterized heterozygote mutation in the CaSR gene
• metal devices or other magnetic material in or on the subjects body which will be hazardous for NMR investigation \[heart pacemaker, brain (aneurysm) clip, nerve stimulators, electrodes, ear implants, post coronary by-pass graft (epicardial pace wires), penile implants, colored contact lenses, patch to deliver medications through the skin, coiled spring intrauterine device, vascular filter for blood clots, orthodontic braces, shunt-spinal or ventricular, any metal implants (rods, joints, plates, pins, screws, nails, or clips), embolization coil, or any metal fragments or shrapnel in the body\].
• BMI \> 35 kg/m2
• tendency toward claustrophobia
• severe thyroid or liver disorders
• any acute illness within 2 weeks prior the study
• donation of blood within 30 days prior the study
• pregnancy

Sponsors & Collaborators

• Medical University of Vienna: lead

Study Sites (1)

Medical University Of Vienna, Department of Internal Medicine III

Vienna, Vienna, 1090, Austria

RECRUITING

MeSH Terms

Conditions

Diabetes Mellitus, Type 2; Prediabetic State; Insulin Resistance; Glucose Intolerance; Diabetes Mellitus, Type 1

Condition Hierarchy (Ancestors)

Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases; Hyperinsulinism; Hyperglycemia; Autoimmune Diseases; Immune System Diseases

Study Officials

• Michael Krebs, Prof MD

  Medical University of Vienna, Department of Internal Medicine III, Division of Endocrinology and Metabolism

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Peter Wolf, MD

CONTACT

00436646499456; peter.wolf@meduniwien.ac.at

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Prof. MD

Study Record Dates

• First Submitted: December 18, 2013
• First Posted: December 30, 2013
• Study Start: July 1, 2013
• Primary Completion: December 1, 2017
• Study Completion: July 1, 2018
• Last Updated: March 23, 2017

Record last verified: 2017-03

Data Sharing

• IPD Sharing: Will not share

Locations

AU (1)