Diabetes Mellitus (DM) : Causes, Pathogenesis, Symptoms, Diagnosis & Treatment
- Diabetes mellitus is not a single disease entity but rather a group of metabolic disorders sharing the common underlying feature of hyperglycemia.
- As per the WHO, diabetes mellitus (DM) is defined as a hetrogeneous metabolic disorder characterised by common feature of chronic hyperglycaemia with disturbance of carbohydrate, fat and protein metabolism.
- Diabetes mellitus is a syndrome of impaired carbohydrate, fat, and protein metabolism caused by either lack of insulin secretion or decreased sensitivity of the tissues to insulin thus, constellation of abnormalities caused by insulin deficiency is called diabetes mellitus.
- Since insulin is a major anabolic hormone in the body, deficiency of insulin results in a catabolic state that affects not only glucose metabolism but also fat and protein metabolism.
- Hyperglycemia in diabetes results from defects in insulin secretion, insulin action, or, most commonly, both. The chronic hyperglycemia and attendant metabolic deregulation of diabetes mellitus may be associated with secondary damage in multiple organ systems, especially the kidneys, eyes, nerves, and blood vessels.
- The cause of clinical diabetes is always a deficiency of the effects of insulin at the tissue level.
Depending upon etiology of DM, hyperglycaemia may result from the following:
- Reduced insulin secretion
- Decreased glucose use by the body
- Increased glucose production.
Although all forms of diabetes mellitus share hyperglycemia as a common feature, the underlying causes of hyperglycemia vary widely.
An important point is that although the major types of diabetes arise by different pathogenic mechanisms, the long-term complications in kidneys, eyes, nerves, and blood vessels are the same and are the principal causes of morbidity and death.
Based on common etiology There are two general types of diabetes mellitus:
1. Type 1 diabetes (T1D) / Insulin-dependent diabetes mellitus (IDDM) / Juvenile-onset diabetes
- Type 1 diabetes (T1D) is characterized by an absolute deficiency of insulin secretion caused by pancreatic β-cell destruction, usually resulting from an autoimmune attack.
- Type 1 diabetes accounts for approximately 10% of all cases.
- Type 1 diabetes most commonly develops in childhood, becomes manifest at puberty, and progresses with age.
- Most patients with type 1 diabetes depend on exogenous insulin for survival; without insulin they develop serious metabolic complications such as ketoacidosis and coma.
- Pathogenesis : Currently, pathogenesis of Type 1 diabetes is explained on the basis of 3 mutually-interlinked mechanisms –
– Autoimmune factors,
– Genetic susceptibility,
– Environmental factors
2. Type 2 diabetes (T2D) / non-insulin-dependent diabetes mellitus (NIDDM) / maturity-onset diabetes
- Type 2 diabetes (T2D) is caused by a combination of peripheral resistance to insulin action (Insulin resistence) and an inadequate compensatory response of insulin secretion by the pancreatic β-cells (relative insulin deficiency).
- Approximately 80% to 90% of patients have type 2 diabetes.
- Pathogenesis : Type 2 diabetes is a prototypical complex multifactorial disease. Some causing factors are as follows:
– Genetic factors
– Environmental / Constitutional factors
– Metabolic defects
Based on more specific etiology
1. Genetic Defects of Beta Cell Function
- Maturity-onset diabetes of the young (MODY), caused by mutations in: Hepatocyte nuclear factor 4α gene (HNF4A)—MODY1, Glucokinase gene (GCK)—MODY2, Hepatocyte nuclear factor 1α gene (HNF1A)—MODY3, Pancreatic and duodenal homeobox 1 gene (PDX1)—MODY4, Hepatocyte nuclear factor 1β gene (HNF1B)—MODY5, Neurogenic differentiation factor 1 gene (NEUROD1)—MODY6
- Maternally inherited diabetes and deafness (MIDD) due to mitochondrial DNA mutations (3243A→G)
- Defects in proinsulin conversion
- Insulin gene mutations
2. Genetic Defects in Insulin Action
- Insulin receptor mutations
3. Exocrine Pancreatic Defects
- Chronic pancreatitis
- Cystic fibrosis
- Fibrocalculous pancreatopathy
- Growth hormone excess (acromegaly)
- Cushing syndrome
- Cytomegalovirus infection
- Coxsackievirus B infection
- Congenital rubella
- Thyroid hormone
- β-Adrenergic agonists
7. Genetic Syndromes Associated with Diabetes
- Down syndrome
- Klinefelter syndrome
- Turner syndrome
8. Gestational Diabetes Mellitus
- Diabetes associated with pregnancy
Diabetes can be a devastating disease because the abnormal glucose metabolism and other metabolic derangements have serious pathologic effects on virtually all the systems of the body.
