Diabetes Mellitus

Diabetes Mellitus

Definition : Diabetes mellitus is a metabolic disorder characterised by chronic hyperglycemia associated with disturbance of carbohydrate, fat & protein metabolism.

CLASSIFICATION 

1. Type I diabetes mellitus (10 %) : earlier called - Insulin dependent or Juvenile-onset diabetes.

• Type I A diabetes mellitus : Immune mediated
• Type I B diabetes mellitus : Idiopathic causes

2. Type II diabetes mellitus ( 80 % ) : earlier called - Non-insulin dependent or maturity onset diabetes.

3. Gestational or pregnancy induced diabetes mellitus (4 % )

4. Other specific types of diabetes (10 % ) -

• Genetic defect of β-cell function due to mutations in various enzymes. earlier called maturity onset of the young ( hepatocyte nuclear transcription factor, glucokinase).
• Genetic defect in insulin action ( type A insulin resistance).
• Disease of exocrine pancreas (chronic pancreatitis, pancreatic tumours and post-pancreatectomy).
• Endocrinopathies (acromegaly, cushing's syndrome and pheochromocytoma).
• Drug or chemical induced ( steroids, thyroid hormone, thiazides, β-blockers etc.).
• Infections ( congenital rubella, cytomegalovirus).
• Uncommon forms of immune-mediated diabetes mellitus (stiff man syndrome, anti insulin receptor antibodies).
• Other genetic syndrome (Down's syndrome, Klinefelter's syndrome, Tumour's syndrome).

1. TYPE I DIABETES MELLITUS :  It constitutes about 10% of cases of DM. It is characterised by absolute deficiency of insulin secretion caused by pancreatic β-cell destruction, usually resulting from an autoimmune attack.

A. Type I A DM (Immune-mediated) - Characterised by autoimmune destruction of β-cells resulting in insulin deficiency.

B. Type I B DM (Idiopathic) - Characterised by insulin deficiency with tendency to develop ketosis but autoimmune causes are not found.

Contrasting Features Of Type I and Type II Diabetes Mellitus
No.	Features	Type I DM	Type II DM
1.	Frequency	10 – 20 %	80 – 90 %
2.	Age at onset	Below 35 years	After 40 years
3.	Type of onset	Abrupt and severe	Gradual and insidious
4.	Weight	Normal	Obese / non-obese
5.	Family history	< 20%	About 60 %
6.	Genetic locus	Unknown	Chromosome 6
7,	Diabetes in identical twins	50 % chance	80 % chance
8.	Pathogenesis	Autoimmune destruction of ß cells	Insulin resistance, impaired insulin secretion
9.	Islet cell antibodies	Yes	No
10.	Blood insulin level	Decreased insulin	Normal or increased insulin
11.	Islet cell changes	Insulitis, β-cells depletion	No insulitis, later fibrosis of islets
12.	Amyloidosis	Infrequent	Common in chronic cases
13.	Clinical management	Insulin and diet	Diet, exercise, oral drugs, insulin
14.	Acute complications	Ketoacidosis	Hyperosmolar coma

2. TYPE II DIABETES MELLITUS : It constitutes about 80% of cases of DM. It is caused by a relative insulin deficiency  due to combination of peripheral resistance to insulin action and inadequate compensatory response of insulin secretion by the pancreatic β-cells.

Etiology : 

1. Family history of type 2 DM.
2. Obesity.
3. Habitual physical inactivity.
4. Race and ethnicity ( Blacks, Asians, Pacific Islanders).
5. Previous identification of impaired fasting glucose or impaired glucose tolerance.
6. History of gestational DM or delivery of baby heavier than 4 kg.
7. Hypertension.
8. Dyslipidaemia (HDL level <35 mg/dl or triglycerides >250 mg/dl ).
9. Polycystic ovary disease and acanthosis nigricans.
10. History of vascular disease.

3. GESTATIONAL  OR PREGNANCY INDUCED DM : About 4% pregnant women develop DM due to metabolic changes during pregnancy. Although they revert back to normal glycaemia after delivery, these women are prone to develop DM later in their life.

