Diabetes Mellitus
Definition of Diabetes Mellitus: Diabetes mellitus is a group of metabolic disorders having features of hyperglycemia. The prevalence of diabetes is increasing sharply in developing countries because of more sedentary lifestyles. India and China have the largest prevalence of diabetics.
Table of Contents
Diabetes Mellitus
Diagnosis of Diabetes Mellitus:
Levels of blood glucose in normal, pre-diabetes and diabetes:
Read And Learn More: Pathology for Dental Students Notes
Normally the blood glucose levels are maintained in a very narrow range of 70 to 120 mg/dL:
1. Euglycemic: Individuals are considered to be euglycemic, when
- Fasting glucose level is less than 100 mg/dL, or
- Glucose level less than 140 mg/dL following an OGTT.
2. Pre-diabetes: It is defined as a condition in which there is impaired glucose tolerance, but elevated blood sugar does not reach the criterion accepted for an outright diagnosis of diabetes.
The criteria for diagnosis are:
- Fasting glucose level is greater than 100 mg/dL but less than 126 mg/dL.
- GTT values greater than 140 mg/dL but less than 200 mg/dL.
Risks in pre-diabetes:
- Progression to frank diabetes over time and
- Cardiovascular disease.
3. Diabetes: Any one of three criteria can be used for the diagnosis of diabetes:
- A random glucose level greater than 200 mg/dL, with classical signs and symptoms.
- A fasting glucose level greater than 126 mg/dL on more than one occasion.
- An abnormal oral glucose tolerance test (OGTT), in which the glucose level is greater than 200 mg/dL, 2 hours after a standard carbohydrate load.
Classification of diabetes mellitus:
Diabetes is classified according to etiopathogenesis into different groups but the majority of cases fall into one of two broad classes namely: type 1 and type 2.
Classification of diabetes mellitus:
Type 1 Diabetes (T1D)
- Accounts for ~ 5–10% of all cases.
- Age: Most common in childhood (younger than 20 years of age). Since it can develop at any age, the term “juvenile diabetes” should be avoided.
Cause 1 Diabetes (T1D):
- Autoimmune disease characterized by:
- Pancreatic β-cell destruction
- Absolute deficiency of insulin.
- Idiopathic: It is a rare form in which there is no evidence of autoimmunity.
Pathogenesis of Type 1 Diabetes Mellitus:
Write a short note on the pathogenesis of type 1 diabetes mellitus.
Involves the interplay of both genetic susceptibility and environmental factors.
- Genetic susceptibility: The incidence of type 1 diabetes is greater in twins of affected individuals than in the general population, and greater in monozygotic than in dizygotic twins.
- Environmental factors:
- Viral infections: They may trigger islet cell destruction and associations have been found between type 1 diabetes and infection with mumps, rubella, coxsackie B, or cytomegalovirus.
- Three different mechanisms explain the role of viruses in the induction of autoimmunity.
- Release of hidden or sequestered antigens: Viral infections cause islet injury and inflammation, thereby releasing the sequestered β-cell antigens and activating autoreactive T cells.
- Molecular mimicry: Viruses can produce proteins that mimic β-cell antigens. The immune response produced against the viral protein may cross-react with the self-tissue (β-cell antigens).
- Sharing of antigen epitopes: First viral infections by a predisposing virus, early in life might persist in the β-cells. Subsequent re-infection with a related virus known as precipitating virus, that shares antigenic epitopes may lead to an immune response against the β-cells.
Mechanisms of β-Cell Destruction:
- The autoimmune damage starts many years before the disease becomes clinically evident.
- Hyperglycemia and ketosis occur after more than 90% of the β cells have been destroyed.
Various mechanisms include:
- Failure of self-tolerance in T-cells: It is the basic abnormality in type 1 diabetes.
- Though cytokines: TH1 cells may destroy β cells by secreting cytokines, including IFN-γ and TNF.
- Directly by cytotoxic T cells: The CD8+ CTLs may directly kill β cells.
- Autoantibodies againstβ cell antigens (for example,Islet antigensβ cell enzymes): They are found in 70–80% of patients with type 1 diabetes and in asymptomatic family members. It is not known whether autoantibodies cause injury or are the result of islet injury.
