Pathophysiology of Diabetes Mellitus.

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.

1^st stage- more vascular and GFR is raised

2^nd stage-microalbuminuria

3^rd stage-proteinuria and hypertension

4^th stage-structural changes, reduced GFR, raise in urea and creatinine

5^th 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