Normal Insulin Metabolism and the Glucose Homeostasis

Normal Insulin Metabolism and the Glucose Homeostasis

The normal glucose homeostasis is tightly regulated by three inter related process.

1. Hepatic glucose production
2. Glucose intake and utilization by
3. Insulin secretion.

            Insulin secretion is modulated such that glucose production and utilization rise or fall to maintain normal blood glucose levels, the human insulin MRna is transcribed. Translocation of message occurs in the rough endoplasmic reticulum yielding a pre-pro insulin, there follows a proteolytic cleavage of pre-peptide sequences to yield a pro insulin, and in the golgi apparatus cleavage of the C-peptides to yield insulin sequence, both insulin and c-peptides are stored in secretory granules and secreted together after a physiological stimulus. The release of insulin from the beta cells is biphasic in manner involving the twp pools of insulin. A rise in blood glucose levels results in the glucose uptake into beta cell in facilitated by an insulin dependent glucose transport protein GLUT-2 and leading to an immediate release on insulin presumably that is stored in beta cell granules, if the secretory response persists a delayed and protracted responses will follow, which involves the active secretion of insulin, the most important stimulus that triggers insulin release in glucose which also potentiates the insulin synthesis. The calcium efflux alpha adrenergic stimulus, cyclic AMP glucagon like peptides are also involved in insulin secretion. Intestinal hormones, amino acids such as Luciene, argenine also stimulate insulin release but not synthesis.

Insulin is a major anabolic hormone and is required for:

1. Trans membrane transport of glucose and amino acids.
2. Glycogen formation in liver and skeletal muscles.
3. Glucose conversion to triglycerides.
4. Nucleic acid synthesis
5. Protein synthesis

           

            One of the most important functions of insulin is glucose transport into the following cells.

1. Striated and myocardial cells
2. Fibroblasts
3. Fat cells which represents two third of body mass

            In addition to these metabolic functions insulin like growth hormones initiate a DNA synthesis in certain cells and stimulate their growth and differentiation. Insulin interacts with its target cells by binding to the insulin like receptors composed of two glycoproteins – alpha and beta. Since the amount of insulin bound to the cells is affected by the availability of receptors their numerous functions are important in regulating the action of insulin. Receptor bound insulin triggers number of intracellular responses including  activation  or  inhibition  of  insulin  sensitive  enzymes  in  the  mitochondria, protein synthesis and DNA synthesis.

            One of the earliest defects involved is translocation of glucose transport protein unit (GLUT) from the golgi apparatus to the plasma membranes thus facilitating cellular uptake of glucose. There are several forms of GLUT’s which differ in their tissue distribution, affinity for glucose and sensitivity to insulin.

            The GLUT-4 in muscles and the adipose tissue is the major insulin regulator and transporter, the GLUT-2 on the other hand is present the liver and beta cells of pancreas insulin independent and serves to facilitate rapid equilibration of glucose between extra intracellular compartments.

            Hepatic production of glucose is regulated by number of hormones. Conversely after glucose enter cell sit is metabolized by oxidation to carbon dioxide and water or is stored by non oxidative metabolism as glycogen synthesis, defects in all these regulator steps in glucose homeostasis namely insulin secretion glucose transport glucose production glucose utilization are found in patients of type –2-diabetes.