Lipid and Glycogen Metabolism in Patients With Impaired Glucose Tolerance and Calcium Sensing Receptor Mutations
- Conditions
- Type 2 Diabetes MellitusType 1 Diabetes MellitusFamiliar Hypocalcuric HypercalcemiaPrediabetes (Insulin Resistance, Impaired Glucose Tolerance)Healthy Volunteers
- Interventions
- Device: 1H/ 13C and 31P Magnetic Resonance SpectroscopyOther: Meal Tolerance TestOther: Hyperglycemic-hyperinsulinemic clamp
- Registration Number
- NCT02023489
- Lead Sponsor
- Medical University of Vienna
- 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.
- Detailed Description
Background:
1. Type 2 diabetes mellitus is a main risk factor for cardiovascular disease and heart failure, in part due to diabetic cardiomyopathy. Ectopic intracellular lipid accumulation and impaired glycogen metabolism in skeletal muscle and liver and are closely associated with metabolic impairment in insulin resistant subjects and patients with diabetes mellitus. Recent evidence suggests that increased myocardial lipid accumulation might contribute to the development of myocardial dysfunction by direct toxic effects (lipotoxicity). 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 carbohydrates stored as glycogen in muscle cells serve as readily available energy supply for contracting muscle. 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.
2. Heterozygote inherited inactivating mutations in Calcium Sensing Receptor (CaSR)-gene leads to familiar hypocalciuric hypercalcemia (FHH), specified by mildly elevated plasma Ca and parathyroid hormone concentrations, whereas urine Ca excretion is inadequately low. However, in addition to the parathyroid gland CaSR is expressed in various tissues including the endocrine pancreas and the heart. So far it is unknown whether the endocrine function of the pancreas or myocardial morphology and/or function is altered in patients with FHH.
3. Altered hepatic energy metabolism might play an important role in the development of type 2 diabetes. Additionally, the lack of insulin delivery to the liver via the portal vein in type 1 diabetes might alter liver ATP synthesis. Therefore we aim to investigate hepatic energy metabolism non invasively with MRS.
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.
Hepatic and cardiac lipid and energy metabolism is altered in T1DM.
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 (MRS) and imaging (MRI) 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, type 1 diabetes and patients with heterozygote mutation in calcium sensing receptor.
Relevance:
Despite intensive treatment of cardiovascular risk factors, heart diseases are still the main cause of death in diabetic patients. Thus, elucidation of mechanisms that link impaired lipid and/or glycogen metabolism and energy homeostasis to the development of heart failure appears to be crucial for the development of novel treatment strategies. Additionally, hepatic steatosis plays a challenging, emerging role in the treatment of liver disease, wherefore further insight in hepatic energy metabolism in various endocrine disease is urgently needed.
Recruitment & Eligibility
- Status
- UNKNOWN
- Sex
- All
- Target Recruitment
- 90
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Type 2 Diabetes Mellitus 1H/ 13C and 31P Magnetic Resonance Spectroscopy - Insulin sensitive volunteers Meal Tolerance Test - Insulin sensitive volunteers Hyperglycemic-hyperinsulinemic clamp - Insulin sensitive volunteers 1H/ 13C and 31P Magnetic Resonance Spectroscopy - prediabetic subjects 1H/ 13C and 31P Magnetic Resonance Spectroscopy - familiar hypocalciuric hypercalcemic patients Meal Tolerance Test - Type 1 diabetes mellitus 1H/ 13C and 31P Magnetic Resonance Spectroscopy - Type 2 Diabetes Mellitus Hyperglycemic-hyperinsulinemic clamp - prediabetic subjects Hyperglycemic-hyperinsulinemic clamp - prediabetic subjects Meal Tolerance Test - familiar hypocalciuric hypercalcemic patients 1H/ 13C and 31P Magnetic Resonance Spectroscopy -
- Primary Outcome Measures
Name Time Method change in myocardial glycogen content at baseline and during the third hour of the hyperglycemic clamp/ in the morning and at 5 p.m. after a meal tolerance test 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.
- Secondary Outcome Measures
Name Time Method 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 Myocardial lipid measurements will be performed using localized 1H MRS. Anatomic imaging will be used to guide water suppressed Point RESolved Spectroscopy sequence (echo time, TE= 30 ms; minimal repetition time TR= 3 s; NS=64). The volume of the interest (VOI; approx. 6 - 8 cm3) will be placed over the interventricular septum. . An additional spectrum without water suppression (NS= 2x 4) will be used as internal reference. The spectra will be processed offline using AMARES time domain line fitting as implemented jMRUI software package. The myocardial lipid content will be determined from processed spectra as a ratio of the intensities of CH2 (1.25 ppm) and CH3 (0.8-0.9 ppm) group resonances to the intensity of the water resonance from non-water suppressed spectra of the same VOI.
Trial Locations
- Locations (1)
Medical University Of Vienna, Department of Internal Medicine III
🇦🇹Vienna, Austria