Chair prof dr b jayakumar
This presentation is the property of its rightful owner.
Sponsored Links
1 / 66

Diabetes Mellitus definition, classification & aetiopathogenesis PowerPoint PPT Presentation


  • 95 Views
  • Uploaded on
  • Presentation posted in: General

CHAIR: Prof.Dr.B.Jayakumar . Diabetes Mellitus definition, classification & aetiopathogenesis. Introduction. The prevalence of Diabetes is increasing rapidly,particularly in children and young adults. One third of cases of Diabetes remain undiagnosed.

Download Presentation

Diabetes Mellitus definition, classification & aetiopathogenesis

An Image/Link below is provided (as is) to download presentation

Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author.While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server.


- - - - - - - - - - - - - - - - - - - - - - - - - - E N D - - - - - - - - - - - - - - - - - - - - - - - - - -

Presentation Transcript


Chair prof dr b jayakumar

CHAIR: Prof.Dr.B.Jayakumar.

Diabetes Mellitusdefinition, classification & aetiopathogenesis


Introduction

Introduction

  • The prevalence of Diabetes is increasing rapidly,particularly in children and young adults.

  • One third of cases of Diabetes remain undiagnosed.

  • The burden of death and disability from Diabetes remains great despite broad advances in understanding and therapeutic techniques.


Diabetes mellitus definition classification aetiopathogenesis

  • Only few patients with Diabetes broadly achieve targets for blood pressure,lipid, or glucose management.

  • Only few patients with Diabetes receive all the recommended annual screening evaluations for complications or preventive services.

  • Organised system of health care delivery can achieve better control of diabetes and its comorbidities.


Definition

Definition:

Second century understanding:

  • Diabetes is a dreadful affliction, not very frequent among men, being a melting down of the flesh and limbs in to urine. The patients never stop making water and the flow is incessant…….Life is short and unpleasant.

    Greek Physician Aretaeus of Cappadocia


Present who definition

Present WHO definition:

  • The term diabetes mellitus describes a metabolic disorder of multiple aetiology characterized by chronic hyperglycaemia with disturbances of carbohydrate, fat and protein metabolism resulting from defects in insulin secretion, insulin action, or both.

  • The effects of diabetes mellitus include long-term damage, dysfunction and failure of various organs.


Diabetes mellitus definition classification aetiopathogenesis

  • Diabetes mellitus may present with characteristic symptoms such as thirst, polyuria, blurring of vision, and weight loss.

  • In its most severe forms, ketoacidosis or a non-ketotichyperosmolar state may develop and lead to stupor, coma and, in absence of effective treatment, death.

  • Often symptoms are not severe, or may be absent, and consequently hyperglycaemia sufficient to cause pathological and functional changes may be present for a long time before the diagnosis is made.


Diabetes mellitus definition classification aetiopathogenesis

  • The long-term effects of diabetes mellitus include progressive development of the specific complications of retinopathy with potential blindness, nephropathy that may lead to renal failure, and/or neuropathy with risk of foot ulcers, amputation, Charcot joints, and features of autonomic dysfunction, including sexual dysfunction.

  • People with diabetes are at increased risk of cardiovascular, peripheral vascular and cerebrovascular disease


Diabetes mellitus definition classification aetiopathogenesis

  • Several pathogenetic processes are involved in the development of diabetes. These include processes which destroy the beta cells of the pancreas with consequent insulin deficiency, and others that result in resistance to insulin action.

  • The abnormalities of carbohydrate, fat and protein metabolism are due to deficient action of insulin on target tissues resulting from insensitivity or lack of insulin.


Diabetes mellitus definition classification aetiopathogenesis

Classification:

  • Now Diabetes Mellitus is classified on the basis of the pathogenic process that leads to hyperglycemia.