PATHOGENESIS : Hyperglycaemia may develop due to following causes

• Reduced insulin secretion.
• Decrease glucose use by the body.
• Increased glucose production.

Pathogenesis

Pathogenesis of Type I DM : The basic phenomenon  is destruction of β-cells mass, usually leading to absolute insulin deficiency. While Type I B remain idiopathic. So we will discuss about only Type I A DM.

1. Genetic susceptibility –  

• Identical twins are more prone if either one are affected.
• HLA genes (Commonest locus being affected is on chromosome 6p21 ( HLA D) like HLA DR3 / DR4 with DQ8 haplotype. The non HLA genes like that for insulin or polymorphism in CD25 (normally regulated the function of T cells.

2. Autoimmunity – 

• Presence of islet cell antibodies against GAD (glutamic acid decarboxylase), insulin etc.
• Insulitis, it consists of CD8+ T lymphocytes with variable number of CD4+ T lymphocytes and macrophages.
• Selective destruction of ß-cells while other islet cells (alpha cells, delta cells and PP cells)  are unaffected.
• Role of T cells mediated autoimmunity is supported by transfer of the disease from affected animal to healthy animal by infusing T lymphocytes.
• Association with other autoimmune diseases 10-20% cases like Grave’s disease, Addison’s disease, Hashimoto’s thyroiditis, pernicious anaemia.

3. Environmental factors – 

• Certain viral infection preceding the onset of disease like mumps, measles, coxsackie B virus, cytomegalovirus and infectious mononucleosis.
• Experimental induction with certain chemicals may cause like alloxan, streptozotocin and pentamidine.
• Geographic and seasonal variations.
• Bovine milk protein may also cause. 

Key Points of Pathogenesis of Type I A DM

1. At birth, individual with genetic susceptibility to this disorder have normal ß-cell mass

2. ß-cell act as autoantigens and activate CD4 T lypmhocytes, bringing about immune destruction of pancreatic ß-cells by autoimmune phenomena and tackes months to years. Clinical features of diabetes manifest after  more  than 80% of ß-cell mass has been destroyed.

3. The trigger for autoimmune process appears to be some infectious or environmental factor which specially targets ß-cells.

CLINICAL FEATURES

No.	Features	Type-I DM	Type-II DM
1.	Age	Below 35 years.	Above 40 years.
2.	Onset of symptoms	Abrupt.	Slow and Insidious.
3.	Presentation	Polyuria, polydipsia and polyphagia.	Generally asymptomatic. Polyuria and polydipsia may be present.
4.	Weight	Progressive loss of weight.	Unexplained weakness and loss of weight.
5.	Obesity	Generally absent	Present.
6.	Metabolic complication	Common (Ketoacidosis, hypoglycaemia)	Infrequent (Ketoacidosis)

Sign & Symptoms

COMPLICATIONS

Acute metabolic complications -

1. Diabetic Ketoacidosis.
2. Hyperosmolar hyperglycaemic nonketotic coma (HHS).
3. Hypoglycaemia.

Late systemic complications –

1. Atherosclerosis.
2. Diabetic microangiopathy.
3. Diabetic nephropathy.
4. Diabetic neuropathy.
5. Diabetic retinopathy.
6. Infections ( tuberculosis, pneumonia, pyelonephritis, otitis, carbuncles and diabetic ulcers).

Complications

DIAGNOSIS OF DIABETES

1. Urine testing – Glucosuria and ketonuria. 
2. Single Blood Sugar Estimation. 
3. Screening by Fasting Glucose Test.
4. Oral Glucose Tolerance Test etc.

TREATMENT OF DIABETES MELLITUS

Management of type 2 diabetes -

•  Weight loss.
• Healthy eating ( e.g. fewer calories, fewer food containing saturated fats, high fiber containing food etc.). 
• Regular exercise.
• Blood sugar monitoring.
• Diabetes medications and insulin therapy (e.g. metformin, sulfonylureas, meglitinides, thiazolidinediones, DPP-4 inhibitors, GLP-1 receptor agonists, SGLT2 inhibitors and insulin etc.).

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