· 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.
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
promotes the storage of energy, the synthesis of glycogen, mRNA and proteins.
major tissues (kidney, brain and intestine) are insensitive to the direct
action of insulin.
· 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
· 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.
secretion is a release of signal molecules to
antagonists are hormones opposing the effect of
insulin: Pancreatic and intestinal (glicentin) glucagon, ACTH, growth hormone.
diabetes mellitus refers to all cases, where the
cause is not fully explained.
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
· Somatostatin (GHIH) is a multipotent hormone inhibitor
consisting of a disulphide bridge and 14 amino acid units.
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.
Glucose regulation in the fed state
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
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
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.
Glucose regulation in the fasting state (rest and exercise)
keep our blood [glucose] surprisingly constant around the fasting level,
considering the wide variety of daily activities.
production (gluconeogenesis and glycogenolysis)
must equal glucose combustion in the
fasting state. Thus, a precise relation must exist between the secretion of
insulin and glucagon from the pancreatic islets.
In the fasting state hepatic glycogenolysis produces most of the glucose and the remaining glucose is produced by gluconeogenesis. Hepatic glucose is produced by glycogenolysis (glycogen breakdown to glucose) and by gluconeogenesis (glucose formation from glycogenic amino acids, lactate, glycerol, and
small amounts of pyruvate. Muscle glycogen cannot deliver glucose to the
blood, since muscle tissues lack glucose-6-phosphatase.
In the fasting condition a healthy adult has
a blood [glucose] of 4.5-5.6 mM.
With an average [glucose] of 4 mM in 15 l of extracellular fluid volume (ECV),
therefore, the total glucose content in ECV is 60 mmol or 10.8 g (2 teaspoons
of sugar). This amount is equal to the glucose eliminated in one hour at rest
(60 mmol each hour), but during maximum exercise that same person may use five times more glucose.
The CNS and the erythrocytes neither
synthesise nor store glucose, which is their primary fuel. Any surplus of
glucose is deposited as liver and muscle glycogen.
The liver cells contain an especially efficient
glucose transporter (GLUT 2), and its glucose
uptake rate cannot be increased further by insulin or by other hormones.
Any small fall in blood glucose releases more glucagon. During fasting glycogenolysis,
gluconeogenesis, and lipolysis are dominant. If a normal person does not
eat for 24-48 hours the CNS cells revert to combustion of ketone bodies, and a
reversible condition that is similar to diabetes develops (hunger
The exercise stress on the hypothalamus
increases the activity of the sympathoadrenergic
system, which includes increased secretion of adrenaline from the adrenal
medulla. Sympathoadrenergic activity inhibits the insulin secretion from the b-cells.
Sympathetic activity also increases hepatic glucose production.
We tend to increase glucagon secretion only
if the blood [glucose] falls. A slight fall in blood [glucose] can occur both
during exercise bouts and during prolonged exercise.
During exercise the blood [glucose] is
maintained rather constant by bihormonal interplay between insulin and glucagon.
Generally, an increasing demand of more
energy elicits increased glycogenolysis, lipolysis, and increased
gluconeogenesis caused by insulin-antagonistic hormones (catecholamines,
glucagon, cortisol, and growth hormone).
Adrenaline inhibits the insulin and
stimulates the glucagon secretion, so the blood [glucose] increases.
Somatotropin ‑ human growth hormone (GH) ‑ is an insulin-antagonist, but together with insulin probably the most important anabolic hormone.
Conditions where energy sources are lacking
are hypoglycaemia, hunger, fasting state, exhaustion, and stress. These
conditions trigger the release of GRH from the hypothalamus, which in turn
stimulates the release of GH from the hypophysis. This hormone has a tropic
effect on the a -cells of the pancreatic islets. GH releases glucagon from these cells, just
as sympathetic stimulation from the hypothalamus does.
GH increases blood [glucose] by increasing hepatic
glucose production (glycogenolysis but not its gluconeogenesis) and by
inhibiting the insulin sensitivity of the muscle cells and thus reduces their
glucose uptake. GH also has the same effect on fat cells, mobilising fatty
acids and glycerol. GH stimulates protein synthesis, mitoses, chondrogenesis,
ossification, and phosphate balance, while increasing glycolysis (ie,
anaerobic breakdown of glycogen).
Glucocorticoids are insulin-antagonists. They stimulate the hepatic
glucose production (glycogenolysis and gluconeogenesis) but inhibit the
cellular glucose uptake. Glucocorticoids are permissive and potentiating for
catecholamines and glucagon.