Type 2 Diabetes (T2D)
Write a short note on the pathogenesis of type 2 diabetes mellitus.
- Accounts for ~ 90–95% of diabetic patients.
- The majority of patients are overweight.
- Known as “adult-onset,” it is now found in children and adolescents also.
Pathogenesis of Type 2 Diabetes Mellitus:
Type 2 diabetes is a multifactorial disease.
- Environmental factors play a role and include:
- Sedentary lifestyle
- Dietary habits and associated obesity.
- Genetic factors:
- Type 2 diabetes has a concordance rate of 35% to 60% in monozygotic twins compared with 17% to 30% in dizygotic twins.
- The lifetime risk for type 2 diabetes in an offspring is more than double if both parents are affected.
- Diabetogenic genes have been found.
- There is no evidence of an autoimmune basis.
Metabolic Defects in Type 2 Diabetes:
Two important metabolic defects are
Insulin Resistance:
Definition of Insulin Resistance: Insulin resistance is the decrease/failure of the target (peripheral) tissues to insulin action.
The main factor in the development of insulin resistance is obesity:
- Obesity and insulin resistance: Obesity is associated with type 2 diabetes and visceral obesity is found in more than 80% of patients.
- Distribution of body fat: It has an effect on insulin sensitivity. Central obesity (abdominal fat) is more associated with insulin resistance than are peripheral (gluteal/ subcutaneous) fat depots.
- Consequences of insulin resistance:
- Decreased uptake of glucose in muscle.
- Reduced glycolysis and fatty acid oxidation in the liver.
- Inability to suppress hepatic gluconeogenesis.
β-Cell Dysfunction:
In type 2 diabetes, β-cell dysfunction manifests as inadequate insulin secretion by the pancreatic β cells (relative insulin deficiency) in association with insulin resistance and hyperglycemia. β-cell dysfunction is multifactorial in origin.
Obesity and β-cell dysfunction:
- Compensatory β-cell hyperplasia: Pancreatic β cells initially respond to long-term demands of peripheral insulin resistance by undergoing compensatory hyperplasia leading to increased insulin secretion (hypersecretion).
- β-cell failure (early stage): However, at some point, β cells exhaust their capacity to adapt. β-cell compensation cannot maintain normal blood sugar levels. At ths stage, the patient develop impaired glucose tolerance.
- β-cell failure (late stage): The early stage ofβ-cell failure is followed by decreased insulin secretion, hyperglycemia, and frank diabetes development.
- Direct toxicity by amyloid deposits: In long-standing type 2 diabetes, amyloid deposits in islets is seen in more than 90% of cases. The islet amyloid protein may be directly cytotoxic to islets causing β-cell dysfunction. This may be similar to amyloid plaques involved in the pathogenesis of Alzheimer’s disease.
Pathogenesis Of The Complications Of Diabetes
Write a short note on the pathogenesis of complications in diabetes mellitus.
Pathogenesis is multifactorial and includes:
- Hyperglycemia (glucotoxicity) is the main mediator
- Insulin resistance (described already)
- Obesity (described already).
Diabetes Of Hyperglycemia:
- Control of blood sugar level (glycemic control) can reduce the long-term complications of diabetes.
- Glycemic control is assessed by estimation of glycosylated hemoglobins (HbA1C). HbA1C is formed by the addition of glucose to hemoglobin in red cells.
- HbA1C should be maintained below 7% in diabetic patients and its measurement is helpful in knowing the glycemic control over the lifespan of a red cell (120 days).
Organ Damage by Hyperglycemia:
- Chronic hyperglycemia and metabolic disorders cause secondary damage in multiple organ systems.
- Common organs damaged are kidneys (end-stage renal disease), eyes (adult-onset blindness), nerves, and blood vessels (gangrene of lower extremity).
Effects Hyperglycemia:
The harmful effcts of persistent hyperglycemia on peripheral tissues can be brought out by three distinct metabolic pathways.
Formation of Advanced Glycation End Products (AGEs):
In diabetics, glucose binds to proteins nonenzymatically and is termed nonenzymatic glycosylation.
