PATHOGENESIS AND COMPLICATIONS OF TYPE 2 DIABETES´
Diabetes mellitus is a group of metabolic disorders sharing the common feature of hyperglycemia
Hyperglycemia can result due to
Defects in insulin secretion
Defects in insulin action
Both
Diabetes is classified into two main groups depending upon the pathogenesis
Type 1 diabetes
Type 2 diabetes
Type 2 diabetes
Caused by a combination of peripheral resistance to insulin action and an inadequate secretory response by the pancreatic β cells
Approximately 90 to 95 % of cases of diabetes are type 2 diabetes
Though its called as adult onset but can occur in children and adolescents due to increase rates of obesity
Pathogenesis
Type 2 diabetes is complex disease involving an interplay of genetic, environmental factors and proinflammatory state
Genetic factors
Genetic susceptibility in monozygotic twins and 1st degree relatives are at 5 to 10 folds increased risk of developing Diabetes
Polymorphisms in many genes associated with insulin gene are identified
Environmental factors
Most important – obesity particularly central and visceral obesity
Obesity contributes to metabolic abnormalities of diabetes and to insulin resistance
Sedentary life style is another risk factor independent of obesit
Metabolic defects in Type 2 Diabetes
Two important metabolic defects that characterise type 2 diabetes are
Decreased response of peripheral tissues, especially skeletal muscles, adipose tissue and liver to insulin
Inadequate insulin secretion in the face of insulin resistance and hyperglycemia (β cell dysfunction)
In the early stages, there is compensatory β cell hyperfunction and hyperinsulinemia but later β cells cannot adapt and lead to chronic hyperglycemia leading to complications
Insulin resistance
Insulin resistance results in
Failure to inhibit endogenous glucose production in the liver which contributes to high fasting blood glucose levels
Failure of glucose uptake and glycogen synthesis that occurs in skeletal muscle following a meal contributes to high post prandial blood glucose
Failure to inhibit lipoprotein lipase in adipose tissue, leading to excess of circulating FFA which inturn amplify insulin resistance
In insulin resistance
´Defects in signaling pathways leading to decreased tyrosine phosphorylation of insulin receptor and IRS proteins
´This leads to decreased levels of GLUT 4 levels on the surface of the cell
Exercise causes increased translocation of GLUT 4 to the surface
Obesity and insulin resistance
Risk of diabetes increases as the body mass index increases. Central obesity has more risk than peripheral fat depots
Free fatty acids
Levels of FFA are inversely related to insulin sensitivity
Central adipose tissue is more lipolytic than peripheral sites
Excess of free fatty acids overwhelm intracellular fatty acid oxidation pathways, leading to accumulation of diacylglycerol (DAG) which attenuates the insulin signaling pathway by serine phosphorylation of insulin receptors
Insulin normally inhibits hepatic gluconeogenesis by blocking the activity of phosphoenol pyruvate carboxykinase, which is the first enzymatic step in this process
Attenuated insulin signaling leads to increased phophoenolpyruvate carboxykinase activity that causes increased gluconeogenesis
Adipokines
Adipose tissue acts as endocrine organ releasing hormones called adipokines which include pro hyperglycemic adipokines and anti hyperglycemic adipokines (Leptin and Adiponectin)
Leptin and adiponectin improves the insulin secretion
Adiponectin levels are decreased in obesity this contributes to insulin resistance
Inflammation
Proinflammatory cytokines are secreted in response to excess nutrients such as Free fatty acids and glucose
Excess FFA with in macrophages and B cells activate the inflammasome, a multipotent complex which leads to secretion of the cytokine interleukin IL-1β
Interleukin IL-1β mediates secretion of proinflammatory cytokines from macrophages, islet cells and other cells
interleukin IL-1β and other cyokines released into circulation acts on the sites of insulin action and cause resistance
B cell dysfunction
along with insulin resistance B cell dysfunction is also required for the development of Type 2 diabetes
In the initial stages there is β cell function increase inorder to compensate the insulin resistance but later the β cells are exhausted
Mechanisms that promote β cell dysfunction are
Excess FFA attenuate insulin release and compromise the β cell function (Lipotoxicity)
Chronic hyperglycemia (Glucotoxixity)
an abnormal incretin effect
Amyloid deposition in the islets
Polymorphisms in genes that control insulin secretion
Complications
Acute metabolic complications
Severe and acute metabolic complications of Type 1 diabetes is Diabetic ketoacidosis
In type 2 diabetes, higher portal vein insulin levels prevents unrestricted hepatic fatty acid oxidation
Patient develops hyperosmolar hyperosmotic syndrome due to severe dehydration
Second common acute complication is hypoglycemia usually as a result of missed meal, excessive physical exercise, an excess of insulin administration.