Catecholamines (adrenaline & noradrenaline) are insulin-antagonists. Adrenaline stimulates
hepatic glucose production (glycogenolysis). Catecholamines also stimulate
lipolysis. The increase in mitochondrial oxygen uptake by T3/T4 is potentates by catecholamines.
sensitive neurons in the hypothalamus (the glucostatic
centre) react to hypoglycaemia by releasing glucagon from the pancreatic a-cells
and catecholamines from the adrenal medulla by action of the sympathetic
The glucostatic centre also reacts to
hyperglycaemia to release insulin from pancreatic b-cells,
and to activate hepatic glycogen synthesis by vagal stimuli. Insulin promotes
the entry of glucose into tissues, including the neurons of the hypothalamic
glucostatic centre (but in no other brain neurons). A balanced blood [glucose]
is achieved by sympathetic signals stimulating hepatic glucose production.
This balance theory is called the glucostatic theory. In the glucostatic
theory the hypothalamus is considered a glucostat and the liver is a unique
glucose exchanger, due to the portal system and the hepatic
glucose-6-phosphatase. Leptin is dealt with in Chapter
Since the hypophysis
hormones ACTH and GH are insulin-antagonists the net effect of the hypophysis,
when not balanced by a normal pancreatic insulin secretion, is a reduced
3. The endocrine pancreas
The endocrine pancreas or the pancreatic
islets are synonyms for the production site of four polypeptide hormones:
Glucagon, insulin, somatostatin, and pancreatic polypeptide (PP).
The one million islets of Langerhans are
discrete structures scattered throughout the pancreas, but which only comprise
1% of its total weight. The islets are arranged along fenestrated capillaries,
so that the hormones can pass easily to the portal blood. The islets of
Langerhans receive both sympathetic (adrenergic) and parasympathetic
The membranes of the islet cells contain gap
junctions between neighbour cells, so hormones from one cell can act on its
neighbour (paracrine action). Gap junctions allow passage of small molecules
from one islet cell to its neighbour. In many pancreatic lobules, the a - b - and d - cells form a paracrine syncytium.
3 a. Glucagon
The a-cells of the pancreatic islets is the source
of pancreatic glucagon. Glucagon stimulates adenylcyclase in the hepatocytes.
This enzyme activates phosphorylase that breaks down glycogen. Actually,
glucagon triggers a glycogenolytic cascade, so those considerable amounts of
glucose are released in response to the fall in blood glucose. In addition,
glucagon stimulates the hepatic production of glucose (gluconeogenesis) from
glycerol, alanine and lactate. Glucagon is a direct antagonist to insulin,
being catabolic in its actions (gluconeogenetic, glycogenolytic, lipolytic
& ketogenic, and deaminating amino acids).
Intestinal glucagon (glicentin) is built up
from 69 amino acids. The glucagon from the a-cells
of the pancreatic islets only contains 29 of the 160 amino acid residues in
pro-glucagon. Conditions where there is intracellular lack of glucose (hunger,
insulin deficiency, protein rich meals, and amino acid infusion) liberate
glucagon from the a-cells
of the pancreatic islets to the pancreatic vein and then to the portal vein.
Glucagon stimulates ketogenesis (formation of ketone bodies). High blood
[glucose] and [FFA] inhibit glucagon secretion.
Pancreatic and intestinal
(glicentin) glucagon are hepatic insulin-antagonist. Glucagon stimulates
hepatic glucose production by glycogenolysis in the hepatocytes and thus
increases the blood [glucose].
Glucagon also stimulates gluconeogenesis
from glycogenic amino acids in the liver and thus increases urea-genesis.
Glucagon stimulates ketogenesis (formation of ketone bodies). In addition to
the ketogenic effect, intestinal glucagon is a potent stimulator of insulin
secretion - as are other members of the incretin family. Incretins act by
increasing cAMP in the b-cells.
3 b. Insulin
Banting shared the Nobel Prize with Macleod
in 1923 for their work in identifying the role of insulin in the carbohydrate
metabolism. Their research led to the practice of insulin therapy for
Pre-proinsulin is the precursor of insulin.
When pre‑proinsulin reaches the endoplasmic reticulum, enzymes separate
the molecule from the signal molecule, to form proinsulin. In the Golgi
apparatus enzymes cleave proinsulin to insulin (51 amino acids in two chains:
A and B) and the C peptide (Connecting peptide). Insulin and C peptide are
wrapped in the same secretion granule. The content of these secretion granules
is expelled from the cell by exocytosis.
the secretory granules release proinsulin to the portal blood and later the
extracellular fluid volume (ECV), connecting peptide (C-peptide) and two amino
acids breaks off. The split products are carried to the liver, where half of
the insulin molecules are degraded and extracted. The degradation products are
broken down and eliminated by the kidney. The kidneys only eliminate c-peptide
and its rate of production reflects the rate of insulin secretion. Insulin
contains 51 amino acid residues in two chains (m.w. 5734).
healthy persons the blood glucose concentration, B-[glucose],
is controlled exactly. The fasting value is within the range of 4-7 mM, with
minimum individual variance from day to day, despite varying life conditions
with food and exercise.