- Initial products: The initial products of nonenzymatic glycosylation are chemically known as Schiff bases are labile and can dissociate rapidly.
- Later products: The initial labile products form → stable advanced glycation end products (AGEs). The rate of AGE formation is markedly increased in the presence of hyperglycemia.
- Effects of AGEs: It may be brought out by binding of AGEs to its specifi receptor (RAGE receptor for AGE) or by its direct action.
- Releases pro-inflmmatory cytokines and growth factors from intimal macrophages
- Production of reactive oxygen species in endothelial cells
- Increases procoagulant activity on endothelial cells and macrophages
- Increases proliferation of vascular smooth muscle cells and synthesis of extracellular matrix
- Resist proteolytic digestion → results in decreased removal and increased deposition of protein → trapping of proteins in the glycosylated collagen of the basement membrane thickening.
- Trapping of LDL in the intima → accelerating atherogenesis.
Activation of Protein Kinase C (PKC):
In patients with hyperglycemia, intracellular hyperglycemia stimulates the synthesis of diacyl glycerol (DAG) from glycolytic intermediates. DAG activates intracellular protein kinase C.
Consequences of PKC activation: It produces:
- Proangiogenic molecules such as vascular endothelial growth factor (VEGF) → cause neovascularization characteristic of diabetic retinopathy.
- Profirogenic factors (for example, TGF-β) → result in increased production of extracellular matrix and basement membrane material.
- Plasminogen activator inhibitor (PAI-1) → reduces fibrinolysis and favors vascular occlusion (by forming atherosclerotic plaques or thrombus).
Disturbances in Polyol Pathways:
- Some tissues (for example, Nerves, lenses, kidneys, and blood vessels) do not require insulin for glucose transport.
- Persistent hyperglycemia increases the intracellular glucose in these tissues → excess intracellular glucose is metabolized by the enzyme aldose reductase → to sorbitol (polyol) → to fructose.
- This reaction uses NADPH (the reduced form of nicotinamide dinucleotide phosphate) as a cofactor.
- NADPH is also necessary for the regeneration of reduced glutathione (GSH). GSH protects against injury by free radicals.
- Reduced NADPH → decrease in GSH → increases cells’ susceptibility to oxidative stress.
Morphology of PKC activation: Pancreas
Lesions of the pancreas are not diagnostic and are more common with type 1 than with type 2 diabetes. The morphological changes include:
- Reduced number and size of islets: It is seen in type 1 diabetes which is mild in type 2 diabetes.
- Infiltration of islets (insulitis): Mainly by T lymphocytes predominantly in type 1 diabetes.
- Amyloid deposition within islets: It is observed in and around capillaries and between cells in type 2 diabetes. In advanced stages, the islets may be virtually obliterated and may show fibrosis.
- Increase in the number and size of islets.
Blood Vessels:
- Hyaline arteriolosclerosis: It can be found in hypertension, elderly nondiabetics without hypertension and more severe degree in diabetics also.
- In diabetics, it is related to the duration of diabetes and the level of blood pressure.
- It is characterized by amorphous, hyaline thickening of the wall of the arterioles, which may narrow the lumen of the vessel.
- Diabetic microangiopathy: It is characterized by diffuse thickening of basement membranes, which is mostly seen in the capillaries of the skin, skeletal muscle, retina, renal glomeruli, and renal medulla.
- Though capillaries show basement membrane thickening, they are leakier to plasma proteins than normal.
- The microangiopathy results in diabetic nephropathy, retinopathy, and some forms of neuropathy
Diabetic Nephropathy — Renal Changes in Diabetes:
Write a short note on renal changes in diabetes mellitus (diabetic nephropathy).
Diabetic nephropathy is the term used for collective lesions that often occur together in the diabetic kidney. Diabetic nephropathy can develop in both insulin-dependent type 1 diabetes and type 2 diabetes.
- The kidneys are the main targets of diabetes.
- Renal failure is second only to myocardial infarction as a cause of death in diabetes.
Renal lesions in diabetes can involve any component. Four lesions are encountered namely:
Write a short note on the KW lesion.
