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

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

Interventions

DEVICE

1H/ 13C and 31P Magnetic Resonance Spectroscopy

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.

OTHER

Meal Tolerance Test

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).

OTHER

Hyperglycemic-hyperinsulinemic clamp

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.

Sponsors & Collaborators

• Medical University of Vienna

  lead OTHER

Principal Investigators

• Michael Krebs, Prof MD · Medical University of Vienna, Department of Internal Medicine III, Division of Endocrinology and Metabolism

Study Design

Allocation

NON_RANDOMIZED

Purpose

BASIC_SCIENCE

Masking

NONE

Model

PARALLEL

Eligibility

Min Age

18 Years

Max Age

90 Years

Sex

ALL

Healthy Volunteers

Yes

Timeline & Regulatory

Start

2013-07-31

Primary Completion

2017-12-31

Completion

2018-07-31

Countries

• Austria

Study Locations