Blood Glucose And Diabetes:

Study Objectives

· To define glicentin, gluconeogenesis, glycogenolysis, glycolysis, hyperglycaemia, hypoglycaemia, incretins, insulin antagonists, paracrine secretion, primary and secondary diabetes mellitus.

· To describe the structural and functional characteristics of the Langerhans islets with cell types and hormones produced. To describe the incretin effect, insulin effects, the insulin receptor, and the glucose transporter. To describe disorders of the different cell types and their clinical picture. To describe methods for evaluation of the glucose combustion.

· To draw oral and intravenous glucose tolerance curves with linear and logarithmic ordinates for blood glucose concentration.

· To explain the biosynthesis and the effects of insulin, glucagon, pancreatic polypeptide (PP) and somatostatin. To explain the glucose metabolism and the control of blood glucose in the fed and the fasting state. To explain the consequences and the therapy of high and low blood glucose disorders.

· To use the above concepts in problem solving and in case histories.

Principles

· The physiological principle in treatment of diabetes is to inject a fast-acting insulin three times a day just before meals and a slow-acting insulin at night.

· Insulin promotes the storage of energy, the synthesis of glycogen, mRNA and proteins.

· Certain major tissues (kidney, brain and intestine) are insensitive to the direct action of insulin.

Definitions

· Glicentin is intestinal glucagon. Glicentin is built up from 69 amino acids in contrast to pancreatic glucagon, which consists of 29 amino acid moieties.

· Gluconeogenesis refers to formation of new glucose from glycogenic amino acids, lactate, glycerol and pyruvate.

· Glycogenolysis refers to glycogen breakdown to glucose in the liver.

· Glycolysis refers to anaerobic breakdown of glycogen.

· Hyperglycaemia is a condition, where the blood glucose is above 6.7 mM.

· Hypoglycaemia refers to a serious condition, where the blood glucose is below 2 mM.

· Incretins are hormones, which strongly potentiates the insulin secretion induced by the rising blood [glucose]. The incretins cause a much larger insulin secretion than the iv. administration of glucose, even at the same rise in blood [glucose]. This extra insulin secretion is called the incretin effect.

· Ketogenesis refers to accelerated lipolysis with liberation of free fatty acids to the blood. Free fatty acids are broken down to fatty acyl carnitine within the liver cells, and this molecule is converted into acetyl CoA, which in turn reach the mitochondria, where ketone bodies are formed.

· Paracrine secretion is a release of signal molecules to neighbour cells.

· Insulin antagonists are hormones opposing the effect of insulin: Pancreatic and intestinal (glicentin) glucagon, ACTH, growth hormone.

· Primary diabetes mellitus refers to all cases, where the cause is not fully explained.

· Secondary diabetes mellitus is caused by hypersecretion of one or more of the many catabolic hormones with hyperglycaemic effect (adrenaline, noradrenaline, glucagon, glucocorticoids and growth hormone) or by total destruction of the pancreas from pancreatitis or carcinoma. The hormone disorders are phaeochromocytoma, glucagonoma, Cushing’s syndrome and acromegaly.

· Somatostatin (GHIH) is a multipotent hormone inhibitor consisting of a disulphide bridge and 14 amino acid units.

Essentials

This paragraph covers 1. the blood glucose regulation in the fed state, as well as in 2. the fasting states. Also 3. The endocrine pancreas, and 4. Pancreatic exocrine control is dealt with.

1. Glucose regulation in the fed state

In the absorptive state after a balanced meal, nutrients enter the blood and lymph from the gastrointestinal tract (as monosaccharides, triglycerides, and amino acids). All the blood passes directly to the liver, which converts most of the other monosaccharides into glucose. Much of the absorbed carbohydrate enters the liver cells, but little of it is oxidised; instead most is stored as glycogen. Absorbed glucose, which did not enter hepatocytes but remained in the blood, is stored as glycogen by muscle cells, or it may enter into adipose tissue. A large fraction is oxidised to CO2 and water in the various cells of the body. Glucose is the major source of energy during the absorptive state. Homeostatic mechanisms maintain the plasma [glucose] within narrow limits in healthy humans, so that the energy needs during the postabsorptive state can be met by stored fuel.

A high glucose intake results in a high blood [glucose] or extracellular hyperglycaemia. Hyperglycaemia increases insulin secretion from the b-cells and inhibits glucagon secretion from the a-cells of the pancreatic islets. These hormones block hepatic glucose production by glycogenolysis and gluconeogenesis. Insulin secretion dominates over all insulin-antagonists (growth hormone, glucagon, cortisol and some catecholamines).

The sight and the smell of a meal triggers cephalic insulin secretion. When the meal reaches the intestine, several peptides of the incretin family are released; this is the intestinal secretion phase. Typical representatives of the incretin family are Gastric Inhibitory Peptide (GIP), glicentin (intestinal glucagon), and glucagon-like peptides (GLP-1 and -2). Incretins strongly potentate the insulin secretion induced by the rising blood [glucose]. The incretins cause a much larger insulin secretion than the iv. administration of glucose, even at the same rise in blood [glucose]. This extra insulin secretion is called the incretin effect. The insulin released following a meal increases the storage rate of glucose-related energy in the liver, muscles and fat tissues. The storage effect is much larger than when glucose is administered intravenously.

Glucose is absorbed through the luminal membrane of the intestinal cells in glucose-Na+ transporter proteins. The two substances pass through the basolateral membrane via separate routes: Glucose passes in a special glucose-transporter, and Na+ is transferred by the Na+-K+‑pump. Glucose transport proteins and insulin receptors are described in Chapter 1.

The filtration flux for glucose (mmol per min) increases proportionally to the concentration in the blood (as for all other filtered substances). Normally, all glucose is reabsorbed in the first part of the proximal renal tubules with a Tmax of 1.8 mmol per min or 320 mg per min.

In other words, the passage fraction falls from one to zero already halfway through the proximal tubules. The excretion flux for glucose is zero in healthy humans.

Glucose appears in the urine of diabetics, who have a blood [glucose] exceeding the appearance thres­hold (10 mM).

Reabsorption of glucose over the luminal membrane of the proximal tubule cell takes place through the glucose-Na+ transporter.

2. Glucose regulation in the fasting state (rest and exercise)

We keep our blood [glucose] surprisingly constant around the fasting level, considering the wide variety of daily activities.

Glucose production (gluconeo