Healthy Volunteers Clinical Trial
Official title:
Myocardial Lipid and Glycogen Metabolism & Cardiac Function in Patients With Impaired Glucose Tolerance or Type 2 Diabetes Mellitus and Calcium Sensing Receptor Mutations - A Cross Sectional Magnetic Resonance Spectroscopy and Imaging Study
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.
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.
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