- Glomerular lesions
- Renal vascular lesions (mainly arteriolosclerosis)
- Pyelonephritis (including necrotizing papillitis)
- Tubular lesions.
1. Glomerular Lesions:
- They are the most important and common renal lesions.
- These include:
- Thickening of capillary basement membrane (GBM)
- Diffuse mesangial sclerosis, and
- Nodular glomerulosclerosis (Kimmelstiel-Wilson nodules).
- Diffse widespread thickening glomerular capillary basement membrane.
- Diffuse mesangial sclerosis: It is characterized by diffuse increase in PAS-positive mesangial matrix and mesangial cells.
- Nodular glomerulosclerosis: It is also called intercapillary glomerulosclerosis or KimmelstielWilson disease and is pathognomonic.
- The glomerular lesion consists of ovoid or spherical, often laminated, nodules of mesangial matrix seen within the mesangial core and situated in the periphery of the glomerulus.
- These nodules can be surrounded by peripheral capillary loops with patent or dilated lumen. The nodules are
- PAS-positive. As the disease advances, the individual nodules increase in size → compress the surrounding capillaries.
- Insulative lesions:
- Fibrin caps: These are prominent subendothelial accumulations of hyaline material in/along capillary loops.
- Capsular drops: They consist of round nodules adherent to Bowman’s capsules and are seen between Bowman’s capsules and the parietal epithelium.
2. Renal Vascular Lesions:
- Hyaline arteriosclerosis (hyalinosis): It involves both the afferent and the afferent arteriole at the hilum of glomeruli. Arteriolosclerosis effrent arteriole is rare in nondiabetics.
- Renal atherosclerosis: It involves arteries and arterioles and is similar to those found in other parts of the body.
Glomerular and arteriolar lesions together produce renal ischemia → leading to atrophy of tubules, interstitial fibrosis, and contraction of the kidney.
3. Pyelonephritis:
It is a tubulointerstitial inflammation of the kidneys.
- Both acute and chronic pyelonephritis occurs in nondiabetics as well as in diabetics. It is more common and tends to be more severe in diabetics than in the general population.
- Necrotizing papillitis (or papillary necrosis): It is one special pattern of acute pyelonephritis and is much more frequent in diabetics compared to non-diabetics. Hyaline arteriolosclerosis narrows blood vessels → reduces the blood supply to the renal medulla → ischemia → causes necrosis of the tips of papillae (papillary necrosis).
4. Tubular Lesions:
- The basement membrane of the tubules shows thickening.
- In patients with high blood sugar levels, the epithelial cells of the proximal convoluted tubules show extensive deposits of vacuoles of glycogen.
- These are known as Armanni-Ebstein lesions.
Electron Microscopy:
- Thickening of the lamina densa of the glomerular basement membrane.
- Increase in the mesangial matrix, particularly in nodular lesions.
- Insulative lesions appear as electron-dense masses.
Immunofluorescence Microscopy: It reveals IgG, albumin, fibrinogen, and other plasma proteins in the GBM.
Clinical Features of Diabetes:
Type 1 Diabetes Mellitus:
- Age: Type 1 diabetes can occur at any age.
- The classical triad of diabetes: It consists of polyuria, polydipsia, polyphagia, and in severe cases ketoacidosis, which are due to metabolic derangements.
- Insulin requirement: In the initial 1 or 2 years, the exogenous insulin required may be minimal because of endogenous insulin secretion → Later,its requirement suddenly increases.
Consequences of Insulin Deficiency:
Insulin is an anabolic hormone and its deficiency → results in a catabolic state, which affects glucose metabolism, fat, and protein metabolism.
1. Carbohydrate metabolism:
- Diminished transport of glucose into muscle cells and adipose tissue.
- Reduction of stored glycogen in the liver and muscle due to glycogenolysis → This further aggravates hyperglycemia.
- When hyperglycemia exceeds the renal threshold level → develops glycosuria → leads to osmotic diuresis → increased the quantity of urine known as polyuria, with loss of water and electrolytes.
- Water loss through urine + hyperosmolarity (due to hyperglycemia) → causes depletion of intracellular water → stimulates the osmoreceptors of the thirst centers of the brain → results in increased thirst known as polydipsia.
