Physiopath 7th lecture

Diabetes type 1 has an autoimmune and genetic pathogenesis but diabetes type 2 is related to
obesity or other types of pathogenesis, and the common cause is the deficiency of insulin.
In diabetes type 1 we have an absolute deficiency of insulin but in diabetes type 2 we have a
relative decrease in insulin with insulin resistance.

Effects of insulin on Glucid metabolism, proteins metabolism and lipids metabolism

Intracellular effects of insulin: insulin is a protein as well as a hormone, has a protein structure.
Insulin binds its specific receptors expressed on the cellular membranes.
Many cells/ many tissues have insulin receptors but the most important tissues expressing a large
number of insulin receptors are the hepatic tissue, adipose tissue and the skeletal muscle tissue.
The complex (insulin and its receptor) will be internalized because the membrane is able to form
a vesicle containing this complex and in, into the cell the receptor will be disconnected and will
be again reuse, while insulin will be processed into the cell!

The effects of insulin will be materialized because of 2ndary intracellular messengers.

Among them it seems that the most important is the cyclic GMP, insulin stimulates the cGMP
and inhibits the cAMP, and to these 2ndary messengers insulin has some effects stimulating

some protein kinase systems (protein kinase modulates phosphorylation and DEphosphorylation
processes).
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Another important effect of the insulin receptor complex is the delivery of calcium from
submembrane structures.

Another effect is inhibition done by insulin over the phosphorylase.

Another effect is the stimulation of membrane sodium potassium ATPase.

The effects on the Glucid metabolism:

Usually the normal effects of insulin:
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Insulin stimulates the glucose entrance into the cell because insulin stimulates
hexokinases.
Another activity of insulin is that the insulin stimulates the intracellular metabolization of
glucose by activating glycolysis, activating and stimulating krebs cycle, and insulin
increases the activity of the phosphate pentose shunt,
So because of this activation of the pentose phosphate shunt insulin will stimulate the
production of ribose used in nucleic acid synthesis and the production of NADPH
necessary for fatty acids and cholesterol synthesis.

Insulin stimulates Glycogenesis in the hepatic cell.

Insulin is an anabolic hormone stimulating in general, synthesis of proteins and other
forms of lipids and other forms of storages
So the storage form of glucose is the glycogen, and insulin stimulates the glycogen
synthase and synthesis.

Insulin inhibits glycogenolysis.

Insulin can stimulate glycogen synthesis, inhibit glycogen breakdown
So all these activities produce hypoglycemia and in the condition of insulin deficiency all
these effects will be inversed leading to hyperglycemia.

RENAL THRESHOLD: the level of blood glucose is high in which kidneys fail to reabsorb, and thus spill glucose
into urine!!

If hyperglycemia reaches renal threshold , which is over 180 mg/deciliter that means that the
reabsorption of the glucose in the proximal tubule will be overpassed so we will have glucose
urea, and glucose is an osmotic substance which means itll attract water !!!
And so we will have:

Polyuria
Dehydration (loss of water): if we have extracellular dehydration usually its hypertonic
because sodium remains in high concentration in the extracellular space.
To this hyper tonicity the hyperglycemia also participates so we will have hypernatremia
(results when there is a net water loss or a sodium gain) and hyperglycemia BUT we
know from the movement disturbances in hydro electrolyte balance, that if we have
hypertonic dehydration the water tends to get out from the cells and the effects of these
movements will be:

Partially compensation of the extracellular dehydration but in turn we will have also intracellular
dehydration , intracellular dehydration at the level of the neuronal centers like thirst center will
stimulate the thirst center and the behavior will be changed so the patient will have Polydipsia
(drink water to compensate the water loss) .
In the same time because of insulin deficiency entrance of glucose into the cells decreases, the
nervous cells from the hunger center are insulin dependent (use glucose) .
usually in the nervous cells enter free but in those cells of the hunger centers the glucose is
insulin dependent so if we have insulin def. the glucose entrance into the hunger center is
decreased so these cells will stimulate the huger sensation and the behavior will be changed into
polyphagia.
So we will have polyphagia polyuria and polydipsia.

