Diabetes Mellitus Modern View
Chronic metabolic disorder characterised by hyperglycemia
with or without glycosuria, resulting from an absolute or relative degeneration
of insulin. Brought about by impairement of insulin production or its release
by beta cells of islets of langerhans.
Pancreas
The endocrine component of the pancreas consists of
different types of cells, alpha cells, beta cells, delta cells, PP cells,
contained in the islets of langerhans which constitute 1 % of its weight .
There are 100,000 islets in the pancreas and each islets contain 1000-3000
cells. Thus altogether there are 100-300 million beta cells in the pancreas.
Pancreatic beta cells can store 200 units of insulin and can release 30-50
units of insulin per day. 95% of pancreas have exocrine function and 5% have
endocrine function. Beta cells secrete insulin, Alpha cells secrete glucagon,
Delta cells secrete somatostatin and PP cells secrete pancreatic polypeptide.
Etiopathogenesis of Type I Diabetes
HLA Assoc iations
Type 1 diabetes is a heterogenous disorder in which several
factors may play a role. Those are HLA system, viral infections and auto immune
process. Type 1 tends to be familial disorder and there is a 25 fold
increase and in the risk among siblings
than the general population. Its inheritance is related to HLA B8, B15, B6,
B21, BW3, DR3 and DR4 are associated with a higher risk of DM.
Infections
Coxsackie B4 has been incriminated toplay a causal role in
the pathogenesis of type 1 DM. The other viruses known to play a role are
mumps, CMV, EBV, varicella and the viruses causing infective hepatitis.
Auto antibodies in Type1 DM
These are the antibodies produced against certain antigens
of the beta cells. They have not been found to have any etiological role in
type 1 diabetes, but mainly serve as , markers of type 1 diabetes.
Type 2 DM
Type 2 DM is considered as a multifactorial or complex
disease due to the complex interaction between various genetic and
environmental factors in its pathogenesis. Agenetic predisposition running
through families is evident. In genetically predisposed individuals several
environmental factors precipitate the onset of diabetes. Important among those
are obesity, physical inactivity, repeated pregnancies, infections, physical or
psychological stress and diabetogenic drugs. Birth of large babies weighing
above 4 kg is a strong pointer to the subsequent development of diabetes in the
mother.
Role of insulin antagonists
Glucose metabolism is delicately balanced by the cordinated
effects of insulin antagonist hormones like glucagon, cortisol, catecholamines
and growth hormones. Fatty acids which compete with carbohydrates for
metabolism in muscle lead to insulin resistance. In hyperlipidaemia insulin
dependant carbohydrate metaboilsm sufferers and a relative insulin resistance
develops.
Amylin
Amylin is normally produced by beta cells and co secreted
with insulin. This amylin has favourable metabolic effects in normal healthy
individuals. But due to several reasons it gets deposited as insoluble fibres
in the islets of patients with type 2 diabetes.
Insulin
This is the hormone produced by the beta cells of the islets
of langerhans and is composed of a alpha polypeptide chains a and b linked
together by two disulphide bonds. The precursor of insulin is pro-insulin from
which c-peptide is broken off to form insulin with a molecular weight of 6000
daltons. Insulin stored in the granules of the beta cells to be discharged into
interstitial fluid under appropriate stimulus. Insulin secreted by the beta cells
evter the portal circulation and liver traps 50-60% . The remaining portion
enters peripheral circulation. This can be estimated as immuno reactive insulin
IRI. Basal values to IRI in healthy is 2-20 Uu/ml.
Since C-peptide is secreted in equimolar quantities with
insulin its level can be estimated to access the functioning beta cell reserve.
The main stimulus for insulin secretion and release in hyperglycaemia caused by
ingestion of carbohydrates . Other stimulus includes rise in amino acids
produced by protein digestion, growth hormones, glucagons, gastrin,
pancreozymin, secretin and several other gut hormones especially gastric
inhibitory polypeptide. Substances having this property are listed as
incretins.
On the target cells insulin bind to specific surface
receptors and then initiates further biochemical events within the cells. The
insulin receptors are large molecular weight proteins which mediate insulin
action. Insulin retards gluconeogenesis in the liver. Insulin helps to build up
adipose tissue by aiding the conversion of glucose into fat and blocks the
escape of fatty acids from fat cells. In conjunction with growth hormones,
insulin enhances the incorporation of amino acids into peptides in the liver
and skeletal muscles.
Pathological Changes
In type 2 DM during the early phase the beta cells are
normal in number only slightly reduced. The beta cells lose their sensitivity
to the hyperglycaemic stimulus for releasing insulin. As a result insulin
secretion loses its smooth and fine relationship with glucose level. It tenda
to be erratic.
Insulin resistance in muscle develops early in persons who
would develop type 2 diabetes later. Beta cell function starts deteriorating
about 10 years before the onset of DM, by which time the beta cell function has
fallen to 30% or less.
