Human Blood Glucose Control
▶Blood glucose norm
Blood glucose control is part of the energy management of the body and is a key homeostatic process. The normal blood glucose load is 4.5–6 mmol l–1 (80–110 mg 100 cm3). Following a high carbohydrate meal, the glucose load stays about the same; an overnight fast will lower it by only about 20%. Departures from the norm are severe in their effects:
● A decrease to less than 3 mmol l–1 leads to hypoglycemia, causing nausea, cold sweat, loss of concentration; coma follows resulting from inadequate fuel to the central nervous system (CNS).
● An increase to more than 9 mmol l–1 leads to hyperglycemia, producing acidosis, glycosurea and coma.
● Glycogen → glucose (glycogenolysis)
● Lactate, alanine, glycerol → glucose (gluconeogenesis) Fatty acids tend to be β-oxidized and fed into the tricarboxylic acid (TCA) cycle. A build-up of acetyl-coenzyme A (acetyl-CoA) from β-oxidation of fatty acids tends to lead to ketone-body formation; for example β-hydroxybutyrate. Excess ketones (e.g. in diabetes mellitus) lead to coma.
Digestion products are absorbed in the gut and carried to the liver. The pancreas near the liver is important for control. About 98% of pancreatic cells produce digestive enzymes, the remaining 2% of the cells, in the islets of Langerhans, produce controlling hormones. α cells make glucagon; β cells make
insulin; δ cells make somatostatin.
Insulin lowers the blood glucose load. Of the islet cells, 60% are β cells: these release insulin, a 51 amino acid polypeptide. Insulin is stored in islets cells in granules bound to zinc. It is released by exocytosis in response to blood with a high glucose load flowing through the pancreas. Autonomic innervation also leads to insulin release, as in anticipation of food or when food reaches the mouth and/or stomach. Calcium channels are activated by glucose (there is no insulin release in a Ca2+-free medium). Calcium binds to calmodulin which promotes fusion of the insulin-containing vesicles in the cell membrane and the secretion of insulin.
Insulin receptors are found on liver, fat and muscle cells. When insulin interacts with its receptors glycogenesis is stimulated, resulting in lowered blood glucose levels. Insulin prevents the conversion of active glycogen synthetase a to inactive glycogen synthetase b. (In obesity, levels of glucose and insulin are often both very high: tissues seem insensitive to insulin, perhaps due to reduced numbers of
receptors. Fasting can increase the number of insulin receptors.)
Glucagon antagonizes insulin by increasing the blood glucose load. α cells make up 25% of islet cells: these release glucagon, a 29 amino acid polypeptide. Glucagon is stimulated less by low glucose, more by stress, fasting or low insulin levels. In periods of low-glucose/high-glucose demand (e.g. exercise, cold), insulin levels are low and glucagon pulls glucose out of store.
It acts on liver cells, where glycogen phosphorylase is activated and glycogen synthetase deactivated. In the absence of insulin, fat and protein breakdown occurs, liberating fatty acids, glycerol and amino acids. Glucagon stimulates amino acid uptake by the liver and generally promotes gluconeogenesis. (Prolonged fasting leads to desensitization of liver cells to glucagon, preventing the continuous breakdown of fat and structural protein.)
Somatostatin is made by the hypothalamus and by islet δ cells: it inhibits growth hormone release. In the pancreas, somatostatin inhibits both insulin and glucagon, that is it has a paracrine (local intercellular messenger control) role. Glucagon release from α cells stimulates insulin release through activating cyclic adenosine monophosphate (cAMP) in β cells and promotes secretion of somatostatin by δ cells. Therefore, a tight feedback loop is used. Somatostatin probably prevents Ca2+ movement in α and β cells; thus the calcium-dependent release of glucagon and insulin is inhibited.
▶Other control systems
Autonomic nervous control
There are numerous nerve endings in the islets; noradrenaline (norepinephrine) stimulates glucagon secretion, acetylcholine stimulates insulin. Insulin and glucose receptors are found in the hypothalamus, a key area for temperature regulation and feeding/satiety control, so the hypothalamus commands the use or storage of glucose. Higher brain input is also important: the expectation of a meal elicits insulin secretion (feedforward); stress results in lowered insulin but raised glucagon levels. Nervous control overrides ‘lower’ local pancreatic controls.
Adrenaline (epinephrine) inhibits insulin, activates glycogen phosphorylase and promotes glycogen breakdown; glucocorticoids act on the liver to deactivate glycogen phosphorylase and to promote synthesis and preservation of glycogen.
Approximately 2% of humans have glucose control failures: a common failure is a high blood glucose load- Diabetes mellitus (e.g. >180 mg 100 cm–3) and glycosurea (glucose in urine).
There are various possible causes (i.e. a multiple etiology):
● Absence of β cells
● Insensitivity of β cells to glucose
● Overactivity of α cells
● Overactivity of δ cells
● Lack of insulin receptors on target cells
● Inability to store glycogen
● Supersensitive glucagon receptors
Two types of diabetes:
● Juvenile-onset, type I, insulin-dependent diabetes: onset is usually at less than 20 years old. People with this form of the disease respond to insulin treatment. They usually lack β cells. There is no glucose clearance, glycogenolysis is extensive and there is no check on glucagon. Fats are hydrolyzed, leading to free fatty acids which are converted to ketones (peardrop breath). Injections of insulin are indicated for treatment. Loss of β cells may be due to viral infections, or there may be an autoimmune etiology.
● Late-onset, type II, noninsulin-dependent diabetes. This is arguably an inherited condition. People with this form of the disease respond to glucose meals by insulin secretion, show no ketosis and have lowered levels of insulin receptors. Treatment is by controlling carbohydrate intake: insulin falls and β cells are receptive again. Autoantibodies to insulin receptors are possibly implicated.