The liver is a glucose exchanger, because it
absorbs glucose from the intestine, stores glucose as glycogen, and produce
glucose from fat and protein residues (gluconeogenesis). The liver releases
glucose to the ECV in exact proportion to the peripheral rate of glucose
utilisation in the postabsorptive state (180-200 g per day).
The brain metabolism of a healthy standard
person requires 100 g of glucose per day. The brain glucose is totally oxidised, ir-regardless of the insulin
Each meal elicits a peak of insulin
secretion, because of the rise in blood [glucose] (Fig. 27-1). The blood [glucose] increases after a meal. Increasing
[glucose] is a strong stimulus to the b-cells of the pancreas. Glucose enters these
cells through GLUT 2. The cells empty their granules into the ECV, and the
granule dissolve immediately after entering the blood. This sequence of events
supplies the blood with insulin, C-peptide and proinsulin in the ratio
Insulin reduces the blood glucose for the
following reasons: insulin increases the cell uptake of glucose (and
potassium) in most tissues (adipocytes, heart and other muscle tissue). The
exceptions are the brain, kidney and erythrocytes. The uptake capacity for
glucose in hepatocytes is so large, that any insulin effect is immaterial.
Insulin promotes the formation of tissue stores from
circulating nutrients (the actions are all anabolic). The insulin receptor is
a tetrameric protein complex with two a-units
extracellularly, and two b-units
traversing the membrane of target cells (ie, skeletal muscle fibres, cardiac
myocytes and adipocytes). The target cells contain the glucose transporter,
GLUT-4. In the absence of insulin, all the GLUT-4 units are located in the
intracellular vesicles. Insulin binding to the insulin-receptor activates the
tyrosine kinase, which resides in the b-units,
and promotes the transport of GLUT-4 vesicles towards the surface of the cell,
where they melt together with the membrane. This phenomenon increases the
number of glucose-channels through the membrane and thus promotes glucose
uptake into target cells. Finally, the insulin-receptor complex is
internalised by the cell, insulin is broken down and the insulin-receptor
recycles to the cell surface for further use.
Glucose is stored in the muscle cells as glycogen, used in the
Krebs cycle or it is broken down to lactate.
In the fat cells glucose is utilised as a
substrate for triglycerides synthesis. In the post-prandial phase, lipolysis
liberates fatty acids (FFA) from triglyceride together with glycerol. Glycerol
and lactate are substrates for hepatic gluconeogenesis.
27-1: Effects of insulin on target cells.
Falling blood [glucose] is called hypoglycaemia, which activates the sympathoadrenergic system and
deplete the glucose-dependent brain for its only fuel. Accordingly, the
hypoglycaemia causes sympathoadrenergic (sweating, hunger, tremor,
tachycardia), and cerebral manifestations (anxiety, disorientation, cramps,
and unconsciousness). The clinical picture is that of hypoglycaemic shock.
Insulin also increases the rate of glycogen
synthesis in the liver and muscles and inhibits the rate of gluconeogenesis.
Insulin is a direct antagonist to glucagon being anabolic in its actions
(increased glucose entry to cells, increased glycogen and lipid synthesis,
decreased protein catabolism and ketogenesis).
Glucose-evoked insulin secretion is the
result of a chain of events in the pancreatic b-cell
27-2: Insulin release from pancreatic b-cell.
1. The glucose uptake takes place through a specific transporter protein
(GLUT-2). The pancreatic b-cell
membrane contains several K+ channels, of which two are directly
involved. This is the K+-ATP channel and the maxi-K+ channel (Fig. 27-2).
2. The hyperglycaemia accelerates the glucose uptake and metabolism and
thus increases the ATP/ADP ratio.
3. Increased ATP closes the K+-ATP channels, so the cell
depolarises (hypopolarises). During hypopolarisation from the normal resting
membrane potential of -70 mV, a threshold is reached at - 50 mV, where the
voltage dependent Ca2+ channels open.
4. The Ca2+ influx triggers exocytosis of insulin and C-peptide
containing granules following vesicular fusion with the cell membrane.
5. Normally, the maxi-K+ channel and other K+ channels stop
depolarisation. When intracellular [Ca2+] and [K+] has
increased, it opens the maxi-K+ channel. The K+ efflux
restores the resting membrane potential (- 70 mV) towards the equilibrium
potential of K+ (-100 mV).
Insulin is a vital hormone. Blood from the
pancreas passes through the liver, where insulin promotes the production of
glycogen from the recently absorbed glucose. The liver destroys a substantial
amount of the insulin, whereas the C-peptide passes the liver undisturbed. The
plasma [C-peptide] is thus a good estimate of insulin secretion. Insulin can
now be synthesized from genetically modified micro-organisms.
Insulin is an anabolic hormone.
Insulin reduces the blood [glucose] because
it increases glycogen synthesis in the liver and muscles. Insulin increases
the uptake of glucose through GLUT 4 (in adipocytes, heart and skeletal
muscles). Insulin inhibits the gluconeogenesis from glycogenic amino acids in
Insulin promotes the storage of energy, the
synthesis of glycogen, mRNA and proteins. Insulin thus reduces urea-genesis.