Signs and symptoms are
Dizziness, confusion, sweating, palpitations and tachychardia
If hypoglycemia continues there is loss of consciousness
Chronic metabolic complications
Four distinct mechanisms have been implicated in the deleterious effects of persistent hyperglycemia on peripheral tissue
Formation of Advanced Glycation end products
Activation of protein Kinase C
Oxidative stress and disturbances in polyol pathways
Hexosamine pathways and generation of Fructose -6-phosphate
Formation of Advanced glycation end products
AGEs are formed as a result of non-enzymatic reactions between intracellular glucose derived dicarbonyl precursors (Glyoxal, methyl glyoxal and 3-deoxy glucosone) with the amino groups of both intracellular and extracellular proteins
Hyperglycemia accelerates AGE formation
AGE binds to specific receptors (RAGE) expressed on inflammatory cells (macrophages and T cells), endothelium, and vascular smooth muscle
Effect of AGE-RAGE signaling axis within the vascular compartment leads to
Release of cytokines and growth factors like
TGFβ – leads to excess deposition of basement membrane material
VEGF – causes diabetic retinopathy
Generation of ROS in endothelial cells
Increased procoagulant activity on endothelial cells and macrophages
Enhanced proliferation of vascular smooth muscle cells and synthesis of extracellular matrix
AGE can directly cross link extracellular matrix proteins
Cross linking of collagen type I molecules in large vessels decrease their elasticity which may predispose these vessels to shear stress and endothelial injury
AGE induced cross linking of type IV collagen in basement membrane decreases endothelial cell adhesion and increases extravasation of fluid
Proteins cross linked by AGEs are resistant to proteolytic digestion and hence cannot be removed
AGE modified matrix components also trap non-glycated plasma or interstitial proteins
In large vessels trapping of LDL retards its efflux from the vessel wall and enhances the deposition of cholesterol in the intima thus accelerating atherogenesis
In capillaries albumin bind to glycated basement membrane, accounting in part for the basement membrane thickening responsible for microangiopathy.
Activation of Protein Kinase C
Intracellular hyperglycemia stimulates denovo synthesis of DAG from glycolytic intermediates which causes excessive PKC activation
The effects of PKC activation are
Production of VEGF, TGF-β and procoagulant proteins plasminogen activator inhibitor – 1 by the vascular endothelium
Oxidative stress and disturbances in polyol pathways
Some tissues like nerves, lenses, kidneys and blood vessels do not require insulin for glucose transport
Persistent hyperglycemia in extracellular milieu leads to increase in intracellular glucose
This excess glucose is metabolized by enzyme aldose reductase to sorbitol and eventually to fructose which utilizes NADPH in his reaction
NADPH is required by the enzyme Glutathione reductase in a reaction that generates reduced glutathione
Hexosamine pathways and generation of Fructose–6-Phosphate
Hyperglycemia induced flux through the hexosamine pathway increases intracellular levels of fructose-6-phosphate which is substrate for glycosylation of proteins which leads to formation of excess proteoglycans
This leads to abnormal expression of TGF β or PAI -1 which further exacerbate the end organ damage.
Macrovascular disease
The hall mark is accelerated atherosclerosis involving the aorta and large and medium sized arteries
Myocardial infarction caused due to atherosclerosis of coronary arteries is the most common cause of death in DM
Gangrene of the lower limb occurs in advanced vascular disease
Hyaline arteriosclerosis leading to hypertension
Microangiopathy
Diffuse thickening of the basement membranes of the small capillaries in the skin, skeletal muscle, retina, renal glomeruli and renal medulla
Thickening of basement membrane is by concentric layers of hyaline material composed predominantly of type IV collagen
These capillaries are more leaky and underlie the development of diabetic nephropathy, retinopathy and neuropathy
Thickening of basement membrane of glomerular capillaries leads to diabetic microangiopathy
Thickening leads to mesangial widening
Thickening of BM of capillaries starts at as early as 2 years
Later thickening of tubular basement membrane occurs
Diffuse mesangial sclerosis
Lesion consists of diffuse increase in mesangial matrix
Initially there is mesangial proliferation but later mesangial increase is associated with overall thickening of GBM and matrix deposition of PAS positive material
As the disease progresses mesangial deposition takes nodular configuration
Also known as “intercapillary glomerulosclerosis” or “Kimmelstiel-Wilson disease”
Glomerular lesions take the form of ovoid or spherical laminated nodules of matrix situated in the periphery of the glomerulus
Nodules are PAS positive and are surrounded by capillary loops
Nodular lesions are accompanied by accumulations of hyaline material in capillary loops or adherent to bowman’s capsules
As the disease advances individual nodules enlarge and compress capillaries, obliterating the glomerular tuft
Both afferent and efferent arterioles show hyalinosis
Later due to arteriole and glomerular lesions, kidney develops ischemia which leads to tubular atrophy, interstitial fibrosis and contraction in size of the kidney
Diabetic ocular complications
The ocular involvement may be in the form of –
Retinopathy due to neovascularization
Microaneurysms of the retinal vessels and hemorrhages
Macular edema
Cataract formation
Glaucoma
Diabetic neuropathy
The most common neural complications are –
Peripheral neuropathy –
Distal symmetric polyneuropathy of lower extremities that affects both motor and sensory function. Upper extremities are also involved (Glove and Stocking pattern)
Mononeuropathy– sudden foot drop, wrist drop or isolated cranial nerve palsy
Autonomic neuropathy – – involving bladder and bowel
Reference
Anirban Maitra. The Endocrine system.In: Robbins and Cotran Pathologic basis of disease.9th edition.volume II.chapter 24. pp 1073-1141.