The effects of insulin def. on the protein metabolism:

Usually insulin stimulates the protein synthesis directly or indirectly
-

Directly insulin stimulates the RNA and DNA polymerases so will stimulate
decodification of the nucleic acids to the protein synthesis ,
Indirectly insulin stimulates ribose production and NADPH because of the pentose
phosphate shunt and in turn ribose will participate to the nucleic acid synthesis.
Other insulin activity is that insulin facilitates the binds formation in the protein
structures.
Insulin activates some transcription factors.
Insulin stimulates Krebs cycle so will offer the energetic support for synthesis in general.

In the same time it inhibits the degradation of proteins by decreasing the activity of
lysosomal enzymes (anabolic effect on the protein metabolism)
But in conditions of insulin def. all these processes will be inversed:
The protein catabolism will be enhanced and the phenomena of tissue repair / recovery
will be impaired
The immunoglobulin synthesis also will be impaired so we have reasons for high
susceptibility to infections and the other consequences.
Enhanced catabolism/ increased urea / increased uric acid and increased creatinine in
plasma.

In the lipid metabolism:

Normally facts of insulin:
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Insulin stimulates the synthesis of fatty acids because insulin stimulates the activity of the
K enzyme. This enzyme stimulates pre FA synthesis and the synthesis of cholesterol by
stimulating the hydroxyl methyl glutamine reductase.
Insulin has an effect on the synthesis of triglyceride, and synthesis of apoproteins in the
hepatic cells.
VLDL is the most important lipoprotein synthesized in the liver cells.
in the same time also in the hepatic cell, insulin decreases the beta oxidation of the fatty
acids because it inhibits the acylcarnitine transferase which is the enzyme responsible of
the FA transfer from the cytoplasm into the mitochondria and in the mitochondria the free
FA are beta oxidized so insulin inhibits this activity .
Another effect of insulin in the adipose tissue: insulin decreases the activity of the
hormone sensitive lipase so in this way decreases the lipolysis and favorizes the lipid
storage in adipose tissue.
Which is the activity of the lipoprotein lipase?
The VLDL become circulating lipoproteins they r transporting triglycerides because they
have large amount of triglycerides in their structure so the triglycerides from the VLDL
will be hydrolyzed by lipoprotein lipase in the endothelial cell resulting in FA and
glycerol.
The glycerol will go back into the circulation because the adipose cells have no enzymes
for glycerol metabolization but fatty acids are used in the synthesis of lipid in the adipose
tissue.
SO insulin stimulates the synthesis of lipoproteins in the hepatic cells and favorizes the
storages of the lipids in the adipose tissue.

In condition of insulin deficiency the apoproteins synthesis will be decreased, the triglyceride
synthesis will be decreased and ofc the VLDL will be decreased.
BUT in plasma we have high triglyceride and high cholesterol concentrations because
apoproteins are produced and arrive the circulation and because of insulin deficiency the activity
of lipoprotein lipase will be decreased and the capacity of metabolization of VLDL will be
decreased.
So they are remaining in the circulation increasing cholesterolemia and triglyceridemia.
In the adipose tissue because of insulin deficiency, the lipase activity will be increased so
there will be hydrolysis of the lipid storage resulting in large amounts of fatty acids that arrive in
circulation (they are arriving in the liver but they are not used in fatty acids synthesis because we
have insulin deficiency) so whats happening with this large amount of FAs In conditions of
insulin deficiency??
These fatty acids will arrive in mitochondria because acylcarnitine transferase isnt inhibited in
insulin lack and in the mitochondria these fatty acids will be transferred into acetyl CoA by beta
oxidation.
In normal conditions Acetyl CoA could be used in the synthesis of:
-