Insulin promotes lipogenesis in the fat
stores; however, it inhibits lipolysis. It may be noted that the glycerol
portion of the triglyceride molecule is a derivative of glucose.
Insulin increases the synthesis of
cholesterol in the liver, in particular the rate of VLDL formation (Very Low
Density Lipoprotein). The dangerous cholesterol fraction is LDL (Low Density
Insulin increases the GLUT 4 transfer of
glucose and K+ into the muscle cell interior.
Certain major tissues (kidney, brain, and
intestine) are insensitive to the direct action of insulin.
3 c. Somatostatin
D-cells or d-cells
are the source of somatostatin, a potent and multipotent hormone inhibitor.
Somatostatin contains a disulphide bridge and 14 amino acid molecules.
Somatostatin produced in the islets inhibits the local secretion of the other
islet hormones, while glucagon stimulates the local release of insulin and
somatostatin. Somatostatin is also produced in the hypothalamus, where it
functions as the Growth Hormone Inhibiting Hormone (GHIH). Pancreatic
somatostatin is released in response to high blood [glucose] and [alanine].
Somatostatin inhibits the secretion of the gastrointestinal tract (but not its
motility) and functions as a synaptic transmitter in the CNS. Persons with
somatostatin-producing tumours develop diabetes and gallstones.
GHIH is synthesized both in the
hypothalamic-pituitary system and in the pancreatic islets. The D-cells of the
pancreatic islets of Langerhans produce GHIH, which controls the function of
the other islet cells by paracrine action. Somatostatin is a multipotent
hormone inhibitor. Somatostatin inhibits Somatotropin (GH) but also TSH,
insulin, and glucagon. Somatostatin blocks the gastrin secretion in the
gastric antrum. Somatostatin inhibits the secretion of digestive fluids, but
increases gastrointestinal motility.
3 d. Pancreatic polypeptide
The cells responsible for pancreatic
polypeptide (PP) secretion are particularly abundant in the head of the
pancreas. PP contains 36 amino acid residues in a linear polypeptide. The
plasma [PP] increase markedly after a protein rich meal, but it is not
released by alanine infusion. The PP secretion is increased by exercise (with
high plasma [alanine]), by fasting and by hyperglycaemia. The plasma [PP] is
suppressed by glucose infusion. PP inhibits the exocrine pancreas and reduces
the gallbladder contractions. This is an appropriate response during exercise
and fasting, where any reduction in blood glucose would trigger a PP release.
Meals, rich in protein and fat, release
pancreatic polypeptides (from the PP-cells).
Pancreatic polypeptide inhibits both enzyme
secretions from the pancreas and the emptying of bile into the small
intestine. This leads to a delay in the absorption of nutrients including
Patients with pancreatic islet cell neoplasm
have elevated plasma [PP].
4. Pancreatic exocrine control
Endocrine glandular tissue is localised in
the Langerhans islets that produces insulin in the b-cells,
glucagon in the a-cells,
somatostatin (GHIH) plus gastrin from the d-
and G-cells, and pancreatic polypeptide (PP) from the P-cells (Fig.
Bombesin, galanin, and neuropeptides are present in pancreatic neurons and act
Stimulation of vagal fibres to the pancreas
enhances the rate of enzyme secretion into the pancreatic juice. Stimulation
of sympathetic fibres reduces bloodflow to the pancreas, and thus inhibits
pancreatic secretion. Gastrin enhances enzyme secretion and insulin
potentiates the effect, whereas somatostatin inhibits secretion from both
acinar and ducts cells (Fig. 27-3: - all).
27-3: Liberation of pancreatic islet hormones.
Diabetes mellitus (DM)
DM is a collective term for a multitude of
metabolic disorders, where lack of insulin (type I diabetes) or insulin
resistance (type II) dominates.
resistance is defined as insufficient
sensitivity to insulin.
The diabetic condition is characterized by
an abnormal glucose tolerance that is documented by the use of a glucose
Besides hyperglycaemia, the overall
phenomena in the diabetic condition are protein
depletion and increased lipolysis with
deposition of lipids in the vascular walls of the brain, heart, kidneys, eyes
All cases of DM where the cause is not fully
explained are termed primary DM,
whereas secondary DM is explainable
and sometimes directly curable.
Secondary DM is caused by hypersecretion of
one or more of the many catabolic hormones with hyperglycaemic effect
(adrenaline, noradrenaline, glucagon, glucocorticoids and growth-hormone, HG)
or by total destruction of the pancreas from pancreatitis or carcinoma. The
hormone disorders are phaeochromocytoma, glucagonoma, Cushing’s syndrome and
Most of the patients with primary DM can be
classified into the two groups already presented above Insulin-Dependent DM
(IDDM) or type I diabetes, and Non-Insulin-Dependent DM (NIDDM) or type II
This paragraph deals with 1.
