Regulation of Blood Glucose Level NABIL BASHIR, 2009

INTRODUCTION Blood sugar concentration, or glucose level, refers to the amount of glucose present in the blood of a human. Normally, in mammals the blood glucose level is maintained at a reference range between about 3.6 and 5.8 mM (mmol/l). It is tightly regulated as a part of metabolic homeostasis.

INTRODUCTION….. There are two types of mutually antagonistic metabolic hormones affecting blood glucose levels: catabolic hormones (such as glucagon, growth hormone, cortisol and catecholamines) which increase blood glucose; and one anabolic hormone (insulin), which decreases blood glucose

INTRODUCTION….. liver is the predominant tissue responding to signals that indicate reduced or elevated blood glucose levels. Low blood glucose triggers release of glucagon from pancreatic α-cells. High blood glucose triggers release of insulin from pancreatic β-cells.

Roles of Insulin and Glucagon in Regulating Blood Glucose Figure 13.9

Glucagon…. Glucagon binding to its' receptors on the surface of liver cells triggers an increase in cAMP production leading to an increased rate of glycogenolysis by activating glycogen phosphorylase via the PKA-mediated cascade. This is the same response hepatocytes have to epinephrine release. The resultant increased levels of G6P in hepatocytes is hydrolyzed to free glucose, by glucose-6-phosphatase, which then diffuses to the blood.

The glucose enters extrahepatic cells where it is re-phosphorylated by hexokinase. Since muscle and brain cells lack glucose-6-phosphatase, the glucose-6-phosphate product of hexokinase is retained and oxidized by these tissues.

Glucagon…..

INSULIN insulin stimulates extrahepatic uptake of glucose from the blood and inhibits glycogenolysis in extrahepatic cells and conversely stimulates glycogen synthesis. As the glucose enters hepatocytes it binds to and inhibits glycogen phosphorylase activity. The binding of free glucose stimulates the de-phosphorylation of phosphorylase thereby, inactivating it.

When blood glucose levels are low, the liver does not compete with other tissues for glucose since the extrahepatic uptake of glucose is stimulated in response to insulin. Conversely, when blood glucose levels are high extrahepatic needs are satisfied and the liver takes up glucose for conversion into glycogen for future needs.

Under conditions of high blood glucose, liver glucose levels will be high and the activity of glucokinase will be elevated. The G6P produced by glucokinase is rapidly converted to G1P by phosphoglucomutase, where it can then be incorporated into glycogen.

Regulation of Glucose Metabolism During Exercise Glucagon secretion increases during exercise to promote liver glycogen breakdown (glycogenolysis) Epinephrine and Norepinephrine further increase glycogenolysis Cortisol levels also increase during exercise for protein catabolism for later gluconeogenesis. Thyroxine promotes glucose catabolism

Regulation of Glucose Metabolism During Exercise Glucose uptake is enhanced by insulin. Exercise may enhance insulin’s binding to receptors on the muscle fiber. Up-regulation (receptors) occurs with insulin after 4 weeks of exercise to increase its sensitivity (diabetic importance).

HORMONAL REGULATION OF BLOOD GLUCOSE OTHER THAN GLUCAGON AND INSULIN:

1) Enhances gluconeogenesis; 2) Antagonizes Insulin. Hormone Tissue of Origin Metabolic Effect Effect on Blood Glucose insulin Pancreatic beta cells 1) Enhances entry of glucose into cells; 2) Enhances storage of glucose as glycogen, or conversion to fatty acids; 3) Enhances synthesis of fatty acids and proteins; 4) Suppresses breakdown of proteins into amino acids, of adipose tissue into free fatty acids. Lowers somatostatin Pancreatic D Cells 1) Suppresses glucagon release from α cells (acts locally); 2) Suppresses release of Insulin, Pituitary tropic hormones, gastrin and secretin Raises glucagon Pancreatic alpha cells 1) Enhances release of glucose from glycogen; 2) Enhances synthesis of glucose from amino acids epinephrine Adrenal medulla 1) Enhances release of glucose from glycogen; 2) Enhances release of fatty acids from adipose tissue. cortisol Adrenal cortex 1) Enhances gluconeogenesis; 2) Antagonizes Insulin. ACTH Anterior pituitary 1) Enhances release of cortisol; 2) Enhances release of fatty acids from adipose tissue. inhibiting uptake by extrahepatic tissues. Growth hormone Anterior pituitar Antagonizes Insulin, inhibiting uptake by extrahepatic tissues. thyroxine thyroid 1) Enhances release of glucose from glycogen; 2) Enhances absorption of sugars from intestine