Free fatty acids

Cholesterol
In krebs cycle

But in condition of insulin deficiency these three metabolic pathways are inhibited so we will
have acetyl CoA accumulation and so acetyl CoA will be condensed forming ketone bodies.
Three forms of ketone bodies are involved: hydroxybutyric acids, acetoacetic acid and
acetone (eliminated through the respiration & smells like apples, but the others 2 are strong
organic acids so they will increase the concentration of hydrogen ions producing metabolic
acidosis which is another effect of this disturbance of lipid metabolism)
We have an excess of Acetyl CoA so we have an excess of triglycerides and cholesterol in
the liver because the syntheses of apoproteins is depressed!
AGAIN this increase of triglycerides and cholesterol in the hepatic cell is because of the
apoproteins deficiency, the triglyceride and the cholesterol cannot be mobilized in the
circulation.
Liver steatosis: accumulation of fat in the liver .

Synthesis of the VLDL is impaired despite this phenomenon we have hyperlipoproteinemia.

different hyperlipoproteinemia in diabetes mellitus why? Because lipoproteins are not enough
metabolized because of the def. of lipoprotein lipase.
So it will increase the risk of atherogenesis due to this hyperlipoproteinemia.

The complications of diabetes mellitus:

We distinguish two different types of complications in diabetes mellitus acute and chronic.
We have acute complications for diabetes mellitus type 1 and acute complications for diabetes
mellitus type 2.
First: the most important complication in diabetes mellitus type 1 is the diabetic ketoacidosis
with its final extreme severe form which is comma ketoacidosis why does it happen?
In diabetes mellitus type 1 we have an absolute deficiency of insulin (very severe deficiency of
insulin) so the lipid metabolism will be very disturbed and we have high mobilization of free FA
from adipose tissue they are arriving in the hepatic cell / in plasma.
In the hepatic cells the free FAs are not used in the three normal metabolic pathways mentioned
before so ketone bodies will be produced & these ketone bodies over production will lead to their
accumulation.

Which is the favorizing factors deriving to ketoacidosis in a diabetic patient and which are the
pathophysiological consequences of this kind of acidosis?
First favourizing Factor: first of all a diabetic patient receiving proper treatment could be
destabilized in aggression, and we saw in the shock etiology, important aggression produces a
discharge of stress hormones like catecholamines & ACTH, all these hormones have antagonic
effects comparing to insulin.
Some medicines could enhance the insulin deficiency and increase the insulin resistance.
If we stopped insulin treatment in diabetic patients, complications occurs:
Increased lipolysis and ofc ketogenesis (accumulation of ketone bodies).
Which are the consequences? Accumulation of organic strong acids means increased hydrogen
ion concentration and so a low PH which are operating in this case in buffer systems.
Bicarbonate will be consumed in the buffering process because of the decreased PH which will
stimulate the respiratory system so we have high bicarbonate, hyperventilation, thats why
patients with this situation have tachypnea and Kussmaul respiration.
Kussmaul respirations or Kussmaul breathing is the abnormal breathing pattern observed in patients suffering from
metabolic acidosis, diabetic ketoacidosis or some other medical condition which causes hyperventilation (a
breathing pattern which involves reduction of carbon dioxide in blood due to increased rate or depth of breathing).

Buffering hyperventilation is a possibility to maintain the PH.

Another important compensation mechanism is the renal excretion of hydrogen ions.
We can add the 2ndary hyperaldosteronism because usually we have low acid base disturbance
separated without hydroelectolyte disturbance!
We have also hydroelectolyte disturbance because the patient will have polyuria so this patient
has hypertonic dehydration and if theres dehydration the renin angiotensin aldosterone
mechanism is stimulated so the reabsorption of sodium and water will be stimulated.
Whats happening with sodium? the concentration of natrium (Natrium is the Latin name of
sodium) will be increased hypotonic dehydration we lose water & the glucose remains at high
level so we have hyperglycemia in DM type 1 (hyperglycemia could be over
400 milligrams/deciliter until 1000 mg/deciliters in severe cases) so sodium will be increased but
sodium concentration could be diluted by the hyperglycemia because glucose in high
concentration attracts water from the cells so not only extracellular dehydration but also
intracellular dehydration .
Whats happening with potassium? Potassium because of metabolic acidosis has a tendency to
get out from the cell in an exchange with hydrogen ion so the concentration of potassium in
plasma will decrease!
Here we have two consequences:

