Tuesday, March 15, 2016

What is the A1C Test?

The disease diabetes mellitus occurs in two different forms – juvenile or adult-onset.  In either case, the source of the illness is lack of or reduced production of the hormone insulin (see image below) whose role is to enhance the uptake of glucose circulating in the blood by tissue cells, especially adipose and skeletal muscle.  Insulin (as seen below) is referred to as a globular protein

Insulin is normally produced by specialized beta cells resident in the Islets of Langerhans within the pancreas.  It has been established that juvenile diabetes is an auto-immune disease in which the immune system of the patient attacks these beta cells.  Adult-onset diabetes, on the other hand, has a strong association with obesity.

This inability to transfer glucose to tissue cells where it is utilized for energy, leads to high concentrations of glucose in the blood (hyperglycemia).  Over a prolonged period of time, this hyperglycemic state results in very serious and ultimately life-threatening complications including blindness, impaired kidney function, cardiovascular issues leading to heart trouble and leaving victims prone to amputation.  These deleterious side effects arise as the excess glucose in the blood reacts with proteins in various tissues throughout the body – this biochemical reaction is referred to as glycosylation.

Once the cause of diabetes was discovered, it was realized that an obvious therapeutic approach is to give the patient insulin from an external source.  Before the advent of DNA recombinant technology, patients were given insulin harvested from cow pancreas (bovine insulin).  Bovine and human insulin are close enough in structure to allow bovine insulin to have an efficacious effect.  Currently, of course, human insulin is readily available.

Over many years of treating diabetic patients with human insulin, it was realized that periodic administration of insulin is not comparable to the body’s finely tuned regulation of insulin production so as to maintain optimal levels of blood glucose.  In response to this deficit, a technology arose to employ the use of an insulin pump in order to maintain a steady stream of insulin along with careful monitoring of blood glucose levels.  In addition, considerable emphasis has been placed on nutrition, exercise and weight control especially in regard to adult-onset diabetes.

Another important tool in the treatment of diabetes is the so-called A1C test.  This test provides information as to the average level of blood glucose over a 3-month time span; it is also referred to as the glycohemoglobin test.  This test measures the amount of glycosylated hemoglobin.  Hemoglobin is the specialized protein in red blood cells that is designed to carry oxygen to the tissues.  This protein reacts with excess glucose in the blood.  Since red blood cells are recycled by the body over a 3-month period, the test provides information about the average level of glucose in the blood over this period of time.  The result of this test is reported as a percentage.  The normal value is about 5.7%.  The higher the percentage, the higher the blood glucose level has been over the past 3 months.

The A1C test is an important tool in determining the efficacy of treatment for diabetic patients.  

Tuesday, March 1, 2016

The Role of the Large Protein Titin in Dilated Cardiomyopathy

There is a serious heart condition referred to as dilated cardiomyopathy (DCM) that is a major cause of heart failure and often results in premature death; this disease is found in one in two-hundred and fifty adults (0.4%).  DCM can originate either as a result of an underlying vascular problem or can have a genetic origin.  This report will focus on the progress that has been made in regards to the genetic implications of this condition.

Through the work of Dr. John T. Hinson at the Division of Cardiovascular Medicine at the Brigham and Women’s Hospital, Boston MA and his colleagues from many diverse institutions, it has been show that mutations of a large protein that constitutes one-half of the sarcomere (a structural unit of a myofibril in striated muscle) are the most common cause for DCM.  This protein is referred to as titin (TTN) (see image below) and the mutations involved result in a truncated version of TTN.  These genetic variants of TTN are referred to as TTN-truncating variants (TTNtvs).

Since the functional significance of TTN within the muscle sarcomere was unclear, the investigators involved in this research, applied the tools of molecular biology to better define the role played by TTN within heart muscle.  To accomplish this, they grew out cardiac micro-tissue cultures comprised of cardiomyocytes derived from pluripotent stem cells (iPS) that were harvested from the patients studied.  When these patient-derived cells were compared to those derived from normal individuals (the controls), it was discovered that, “certain missense mutations like TTNtvs diminish contractile performance and are pathogenic.”

Furthermore, these patient-derived cardiomyocytes also demonstrated sarcomere insufficiency, reduced responses to mechanical and biochemical stress as well as impairment in critical cell signaling pathways.  All of these results, when taken together, point to TTNtvs as playing a causative role in genetically-induced DCM.  This is a significant finding with broad implications.