Vascular Changes
Diabetes show a predisposition to develop vascular lesions
affecting both small and large blood vessels. In micro angiopathy there is
specific involvement of small blood vessels, venular cappillaries, and
arterioles are affected in this process.
Glycosylation of several proteins in the vessel wall results
in increased permeability . The basement membrane is thickened. Ultimately
there is vascular occlusion.Various factors like endothelial damage, increased
plasma viscosity, erythrocyte aggregation, reduced red cell deformability and
increased platelet adhesion lead to mmicroangiopathy. The problem is more
complex and the entire process is still not fully understood. Microangiopathy
affects several other systems. The main lesions are seen in the retina,
kidneys, peripheral nerves, and heart giving rise to diabetic retinopathy,
diabetic nephropathy and many forms of diabetic neuropathy and cardiomyopathy.
Macroangiopathy
The diabetic is prone to develop occlusive disease in medium
sized arteries such as coronary arteries, cerebral and peripheral limb vessels.
These lesions lead to increased risk of ischaemic heart disease , cerebro
vascular accidents and ischaemia to the limbs with intermittent claudication
and peripheral gangrene. It accounts for the steep rise in mortality in middle
aged diabetes.
Retinopathy
The early changes are venous dilation and the appearance of
small clot like micro aneurysms in the peri macular area. Arterial blood is
shunted and this leads to ischemia of retina. Increased vascular permeability
accounts for the formation of exudates. In the next stage dot and blot
hemorrhages and vitreous hemorrhages may develop and vision is seriously
impaired.
As these hemorrhages are absorbed organisation by fibrous
tissue results and multiple bands of retinitis proliferans develop. These lead
to permanent visual impairement. The fibrous bands may contract giving rise to
retinal detachment. Retinopathy is usually associated with nephropathy.
Sometimes in diabetic ketoacidosis with severe hyperlipidemia the fat gives a
milky white appearance to the retinal arteries called “lipemia retinalis”.
Renal lesions
Commonly seen in subjects who have had diabetes over 15-20
yrs. Vascular changes include,
1.arteriosclerosis of renal artery
2.sclerosis of the arterioles
3.glomerulosclerosis
There is thickening of glomerular cappillary basement
membrane. The establishment of glomerular sclerosis is indicated by the
prescence of proteinuria. Further damage to glomeruli results in the
development of chronic renal failure. In initial stages, asymptomatic micro
albumin uria in which upto 200mcg/minute of albumin may be lost in the urine.
In type 1 DM there is elevation of systolic blood pressure
during sleep preceding micro albuminuria. This rise in BP is an important
contributory factor in the developmant of structural changes in the kidneys. It
is absolutely necessary to control bp also with blood sugar to prevent
deterioration.
1st stage- more vascular and GFR is raised
2nd stage-microalbuminuria
3rd stage-proteinuria and hypertension
4th stage-structural changes, reduced GFR, raise
in urea and creatinine
5th stage-GFR grossly reduced, overt renal
failure, azotemia, severe hypertension, cardiac failure, and stage renal failure
Autonomic neuropathy-functional obstruction of bladder,
retension with ocerflow, UTI, further deterioration of renal functions
Urinary Tract Infections-acute and chronic pyelonephritis,
fulminant UTI characterised by ischemic necrosis of ranal pappillae, fleshy
masses in urine-necrosed pappillae, emphysematous pyelonephritis.
Perpheral Nerves
In myelinated fibres, axonal atrophy was considered to be
the primary lesion secondary to ineffective axonal transport. More recent
studies, however provide evidence for the prescence of demyelination and hence
schwann’s cell involvement in the primary lesion. As the myelinated fibres
degenerate , there is an attempt to regenerate, which manifests in the form of
regeneration clustres. With progress of the neuropathy the density of
regeneration clusters also comes down.
Structural abnormalities have also been found in the vessels
supplying the nerve fibres.
Clinical features
Around 50 % of cases with classical symptoms of polyuria,
polyphagia, and weight loss. Other clinical presentations are ;
-non healing ulcers
-recurrent respiratory tract infections or UTI
-rapid changes in refraction of eyes
-steady and unexplained weight loss
-increased tendency for fungal infection
-unexplained peripheral neuropathy
-premature onset of ischemic heart disease, stroke or
vascular chages
-history of over weight babies and recurrent fetal loss in
women
-premature cataract
-impotence in males
-vague ill health
Diagnosis
Estimation of FBS nad PPBS
Urine tests for protein uria, ketonuria, UTI
Glucose Tolerance Test- fasting value 126 mg/dl, PP 200mg/dl
after 75gm of oral glucose
Glycosylated Hb known as HbA1C <6.5%
Prognosis
It’s a life long disease
Depends on prescence or absence of chronic vascular
complications
It has been convincingly brought out the importance of tight
metabolic control in preventing the development of microangiopathy and
arresting its progression.
Reference
KrishnaDas Text Book Of Medicine
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