IDDM, 2. NIDDM, 3.
Insulin shock (hypoglycaemia), 4.
Oral and intrveneous glucose tolerance tests, 5.
treatment of diabetes mellitus, and 6.
Summary of the diabetic condition.
1. IDDM or Type I diabetes
The presentation of IDDM
is typically a young person with a few week history. This is a serious, life
threatening metabolic disease, where continuation of life depends upon insulin
treatment. The first treatment with insulin took place in Canada (1922). Until
then these patients died within half a year in ketoacidotic coma. Persons,
often with hereditary predisposition, are suddenly attacked by autoimmune
destruction of all b-cells
in the pancreatic islets, which results in the complete absence of insulin.
This autoimmune destruction occurs more often in populations, where breast
feeding is unpopular, and protein-rich cow's milk is used generally.
Lack of insulin leads to extracellular
hyperglycaemia, and increased lipolysis.
The classical triad is:
1. Polyuria (osmotic diuresis due to extracellular
hyperglycaemia and glucosuria).
2. Polydipsia and thirst due to the loss of salt and
3. Weightless due to extracellular fluid volume (ECV)
depletion and the breakdown of tissue stores (ie catabolic effect of insulin
deficiency) with rapid wasting.
The intracellular lack of glucose activates
glycogenolysis in the liver and muscle cells; lipolysis and muscular
proteolysis is accelerated. The liberated free fatty acids (FFA) are converted
to ketone bodies, whereby a metabolic acidosis (ketoacidosis) is produced.
A patient with a blood (glucose) above 25 mM
loses consciousness and to such degrees that contact is impossible and
reactions to pain are absent (coma).
Diabetic ketoacidosis is a condition of
insulin deficiency causing increased hepatic ketogenesis. This condition of
uncontrolled catabolism occurs in IDDM, only.
In a young person, the first sign of IDDM
can be coma with diabetic ketoacidosis - a life-threatening condition, if the
patient is alone. This is particularly likely, when the patient is under the
stress of intercurrent illness such as infection with high fever. Also a
recognized IDDM patient can be hit by ketoacidosis during intercurrent
illness, where his insulin demand is increased, or the patient may take too
little insulin because of lost appetite or for any other reason.
deficiency has two consequences. First of all,
the hepatic glucose release accelerates, and secondly the uptake of glucose by
muscle and fat cells in the periphery is reduced. Progressive hyperglycaemia
causes osmotic diuresis with loss of salt and water. The abnormally low ECV is
termed the dehydrate state, and with falling blood volume also renal bloodflow
falls. Insulin deficiency also accelerates the lipolysis (Fig. 27-4).
27-4: The development of ketoacidosis during insulin deficiency (FFA = free
Triglycerides are liberated from adipose
tissue, and the concentration of free fatty acids (FFA) in the blood is
elevated. FFA are broken down to fatty acyl carnitine within the liver cells,
and this molecule is converted to acetyl CoA, which in turn reach the
mitochondria, where ketone bodies (aceto-acetate, acetone, b-hydroxybutyrate)
are formed (Fig. 27-4).
The breath of the patient smell by acetone,
and there is ketosis in the urine. The concentration of ketone bodies in the
blood passes 5 mM, and when pH falls
below 7, there is life-threatening or terminal coma. The condition is called
an acute metabolic acidosis, characterized by a negative base excess. The
patient tries to compensate the metabolic acidosis by hyperventilation,
Most patients with recent IDDM have
circulating antibodies to islet cells, and tend to develop other
organ-specific autoimmune disorders (Addison disease, Hashimotos thyroiditis
and pernicious anaemia). Identical twins show a 40% concordance in developing
IDDM, so life-style must also play a role. There is an association with
HLA-DR4, if also HLA-B8 or HLA-DR3 is present.
2. NIDDM or Type II diabetes
This is a frequent type of DM in particular
in populations with a sedentary life style and obesity. The incidence
increases with age and development of obesity, which is reflected in the name maturity-onset
diabetes. The prevalence is high in Afro-Caribbean and Asian population
groups. The onset of NIDDM is sometimes triggered by Intercurrent illness or
by pregnancy, but not by immunological reactions.
NIDDM is a complex of
polygenic disorders. Certain families show an autosomal dominance. the genetic
defects differ and many mutations are known. One is the gene on chromosome 7,
which code for glucokinase. Identical twins show almost absolute concordance in development of NIDDM.
The much more frequent type II diabetes (maturity-onset)
is the result of insulin resistance and b-cell
defects. Type II diabetes also occurs in younger persons, especially in
persons with a high fat-low muscle mass.