Insulin Synthesis and Secretion Insulin is small protein, with a molecular weight of about 6000 Daltons. It is composed of two chains held together by disulfide bonds. The amino acid sequence is highly conserved, and insulin from one mammal almost certainly is biologically active in another. many diabetic patients are treated with insulin extracted from pig pancreas.

Biosynthesis of Insulin Insulin is synthesized in beta cells in the pancreas. The insulin mRNA is translated as a single chain precursor called preproinsulin, and removal of its signal peptide during insertion into the endoplasmic reticulum generates proinsulin.

Proinsulin consists of three domains: an amino-terminal B chain, a carboxy-terminal A chain and a connecting peptide in the middle known as the C peptide. Within the endoplasmic reticulum, proinsulin is exposed to several specific endopeptidases which excise the C peptide, thereby generating the mature form of insulin. Insulin and free C peptide are packaged in the Golgi into secretory granules which accumulate in the cytoplasm.

When the beta cell is appropriately stimulated, insulin is secreted from the cell by exocytosis and diffuses into islet capillary blood. C peptide is also secreted into blood, but has no known biological activity.

Control of Insulin Secretion Insulin is secreted in primarily in response to elevated blood glucose. Glucose is transported into the beta cell by facilitated diffusion through a glucose transporter; elevated concentrations of glucose in extracellular fluid lead to elevated concentrations of glucose within the beta cell.

Elevated concentrations of glucose → ↑influx of extracellular calcium → ↑exocytosis of insulin-containing secretory granules . Increased levels of glucose within beta cells also appears to activate calcium-independent pathways that participate in insulin secretion

Almost immediately after the infusion begins, plasma insulin levels increase dramatically. This initial increase is due to secretion of preformed insulin, which is soon significantly depleted. The secondary rise in insulin reflects the considerable amount of newly synthesized insulin that is released immediately. elevated glucose not only simulates insulin secretion, but also transcription of the insulin gene and translation of its mRNA.

The figure below depicts the effects on insulin secretion when enough glucose is infused to maintain blood levels two to three times the fasting level for an hour.

The Insulin Receptor and Mechanism of Action Like the receptors for other protein hormones, the receptor for insulin is embedded in the plasma membrane. The insulin receptor is composed of two alpha subunits and two beta subunits linked by disulfide bonds. The alpha chains are entirely extracellular and house insulin binding domains, while the linked beta chains penetrate through the plasma membrane.

The insulin receptor is a tyrosine kinase. Binding of insulin to the alpha subunits causes the beta subunits to phosphorylate themselves (autophosphorylation), thus activating the catalytic activity of the receptor. The activated receptor then phosphorylates a number of intracellular proteins, which in turn alters their activity, thereby generating a biological response.

Several intracellular proteins have been identified as phosphorylation substrates for the insulin receptor, the best-studied of which is insulin receptor substrate 1 or IRS-1. When IRS-1 is activated by phosphorylation, a lot of things happen. Among other things, IRS-1 serves as a type of docking center for recruitment and activation of other enzymes that ultimately mediate insulin's effects..

Glucagon is a linear peptide of 29 amino acids. Glucagon is synthesized as proglucagon and proteolytically processed to yield glucagon within alpha cells of the pancreatic islets.