One of them will act on the cells forming electric potential and using this electric
potential, like nephric cells/ cardiac cells and /neuromuscular structures so we will have
extracellular hyperpotassemia and decrease in intracellular potassium this imbalance
will produce muscular weakness and will affect the nervous cell function and will affect
the cardiac cell function .
weakness in the muscular cell will result in general weakness but most important is the
weakness in the digestive structures( occlusion vomiting) these disturbances in
digestion with losing other liquids and electrolytes by intestinal occlusion and vomiting
will aggravate the hydroelectolyte disturbance and finally the metabolic acidosis and the
accumulation of ketone bodies could become decompensated and can affect directly by
the hydrogen ions concentration, the function of the nervous cell,
But associating this hydroelectolyte disturbance is cellular dehydration hypernatremia
and hyper kalemia!

All of them will affect the nervous cell function and the electrogenic processes of the nervous
cell and all of them lead into the extreme form of ketoacidosis.
When the PH decreases under 7.2 coma occurs!

Its interesting for the potassium that the most important disturbance is hyper Kalemia but in
general the potassium is decreased why? Because potassium is lost from the kidney in the
compensation of acidosis process and also in the 2ndray aldosteronemeia so we have a
hyperkalemia with an imbalance between and intracellular and extracellular spaces.
The natremia (The presence of sodium in the blood) could be increased but dont forget the
dilution effect of hyperglycemia. So when you measure the natremia in such kind of patients you
have to take in account that that natremia could be diluted in this severe hyperglycemia so we
have to take care and evaluate the entire content of sodium ofc.
And dont forget that the absolute deficiency of insulin inhibits in fact the sodium potassium
ATPase.

In DM type 1 the principal acute complication is ketoacidosis ofc associated with

hypotonic dehydration.
In DM type 2 we have another type of acute complication we have no ketoacidosis, the
usual acute complication of DM2 is the hyperosmolar comma without ketoacidosis.
Theres hyperglycemia contributing to hyperosmolarity and maybe hypernatremia due to
water loss.

Why we dont have ketoacidosis? because the insulin deficiency isnt so severe (its a relative
insulin deficiency), and we have another component of insulin resistance so its enough insulin
to not accumulate acetyl CoA into the liver and to not produce ketone bodies and to produce a
metabolic acidosis by this way .
So in DM2 the most important mechanism deriving to such an acute complication is
dehydration/polyuria the osmotic polyuria/losing water and producing a hypertonic dehydration
with obligatory increased natremia.
Hyperglycemia isnt so severe in DM type 1, in DM type 2 hyperglycemia could arrive to 500600mg/dL
Obligatory increased natrium (sodium) and again potassium could be hyperpotassemia with loss
of potassium to the kidney!
We have extracellular hypertonic dehydration now this dehydration will affect the nervous cell
producing intracellular dehydration! Remember if we have a loss of water from extracellular
space and this space remains hypertonic the water will be partially transferred from the
intracellular to the extracellular space so we will have also intracellular dehydration!! And
nervous cells are sensitive to dehydration! Hypernatremia and hyperpotassemia will affect the
cell functioning and so leading to comma!
and another thing, dehydration ( loss of water) and we have hypovolemia and peripheral
vasoconstriction and ofc ischemia in these conditions and if we have ischemia it means we have

high production of lactic acid so we also have a decrease of metabolic acidosis also in
hyperosmolar components but this metabolic acidosis is lactic acidosis not ketone acidosis .
The effects of acidosis: when the acidosis is decompensated, metabolic acidosis will affect the
vessels responsiveness to vasoconstrictor factors & will affect the myocardium contractility and
ofc will affect the nervous cell function.
So hyperosmolar comma we saw that hyperglycemia is around or over 500, we know that insulin
deficiency is relative and the hyperosmolarity is done by hyperglycemia and hypernatremia
could associate lactic acidosis and lets see the favourizing factors!
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The favourizing factors could be important aggression stabilizing the balance between
endogenous insulin treatments so diabetes which could be equilibrated by the treatment
can be disturbed by an important aggression because important aggression could
stimulate the delivery of stress hormones.