A strong genetic element is always present, but inactivity and stress (an inactive life
style with a low endurance capacity) seems to be involved in the development
of type II diabetes. - Lack of exercise predisposes one to obesity, a
condition that greatly decreases insulin
sensitivity of the target cells (adipocytes, heart and skeletal muscle
tissues). Reduced glucose combustion creates hyperglycaemia. The
hyperglycaemia elicits insulin secretion from defective b-cells
in some patients, resulting in raised serum [insulin]. Since insulin is
present, the acute complications such as ketonaemia and metabolic acidaemia
(often found with IDDM) are rare in these patients. The high serum [insulin]
may further down-regulate the activity of their insulin receptors. The insulin secreted in NIDDM patients does not
increase the uptake of glucose as in normal persons. Many NIDDM patients need
much more insulin for a given test effects than IDDM patients and healthy
An inactive life style for years, with
redundant food intake, seems to be involved in the development of NIDDM in
persons with a genetic predisposition. Lack of regular physical activity with
development of overweight, increases the incidence if NIDDM. The impaired
glucose tolerance is demonstrated by a glucose
The insulin secretion is abnormal in
patients with NIDDM, although they typically possess half of their b-cell
mass at autopsy. The destroyed b-cells
is filled with amyloid material (islet amyloid polypeptide, IAPP). IAPP is a
possible antagonist to insulin, and explain some cases of insulin
Many older patients with NIDDM have no
symptoms, but a routine examination reveals glucosuria or a raised blood [glucose].
Other patients are tired, have minor genital infections or sugar spots on
their underwear. Some patients present with established late-complications such as retinopathy (blindness), nephropathy, arteriosclerotic disorders
(cerebrovascular insults, myocardial infarction, intermittent claudication,
gangrene), susceptibility to infection or neuropathy.
NIDDM can be caused, theoretically, by 1. b-cell
defects including genetic defects, resulting in
abnormal insulin production, or by 2.
target cell defects including receptor failure. The possible defective
sites in 1. and 2. have one common denominator. They are all key
proteins (hormone, receptors and transporters). Muscular activity is
required to stimulate the normal production of key
proteins. NIDDM relates to inactive life style.
The basic problem is therefore possibly a
genetically and activity dependent defect
in key protein production in the cell interior. Actually, a genetic defect
has just been demonstrated at certain steps of insulin action in a subset of
patients of late-onset NIDDM.
3. Insulin shock (hypoglycaemia)
A high blood [insulin] will cause tissues to
store away the available blood glucose rapidly, mainly through muscular GLUT
4, and stop simultaneously the production of new glucose.
A low blood glucose level elicits a large
secretion of glucagon to the portal blood. Glucagon is the most important
insulin-antagonist. Glucagon increases hepatic glucose production (enhancing
glycogenolysis, gluconeogenesis and protein breakdown). Low glucose levels
trigger glucagon production, even from denervated, pancreatic a-
cells; hence, they must be glucose sensitive.
An increased catecholamine secretion from
sympathetic nerve endings (NA) and Ad from the adrenal medulla (elicited from
the hypothalamic glucostat via the sympathetic nervous system) helps within
minutes to compensate, as catecholamines stimulate glycogenolysis, increase
lipolysis and inhibit peripheral glucose uptake. Hours later, cortisol and GH
also contribute. An appropriate rise of plasma [cortisol] in response to
insulin-induced hyperglycaemia documents an intact CRH-ACTH-adrenal axis, and
this is the most widely used stress test.
Adrenergic effects, such as trembling
fingers, tachycardia, and muscular stiffness warn the hypoglycaemic patient.
The glucose consumption by the heart and brain continues. The lack of glucose
in the brain makes the patient uneasy at first; he is then insecure, anxious
and has cold sweat. Later in hypoglycaemia, the patient becomes confused,
furious and denies with slurred speech to take glucose.
Blood [glucose] below 2.5 mM elicits
hypoglycaemic shock with loss of consciousness (somnolence, sopor or coma),
universal cramps and respiratory stop (Fig. 27-5).
Intravenous injection of glucose (50%) is
the rational therapy for hypoglycaemic coma. The patients wake up almost
immediately, and are then often in a hyperglycaemic state.
27-5: Consequences of hypoglycaemic shock.
The b-cell defects are insufficiently described.
Type 2 diabetics do not produce sufficient levels of ATP in the pancreatic b-cells
to completely block the K+ -ATP channels (Fig.
27-2). Thus, the b-cell
does not hypopolarize adequately in response to hyperglycaemia. Therefore, the
voltage dependent Ca2+ -channels is insufficiently activated, and
intracellular [Ca2+] do not increase enough to trigger the insulin
exocytosis needed. Sulfonylurea compounds close the K+-ATP-channels
and thus help to treat type 2 diabetes.
4. Oral and intravenous glucose
The test is performed orally or
test. The patient drinks a glucose solution
containing 75 g glucose within four minutes (WHO). The blood concentration in
venous plasma ([glucose]) is followed over 3 hours by blood sampling.