2. Protein and fat metabolism:
- Insulin deficiency → causes catabolism of proteins and fats → produces a negative energy balance → leads to increased appetite (polyphagia).
- In spite of increased appetite, the catabolic effects of insulin result in paradoxical loss of weight and muscle weakness.
3. Diabetic ketoacidosis:
1. Serious complications of diabetes
2. More common and marked in type 1 diabetes, but may also occur in type 2 diabetes.
3. Mechanism:
- Diuresis and dehydration: Marked insulin deficiency + associated epinephrine release → stimulates the secretion of glucagon → leads to decreased peripheral utilization of glucose + increased gluconeogenesis → causes severe hyperglycemia (the blood glucose levels of 500 to 700 mg/dL) → osmotic diuresis and dehydration (characteristic features of ketoacidosis).
- Activation of the ketogenic machinery:
- Insulin deficiency → stimulates lipoprotein lipase → which breaks down fat stores → increases the free fatty acids levels.
- Free fatty acids are esterified to fatty acyl-coenzyme A in the liver.
- In the mitochondria of liver cells, fatty acyl-coenzyme A molecules are oxidized to ketone bodies (acetoacetic acid and β-hydroxybutyric acid).
- When the rate of production of ketone bodies exceeds the rate of utilization by peripheral tissues, it results in ketonemia and ketonuria.
- If the excretion of ketone bodies in the urine is compromised by dehydration, it results in systemic metabolic ketoacidosis.
Type 2 Diabetes Mellitus:
- Age: Usually occurs in older above the age of 40 years and frequently in obese individuals. Due to the increase in obesity and sedentary lifestyle, it is now detected also in children and adolescents.
- Presentation: Polyuria, polydipsia, unexplained weakness or weight loss. Ketoacidosis is infrequent and presentation is usually mild.
- In asymptomatic individuals, the diagnosis is made after routine blood or urine testing.
- Differences between type 1 and type 2 diabetes mellitus are listed in Table.
Differences between type 1 and type 2 diabetes mellitus:
List the differences between type 1 and type 2 diabetes mellitus.
Complications of type 1 diabetes mellitus :
Write a short note on complications of type 1 diabetes mellitus.
- Complications are similar in both type 1 and type 2 diabetes.
- Long-term complications of diabetes usually develop about 15 to 20 years after the onset of hyperglycemia. They are responsible for the majority of the morbidity and mortality.
Diabetic Macrovascular Disease:
The lesions of large- and medium-sized muscular arteries are the most common causes of mortality in long-standing diabetes. These include:
- Atherosclerosis: Diabetes is one of the major modifiable risk factors for atherosclerosis and other cardiovascular morbidities. Atherosclerosis is more severe and occurs at an earlier age.
- Myocardial infarction: It is due to atherosclerosis of the coronary arteries and is the most common cause of death in diabetics. Diabetics have a greater risk of coronary artery disease and cardiovascular complications than non-diabetics.
- Gangrene of the lower extremities: It results from advanced vascular disease and is more common in diabetics.
- Renal vascular insufficiency.
- Cerebrovascular accidents (stroke).
Microvascular Disease (Microangiopathy):
It involves small vessels and is characterized by capillary dysfunction in target organs and is mainly observed in kidneys (nephropathy), retina (diabetic retinopathy), and peripheral nerves (neuropathy).
- Diabetic nephropathy: About 30% to 40% of all diabetics develop nephropathy (discussed above) and is the leading cause of end-stage renal disease.
- Diabetic retinopathy: It develops in ~60% to 80% of diabetics, about 15 to 20 years after diagnosis. The basic lesion of retinopathy is neovascularization caused by hypoxia-induced overexpression of VEGF in the retina. Diabetics have an increased risk for glaucoma and cataract formation.
- Diabetic neuropathy: It may involve the central and peripheral nervous systems.
Diabetic Dyslipidemia:
- It is a condition in which there are increased blood levels of triglycerides and LDL and decreased levels of high-density lipoprotein (protective).
- Increased Susceptibility to Infections
- Infections of the skin, tuberculosis, pneumonia, and pyelonephritis are common in diabetes.
Leave a Reply