Other possibilities is that the patient doesnt respect anymore the diet (ingests Glucids or
can make a change on the medication).

Chronic complications of DM!

Chronic complications are those which occur over a longer period of time and involve changes in
blood vessels, tissue and organs. Persistent hyperglycemia damages blood vessels which may
lead to many disorders, such as cardiovascular and cerebrovascular disease. Damage to blood
vessels within the eye can result in diabetic retinopathy and ultimately blindness. Pathological
changes within the kidneys cause diabetic nephropathy and kidney failure, while damage to
peripheral nervous tissue will ultimately lead to diabetic neuropathy (A combination of vascular
and neurological damage can result in erectile dysfunction).
Usually the chronic complications are consequences of diabetic angiopathy and we distinguish
two types of diabetic angiopathy macro and microangiopathy!
Macroangiopathy involving the great vessels and microangiopathy involving the small vessels!
Macroangiopathy has 3 pathogenic mechanisms:
We saw hyperigyleridemia/ hypercholesterolemia because of the imbalance done by the insulin
deficiency.
We saw disturbance in the lipoprotein synthesis with cholesterol and triglyceride accumulation in
the liver, they cannot be delivered in this form in plasma. Some lipoproteins are produced but
these lipoproteins with high concentration of triglyceride and may be high concentration of

glucose cannot be metabolized & cannot be taken by the endothelial cells because lipoprotein
lipase is inhibited.
And in this condition we have a low level of low density lipoproteins containing high quantities
of cholesterol and cholesterol will be taken in excess in the endothelial cell but isnt used,
cholesterol will overload the endothelial cells and the endothelial cells will become bigger and
rigid so the vessel wall will be more rigid and more fragile in the same time. The blood flow
varying so these rigid walls can be injured because of these variations.

Another important activity is done by the triglycerides, the VLDL degradation and triglycerides
degradation results in high quantities of lysolecithin which is cytotoxic so rigidity and
cytotoxicity favorizes micro lesions on the vessel wall and if we have micro lesions we will have
inflammation and coagulation.
LDL could arrive through micro lesions in the sub-endothelial spaces and here the perivascular
macrophages can be activated because already inflammation has occurred and can give
cytokines/ growth factors and free oxygen radicals,
LDL accumulated here can be oxidized and easily bound by macrophages so they become more
atherogenious!
The cytokines /GF the free oxygen radicals delivered by the macrophages will affect the
structures of the vessel wall favourizing proliferation, increasing wall thickness and finally
favourizing atherogenesis.
You can add thrombocyct formation and decreased lumen of the vessel.
Another process for macroangiopathy is the glycosylation of the structural proteins in conditions
of long term hyperglycemia, the non-enzymatic glycosylation of the proteins becomes
irreversible because theres a physiological glycosylation of proteins ,usually at normal
concentrations of glycaemia the glycosylation is reversible but in conditions of long term and
severe hyperglycemia the proteins will be glycosylated and will remain like stable products and
these advanced glycosylated products are named advanced glycation end products .
We are interested about structural proteins and the most important is the collagen.
Collagen glycosylation will produce a decrease in its elasticity! Glycogen will become more
rigid and will participate in the rigidity of all affected vessel walls.
Theres also a glycosylation of the LDL because LDL contains proteins and not only the proteins
from the vessel wall will be glycosylated also some proteins in plasma! Glycosylated LDL has
another effect, they can establish covalent binds with sub endothelial matrix proteins and they
will stimulate the clotting cascade!