Normal individuals start from a low fasting
[glucose] such as 5.5 mM or less.
The blood [glucose] peaks after one hour and returns
to normal within two hours (less than 6.7 mM in Fig. 27-5). Persons with impaired
glucose tolerance start with a fasting level less than 7.8 mM, and after 2
hours the level is 7.8-11.1 mM.
27-5: Oral glucose tolerance curves for a normal person, a diabetic, a patient
with hyperthyroidism and a patient with myxoedema.
patient typically starts from a high fasting [glucose], such as values
above 7.8 mM, and increase to a very high level. The blood [glucose] is not
back to normal within two hours, but stays above 11.1 mM. This test pattern is
the clinical WHO criterion of diabetes (Fig. 27-5).
A patient with hyperthyroidism (Graves
disease or Morbus Basedowii) has a rapid intestinal absorption and a rapid
combustion of glucose. The myxoedematous patient has a slow absorption and a
slow combustion of glucose.
27-6: Results of i.v. glucose tolerance tests from a normal person and from a
(i.v.) test. We inject 25 g glucose intravenously over a
period of 4 minutes. We then measure the blood [glucose] every 10 min for at
least an hour in order to determine the half-life from a semi-logarithmic plot
(Fig. 27-6). The metabolic combustion rate for glucose is exponential, so it
is easy to calculate the metabolic rate constant (k) expressed in percentages.
Note that the metabolic rate constant k here is the amount of glucose combusted
divided by the total amount of glucose in a mainly extracellular distribution
volume. The half-life (T1/2) is equal to 0.693/k.
All glucose combustion rates above
1.2% per min are normal.
27-7: Intravenous Glucose Tolerance Test
5. Treatment of diabetes mellitus
A normal person with three meals per day
will have three peak concentrations
of glucose and insulin in his blood. It is possible to obtain such a time
profile in a diabetic person by the following strategy. Inject a fast‑acting
insulin three times a day just before meals and a slow‑acting insulin at
night. This is the physiologic principle.
The aim of this procedure is to reduce the number of acute and chronic
complications for diabetics.
All diabetics are recommended to eat healthy
just like anyone else. When diet alone is insufficient to achieve a
satisfactory blood glucose, a slim type II diabetic is treated with
sulphonylurea compounds. The obese type II diabetic is treated with a
biguanide called metformin. Patients, who have been in metabolic acidosis, are
usually treated best with insulin.
6. Summary of the diabetic condition
A poorly controlled diabetic condition leads
to extracellular hyperglycaemia, glucosuria, metabolic acidosis, polyuria
(osmotic diuresis), dehydration and polydipsia. The osmotic diuresis leads to
the excretion of Na+ and water, which results in Na+ and
Intracellular lack of glucose activates
glycogenolysis in the liver and muscles, and accelerates muscular proteolysis
and lipolysis. This liberates free fatty acids, which are converted to ketone
A patient with hyperglycaemia above 25 mM
loses consciousness to such a degree that contact is impossible (ie, coma).
The increased rate of cholesterol production
increases the occurrence of atherosclerosis and of diabetic nephropathy.
Albuminuria, hypertension and low GFR characterise diabetic nephropathy.
Multiple Choice Questions
I. Each of the following five statements
have True/False options:
A. Peptides and
protein hormones are lipophobic.
B. Infertility is a
diagnosis used on a couple, which have been unable to conceive during one year of unprotected intercourse.
hypoadrenalism is also called Addison’s disease.
D. Nephrogenic diabetes insipidus, is a condition where the renal cells
are resistant to ADH.
E. Glycerol and
lactate are substrates for hepatic gluconeogenesis.
II. Each of the following five statements have
A. Receptors are frequently glycosylated, so one signal molecule linked to
a receptor is always enough to elicit a response.
B. The incidence of
atherosclerosis is correlated to the total [cholesterol],
and the [LDL]/ [HDL] ratio in blood plasma.
exercise, nicotinic acid and alcohol increase the plasma-HDL.
stimulates the luminal gastric proton-pump.
are primarily paracrine hormones, which act through receptors linked to
Case History A
19 year old male, body weight 80 kg, was
suddenly complaining of fever during his work and ordered home to bed. The
patient was living alone. Fortunately a colleague visited him the next
morning. He had to break the door down and found the patient unconscious. The
patient arrived at the hospital in deep coma. A blood sample from the radial
artery showed the following results: b-cell
antibodies, PaCO2 27 mmHg, pH 7.21, actual bicarbonate 10.5 mM, O2 saturation 0.96
and [glucose] 32 mM (5.75 g/L). The Base Excess is -15 mM in the extracellular fluid volume
(see Fig. 17-12). The urine
contained glucose and ketone bodies.
patient's breathing was deep and fast, his heart rate was 115 beats/min, and
his blood pressure was 90/55 mmHg. The mucous membranes of the mouth were dry
and the tonsils were enlarged and infected. The rectal temperature was 39.9
the condition of the patient concerning thermo-balance, carbohydrate
metabolism, acid-base balance and fluid balance.
a rational treatment of the four homeostatic disturbances mentioned in 1.
eight hours of treatment the blood pH was 7.41 and PaCO2 42
mmHg, but the patient is still hyperventilating. Explain why.
