Unit – 2
CLASSIFICATION AND PATHOGENESIS
OF DIABETES MELLITUS
LEARNING OBJECTIVES OF THIS MODULE
• Be able to classify diabetes based on the
• Describe the role of endocrine pancreas in glucose homeostasis.
• Understand the autoimmune mediated pathogenesis the of type 1 Diabetes
• Understand the role of the various factors in the
pathogeneses of type 2 Diabetes
Diabetes Mellitus (DM)
• Diabetes Mellitus is a metabolic disorder characterized by
• Glucose level in the blood is controlled by several hormones
• Insulin secreted by beta-cells of Islet of Langerhans of pancreas is the major hormone which controls the level of glucose in blood
• Diabetes mellitus results either from an inadequate secretion of insulin, an inadequate response of target cell to insulin or combination of these factors
• Several other mechanisms including the glucagon level, hepatic glucose production, renal glucose reabsorption and the incretin hormones play significant role in the pathogenesis particularly of type two diabetes.
Islets of Langerhans
1. β-cells: Synthesize Insulin
2. α-cells: producing glucagon,
3. δ-cells: producing somatostatin,
4. ε-cells: producing ghrelin and
5. pancreatic polypeptide (PP) cells: producing
• The β-cells are the most numerous, tend to be located more centrally in islet structures and are surrounded by the other cell types.
MAJOR INSULIN ACTION IN GLUCOSE HOMEOSTASIS
> Normal insulin action in different human tissues : Muscle tissue > glucose uptake and utilization
Liver > glycogen storage, glycolysis
> glycogenolysis, gluconeogenesis
Fat tissue synthesis, lipolysis (ketogenesis)
✓ The plasma glucose concentration is determined by a balance between glucose entry from the gastrointestinal tract and hepatic glucose production Vs tissue glucose uptake and metabolism
DM is classified into four general categories
Is based on the etiology (pathogenesis) not the treatment type or age of onset:
Type 1 diabetes: due to B-cell destruction, usually leading to absolute insulin deficiency
Type 2 diabetes: results from a progressive insulin secretory defect on the background of insulin resistance
Gestational diabetes mellitus (GDM): hyperglycemia diagnosed in the second or third trimester of pregnancy that is not clearly overt diabetes
Specific types of diabetes: DM due to specific causes e.g. drug (such as steroid induced DM)
CLASSIFICATION OF DM IN AN INDIVIDUAL PATIENT…
• Some patients cannot be clearly classified as having either type 1 or type 2 DM.
• Exception to the above guideline happens frequently
i.e. Young people developing Type 2 DM and Older
individuals developing Type 1 DM.
• Also presentation with diabetic ketoacidosis is not necessarily limited to type 1 DM.
• Hence difficulties in diagnosis may occur in children, adolescents, and adults, with the true diagnosis becoming more obvious over time.
PATHOGENESIS OF DIABETES MELLITUS
I. Pathogenesis of Type 1 Diabetes Mellitus
• It is characterized by loss of the insulin producing pancreatic beta-cells of islet of Langerhans
• Sensitivity and responsiveness to insulin are usually normal
• Type 1 DM accounts for less than 10% of the general diabetic population globally
• Type 1 DM affects children and adolescents
predominantly but can also occur in adults
• Loss of beta-cells leading to Type 1 DM is caused by an autoimmune destruction i.e. antibodies directed against insulin and Islet proteins
I. Pathogenesis of Type 1 DM….
• ~ 85% of T1DM patients have circulating islet cell antibodies
✓ Majority also have detectable anti-insulin
• Most islet cell antibodies are directed against glutamic acid decarboxylase (GAD) within pancreatic beta cells
• Three main factors are involved in type 1 DM pathogenesis
a) Genetic predisposition
b) Triggering environmental factor (s)
c) Development and progression of auto-Immunity
• Chronic autoimmune disorder occurring in genetically susceptible individuals
– May be precipitated by environmental factors
I. Pathogenesis of Type 1 DM….
• Immune system is triggered to develop an autoimmune response against
– Altered pancreatic beta cell antigens
– Molecules in beta cells that resemble a viral protein
✓ Is a slow T-cell mediated Auto-immune disease
✓ Destruction of the insulin secreting cell in the
pancreatic islets takes place over many years
✓ The pathological changes in the pre-diabetic pancreas in Type 1 DM is characterized by Insulitis which is the infiltration of Islet with mono-nuclear cells containing activated macrophages, helper cytotoxic T lymphocytes, Natural Killer cells, B-lymphocytes.