The most significant complications of diabetes are vascular abnormalities, renal damage, and lesions affecting the peripheral nerves and eyes.
There is extreme variability among patients in the time of onset of these complications, their severity, and the particular organ or organs involved. In persons with tight control of their diabetes,the onset may be delayed.
The pathogenesis of the long-term complications of diabetes is multifactorial, although persistent hyperglycemia (glucotoxicity) seems to be a key mediator.
Diabetes mellitus may develop following complications which are broadly divided into 2 major groups:
Acute metabolic complications
- These include diabetic ketoacidosis, hyperosmolar nonketotic coma, and hypoglycaemia.
Late systemic complications : These are as follows-
- Diabetic Macrovascular Disease e.g. Hyaline arteriolosclerosis, Renal atherosclerosis and arteriolosclerosis
- Diabetic Microangiopathy
- Diabetic Nephropathy e.g. Diffuse mesangial sclerosis, Nodular glomerulosclerosis & Pyelonephritis
- Diabetic Neuropathy
- Ocular Complications of Diabetes e.g. Retinopathy, Cataract formation, & Glaucoma.
The microangiopathy underlies the development of diabetic nephropathy, retinopathy, and some forms of neuropathy.
At least 3-4 distinct metabolic pathways seem to be involved in the pathogenesis of longterm complications; it is likely that all of them play a role in a tissue-specific manner.
- Non-enzymatic protein glycosylation / Formation of advanced glycation end products (AGEs).
- Activation of protein kinase
- Disturbances in polyol pathways
- Excessive oxygen free radicals
Blood glucose levels normally are maintained in a very narrow range, usually 70 to 120 mg/dL.
Hyperglycaemia remains the fundamental basis for the diagnosis of diabetes mellitus
The following investigations are helpful in the diagnosis of diabetes mellitus:
1. Urine testing
- Urine tests are cheap and convenient but the diagnosis of diabetes cannot be based on urine testing alone since there may be false-positives and false-negatives.
- Urine is tested for the presence of glucose and ketones.
- Glucosuria – Benedict’s qualitative test
- Ketonuria – Rothera’s test (nitroprusside reaction) and strip test
2. Single blood sugar estimation
- For diagnosis of diabetes, blood sugar determinations are absolutely necessary.
- Folin-Wu method of measurement of all reducing substances in the blood including glucose is now obsolete.
- Currently used are O-toluidine, Somogyi-Nelson and glucose oxidase methods.
- Whole blood or plasma may be used but whole blood values are 15% lower than plasma values.
3. Screening by fasting glucose test
- Individuals with fasting glucose concentration of 126 mg/dL or higher on more than one occasion are labelled as diabetics.
4. Oral glucose tolerance test
- Individuals with fasting value of plasma glucose higher than 126 mg/dl and when plasma glucose concentration is 200 mg/dL or higher 2 hours after a standard carbohydrate load (75 g of glucose) are labelled as diabetics
5. Other tests : A few other tests are sometimes performed in specific conditions in diabetics and for research purposes:
- Glycosylated haemoglobin (HbA1C)
- Glycated albumin
- Extended GTT
- Intravenous GTT
- Cortisone-primed GTT
- Insulin assay
- Proinsulin assay
- C-peptide assay
- Islet autoantibodies
- Screening for diabetes-associated complications
The diagnosis of diabetes is established by elevation of blood glucose by any one of three criteria:
- A random blood glucose concentration of 200 mg/dL or higher, with classical signs and symptoms
- A fasting glucose concentration of 126 mg/dL or higher on more than one occasion.