24 hours of treatment all blood gas values were normal and the patient was
resituated. Why did the patient stop to hyperventilate?
Case History B
female of 49 years and with a
height of 1.52 m is in hospital due to obesity and related problems. Her
weight is 74 kg. She has developed skin mycoses and multiple boils. In the
morning (fasting state) a blood sample shows a blood [glucose] of 7.4 mM, but
glucose is not found in the urine.
the hospital her total body water is measured following intravenous injection
of radioactive water (5.5 × 107 Becquerel or Bq tritium water). Her bladder is emptied at the
time of injection. Two hours later the bladder is drained for 95 ml of urine
with a concentration of 1 598 400 Bq per l.
this time the indicator is evenly distributed in the total body water with a
concentration of 1 520 700 Bq per l. The amount of indicator lost in the urine
is 2/3 of the total loss.
1. What is the principle
for estimation of total body water?
2. Calculate the total body
water in litres and in fraction of her body weight.
3. Is this a normal result?
4. The patient is obese,
but is this a serious overweight?
5. Does she have symptoms
and signs of complications?
Case History C
23-year old male was saved after 30 days in the ruins of a house following
earth quake. There was no food but sufficient water. At the arrival to the
hospital the patient was in syncope with frequent, deep respiration, and the
expired air smelled of acetone. The skin was dirty with brown pigmentation.
The cardiac rate was 85 bpm, and the arterial blood pressure was 11.3/7.3 kPa
blood [glucose] was 2.2 mM, and the plasma [FFA] was increased. The serum concentrations of proteins and essential amino acids
were reduced. The blood [haemoglobin] was 95 g l-1. There was moderate antidiuresis with ketonuria with
signs of water retention and a high nitrogen loss in the urine.
patient was treated with parenteral administration of glucose, amino acids and
electrolytes. Following the glucose intake, the blood [glucose] was increased to 10 mM, and glucosuria occurred. A glucose tolerance
test was performed and resulted in a high blood [glucose] level that had not reached the normal level within 2 hours.
the energetic events leading to survival.
did the patient smell of acetone?
happened to the carbohydrate metabolism of the patient?
the high nitrogen loss in the urine.
· 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.
· Somatotropin ‑
human growth hormone (GH) ‑ is an insulin-antagonist, but together with
insulin probably the most important anabolic hormone.
· Glucose sensitive
neurons in the hypothalamus (the glucostatic centre) react to hypoglycaemia by
releasing glucagon from the pancreatic a-cells
and catecholamines from the adrenal medulla by action of the sympathetic
· Since the hypophysis
hormones ACTH and GH are insulin-antagonists the net effect of the hypophysis,
when not balanced by a normal pancreatic insulin secretion, is a reduced
· The endocrine
pancreas or the pancreatic islets are synonyms for the production site of
four polypeptide hormones: Glucagon, insulin, somatostatin, and pancreatic
· Insulin is
synthesized as proinsulin, which is stored in granules close to the cell
membrane of the b-cells
of the pancreatic islets. When the secretory granules release proinsulin to
the portal blood and later the extracellular fluid volume, connecting peptide
(C-peptide) and two amino acids breaks off.
· A poorly controlled
diabetic condition leads to extracellular hyperglycaemia, glucosuria,
metabolic acidosis, polyuria (osmotic diuresis), dehydration and polydipsia.
The osmotic diuresis leads to the excretion of Na+ and water, which
results in Na+ and ECV depletion.
· Intracellular lack of
glucose activates glycogenolysis in the liver and muscles, and accelerates
muscular proteolysis and lipolysis. This liberates free fatty acids, which are
converted to ketone bodies.
· A patient with
hyperglycaemia above 25 mM loses consciousness to such a degree that contact
is impossible (ie, coma).
· The increased rate of
cholesterol production increases the occurrence of atherosclerosis and of
hypertension and low glomerular filtration rate characterise diabetic
K., C. Bjørbæk, H. Vestergaard, T. Hansen, S. Echwald, and O. Pedersen.
"Aminoacid polymorphisms of insulin receptor substrate-1 in
non-insulin-dependent diabetes mellitus." The Lancet 342: 828-832, 1993.
F.M. and S.J.H. Ashcroft. "Insulin." IRL
Press at Oxford Univ. Press, Oxford 1992.
F.G. and C. H. Best. "Internal secretion of pancreas." J.
Lab. and Clin. Med. 7: 251-326, 1922.
P.R. "Nutrient regulation of insulin secretion." Portland
Press Ltd., London 1991.