II. Pathogenesis of Type 2 Diabetes Mellitus
• Type 2 DM is a heterogeneous disorder
• It encompasses a range of disorders with the common phenotype of hyperglycemia.
• Accounts for more than 90% of diabetic cases in many populations.
• It is characterized by impaired insulin secretion,
insulin resistance, increased hepatic glucose
production and abnormal fat metabolism.
• Insulin resistance is believed to be an early defect and a root cause in Type 2 DM
• At the time of diagnosis, both impaired insulin
secretion and insulin resistance are already established.
II. Pathogenesis of Type 2 DM……..
• Insulin resistance may be the result of genetic factors, obesity, decreased physical activity or glucose toxicity
• Insulin resistance in the liver, muscle, and adipose tissue leads to
✓increased hepatic glucose production
✓ decreased glucose uptake in peripheral tissues
✓ increased lipolysis
• Several other important factors play significant role in the pathogenesis of type 2 DM including abnormalities involving the glucagon and incretin levels and effects
• There is no evidence of immune activation in type 2 DM
Type 2 DM is progressive and a continuum
• Insulin resistance leads to a compensatory increase in insulin secretion by the β-cells of the pancreas (hyperinsulinaemia) in order to achieve normoglycemia
• β-cell function eventually starts to decline, resulting in impaired glucose tolerance (IGT) and Type 2 DM
• The β-cells are also damaged by lipotoxicity and glucotoxicity.
• Mean β-cell function is < 50% at the diagnosis of Type 2 DM, and keeps deteriorating over the years as seen in the United Kingdom Prospective Diabetes Study (UKPDS)
Other pathophysiologic changes in type 2 DM
• Decreased incretin effect
– Effect of food on secretion of GIT hormones mainly GLP-1 and GIP which facilitate insulin secretion. This response is also defective in Type 2 DM
• Altered glucagon-insulin dynamics in response to meals
– Delayed and suppressed insulin response and failed normal postprandial decline in glucagon concentrations
– Insulin is not sufficient to drive glucose uptake in the body tissue and the increased glucagon and decreased insulin cause the liver to inappropriately release glucose into the blood.
– The resultant effect is fasting hyperglycemia or increasing postprandial glucose
• Increased renal glucose re-absorption
– Increased SGLT-2 expression and activity in renal epithelial cells from patients with DM compared with normoglycemic individuals
III. Pathogenesis of Gestational Diabetes Mellitus
• It involves combination of inadequate insulin secretion and responsiveness (see type 2 DM pathogenesis)
• Develops during pregnancy and improve or disappear after delivery in most cases
• Individuals at higher risk for Gestational Diabetes include :
✓ Obese woman
✓ Those with previous history of glucose intolerance
✓ Any pregnant woman who has elevated fasting, or random blood glucose level.
✓ Those with a history of gestational diabetes mellitus.
✓ Those with a history of large for gestational–agebabies (>4kg)
✓ First Degree relative with DM
✓ Maternal age >25 years of age
✓ Previous unexplained perinatal loss or birth of a malformed infant
IV. Pathogenesis of Specific types of
DM due to specific causes such as :
✓ monogenic diabetes e.g. maturity-onset diabetes of the
✓ endocrinopathies like thyrotoxicosis, Cushing’s syndrome
✓ diseases of the exocrine pancreas (e.g. cystic fibrosis)
✓ drug or chemical-induced diabetes (steroids, ART, Cytotoxic drugs)
END Of UNIT – 2