- An abnormal oral glucose tolerance test (OGTT), in which the glucose concentration is 200 mg/dL or higher 2 hours after a standard carbohydrate load (75 g of glucose).
The onset is marked by polyuria, polydipsia, polyphagia, and in severe cases, ketoacidosis, all resulting from metabolic derangements .
Diabetes is characterized by following symptoms:
- Polyuria (passage of large volumes of urine causing a profound loss of water and electrolytes),
- Polydipsia (excessive drinking),
- Polyphagia (increased appetite),
- Weight loss & muscle weakness,
Hyperosmolar nonketotic coma .
Diabetes can be characterized by several complications though in most instances, these complications appear approximately 15 to 20 years after the onset of hyperglycemia. Following complications are frequently observed:
- Cardiovascular events such as myocardial infarction, renal vascular insufficiency, and stroke (cerebrovascular accident) due to atherosclerosis (macrovascular disease).
- Diabetic nephropathy
- Visual impairment
- Diabetic neuropathy
- Gangrene, bacteremia, pneumonia due to susceptibility to infections of the skin, as well as to tuberculosis, pneumonia, and pyelonephritis.
Type 1 & 2 diabetic patients can be segregated clinically as follows:
- In Type 1 diabetes onset usually in childhood and adolescence while in Type 2 diabetes onset usually in adulthood; increasing incidence in childhood and adolescence.
- In Type 1 diabetes normal weight or weight loss preceding diagnosis while in Type 2 diabetes vast majority of patients are obese.
- In Type 1 diabetes progressive decrease in insulin levels while in Type 2 diabetes increased blood insulin (early); normal or moderate decrease in insulin (late).
- In Type 1 diabetes circulating islet autoantibodies while in Type 2 diabetes no islet autoantibodies.
- In Type 1 diabetes diabetic ketoacidosis in absence of insulin therapy while in Type 2 diabetes nonketotic hyperosmolar coma.
· To relieve symptoms
· To prevent acute hyperglycaemic complications i.e. ketoacidosis and the hyperosmolar state.
· To prevent treatment-related hypoglycaemia
· To achieve and maintain appropriate glycaemic targets
· Fasting blood glucose between 4 – 6 mmol/L
· 2-hour post-meal blood glucose between 4 – 8 mmol/L
· Glycated haemoglobin 6.5 % or less
· To ensure weight reduction in overweight and obese individuals
· To prevent chronic complications of diabetes by maintaining
· The glycaemic targets noted above
· Blood pressure less than 130/80 mmHg
· LDL-cholesterol less than 2.5 mmol/L
1. Non-pharmacological treatment
· All patients with diabetes require diet therapy.
· All patients (and close relations who cook or control their meals) must be referred to a dietician or diet nurse for individualized meal plans. In general, patients must;
· Avoid refined sugars as in soft drinks, or adding sugar to their beverages. Artificial sweeteners and ‘diet’ soft drinks, which do not contain glucose, may however be used.
· Be encouraged to have complex carbohydrates (e.g. kenkey, yam, plantain etc.) instead.
· A day’s diet must generally consist of;
· Carbohydrates (60%), protein (15%) and fat (25%) mostly of plant-origin and low in animal fat.
· A reduced total caloric content (portions) and an increase in the amount of fibre e.g. vegetables, fruits and cereals.
· Regular, simple exercise e.g. 30 minutes brisk walking at least 3 days a week in ambulant patients
· All advice on exercise must give consideration to the patient’s age and the presence of complications and other medical conditions.
2. Pharmacological treatment
First generation Second generation Tolbutamide Glibenclamide (Glyburide) Glipizide Gliclazide Glimepiride