Another effect of LDL which is both glycosylated and oxidized is that it could be chemotactic
hormone?
Chemotactic means attraction but also activation of monocytes attracted out of the vessel and
become macrophages and they are also activated so they are entering in inflammation.
And another process for macroangiopathy is done because glucose enters in the endothelial cells
of these walls freely but the metabolization of glucose in these cells is insulin dependent, we
have insulin deficiency so whats happening with this glucose? Glucose will take some
metabolic pathways -insulin independent - and these pathways are two which are the polyol
pathway and the glucuronic acid pathway!
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Polyol pathway: The glucose is metabolized into polyhydric alcohols so insulin

independent. Because of insulin deficiency two enzymes are activated sorbitol
dehydrogenase and aldose reductase and because of these two enzymes the glucose will
be metabolized to sorbitol and fructose and these are two polyhydric alcohols (polions)!

In insulin def. this pathway is hyperactive and these two alcohols are non-diffusible to the
membranes! They are produced in high quantities into the cell, they remain here they cannot be
metabolized further and they are osmotic molecules they are attracting water!
So the cells are becoming hyperhydrated and the final process will lead to Hydropic degeneration
(Acute cellular swelling, Cloudy Swelling) and finally cellular death.
-

And the 2nd pathway for insulin independent metabolization of the glucose is the glucoric
acid pathway.

Glucoronic acid resulted from the glucose metabolism will participate in the synthesis of
mucopolysaccharides and mucopolysaccharides in the vessel wall structure will participate to the
rigidity and to the thickness and ofc atherogenesis so by clinical point of view, diabetic
macroangiopathy will be manifested through ischemical disease because these vessels with
thicker walls will have a decreased lumen and so we have ischemic heart disease / arterial
hypertension / peripheral ischemia / cerebral ischemia !

Whats happening in diabetic microangiopathy:

in the small vessels, endothelial cells will use glucose entering in metabolic pathways (insulin
independent) and in here the pathway which is used is a glucuronic acid pathway (no polyol
pathway) because these cells dont have the enzyme sorbitol dehydrogenase!
Only Glucoronic acid pathway forming mucopolysaccharides and these mucopolysaccharides
contributes to the rigidity and thickness of the vessel wall.

Another process here is the glycosylation of the structural proteins, the glycosylation of the
collagen and the glycosylation of the extracellular matrix proteins this glycosylation will
modify the elasticity of these proteins increasing the rigidity and thickness of the vessel wall and
decreasing the vessel wall lumen , these processes will favorize micro lesion injuries ofc
favorizing inflammation and coagulation micro thrombosis / these micro thrombosis could
obstruct these small vessels producing small necrosis.
And finally the thought mechanism of microangiopathy is the glycosylation of the hemoglobin
(this isnt a structural protein its a circular protein) but hemoglobin is important for the oxygen
transport!
Glycosylated hemoglobin has a high affinity for oxygen so the delivery for oxygen to tissues will
be decreased again why? Again hypoxia and ischemia because of insulin deficiency theres
decreased glycolysis and decreased 2-3D phosphoglycerate.
Increased affinity means that oxygen will not be easily delivered into the tissue so we have
oxygen saturation for hemoglobin but the tissue has no oxygen so ischemia.
The ischemic phenomena in the micro thrombosis obstruction in different tissues will offer the
possibility of micro infarcts/micro necrosis and this microangiopathy will have by clinical point
of view some important THINGS:
First diabetic renal pathway.
Diabetic glomerulosclerosis deriving to renal failure and associating arterial hypertension and
finally diabetic neuropathy because this microangiopathy affects vasa vasorum (small vessels
vascularizing the nerves).
The Hydropic degeneration affects not only the cells in the big arteries affects also the cells in
the crystalline so the diabetics could have cataracts and affecting also the Schwann cells
surrounding the nerves so this is another contribution to diabetic neuropathy.
Diabetic neuropathy is somatic affecting the proprioceptic susceptibility and especially in the
inferior Limbs but can be also visceral, this is very important because can produce GI paresis/
can affect not only by paresis but also affect the motility of the GI tube.
Can produce cardiovascular modifications like tachycardia, orthostatic hypotension.
Can produce urinary symptoms because of the control of the urinary bladder sphincter, can
produce sexual dysfunction especially for males.