  • I. Type 1 diabetes

    A. Immune-mediated

       B. Idiopathic

    II. Type 2 diabetes


Diabetes mellitus definition classification aetiopathogenesis

  • III. Other specific types of diabetes

  •   A. Genetic defects of Beta cell function characterized by mutations in:

  •     1. Hepatocyte nuclear transcription factor (HNF) 4alfa (MODY 1)

  •     2. Glucokinase (MODY 2)

  •     3. HNF-1alfa (MODY 3)

  •     4. Insulin promoter factor-1 (IPF-1; MODY 4)

  •     5. HNF-1beta (MODY 5)

  •     6. NeuroD1 (MODY 6)

  •     7. Mitochondrial DNA

  •     8. Subunits of ATP-sensitive potassium channel

  •     9. Proinsulin or insulin conversion


Diabetes mellitus definition classification aetiopathogenesis

  • B. Genetic defects in insulin action

  •     1. Type A insulin resistance

  •     2. Leprechaunism

  •     3. Rabson-Mendenhall syndrome

  •     4. Lipodystrophy syndromes

  • C. Diseases of the exocrine pancreas—pancreatitis, pancreatectomy, neoplasia, cystic fibrosis, hemochromatosis, fibrocalculouspancreatopathy, mutations in carboxyl ester lipase


Diabetes mellitus definition classification aetiopathogenesis

  •   D. Endocrinopathies— acromegaly, Cushing's syndrome, glucagonoma, pheochromocytoma, hyperthyroidism, somatostatinoma, aldosteronoma.

  • E. Drug- or chemical-induced— Vacor, pentamidine, nicotinic acid, glucocorticoids, thyroid hormone, diazoxide, -adrenergic agonists, thiazides, phenytoin, -interferon, protease inhibitors, clozapine


Diabetes mellitus definition classification aetiopathogenesis

  • F. Infections— congenital rubella, cytomegalovirus, coxsackie.

  • G. Uncommon forms of immune-mediated diabetes — "stiff-person syndrome , anti-insulin receptor antibodies.


Diabetes mellitus definition classification aetiopathogenesis

  • H. Other genetic syndromes sometimes associated with diabetes— Down's syndrome, Klinefelter's syndrome, Turner's syndrome, Wolfram's syndrome, Friedreich's ataxia, Huntington's chorea, Laurence-Moon-Biedl syndrome, myotonic dystrophy, porphyria, Prader-Willi syndrome.

  • IV. Gestational diabetes mellitus (GDM)


Aetiopathogenesis

Aetiopathogenesis:

  • I.Type 1 Diabetes

  • A. Immune-mediated:

  • Type 1 DM is the result of interactions of Genetic Environmental & Immunological factors leading to destruction of beta cells and insulin deficiency.


Diabetes mellitus definition classification aetiopathogenesis

  • Geneticfactors:

  • Susceptibility to type 1 DM involves multiple genes

  • The major susceptibility gene for type 1 DM is located in the HLA region on chromosome 6.

  • Commonly associated haplotypes are HLA DR3 and/or DR4, DQA1*0301, DQB1*0302, and DQB1*0201.


Diabetes mellitus definition classification aetiopathogenesis

  • Genetic loci contributing susceptibility to Type 1 DM are polymorphisms in the promoter region of the insulin gene, the CTLA-4 gene, interleukin-2 receptor, and PTPN22.

  • Although the risk of developing type 1 DM is increased tenfold in relatives of individuals with the disease, most individuals with type 1 DM do not have a first-degree relative with this disorder.


Diabetes mellitus definition classification aetiopathogenesis

  • Environmental factors:

  • Environmental triggers include viruses (coxsackie and rubella most prominently), bovine milk proteins, and nitrosourea compounds.

  • Identification of an environmental trigger has been difficult because the event may precede the onset of DM by several years.


Diabetes mellitus definition classification aetiopathogenesis

  • Immunologic Factors:

  • Following abnormalities in humoral and cellular arms of immune system have been identified.

  • 1)Islet cell autoantibodies 2)Activated lymphocytes in islets,peripancreatic lymph nodes and systemic circulation 3) T lymphocytes that proliferate when stimulated with islet proteins; and 4) release of cytokines within the insulitis


Diabetes mellitus definition classification aetiopathogenesis

  • Pancreatic islet molecules targeted by the autoimmune process include

  • Insulin, glutamic acid decarboxylase (GAD), ICA-512/IA-2 , and phogrin (insulin secretory granule protein).


Diabetes mellitus definition classification aetiopathogenesis

  • These Genetic Environmental & Immunological factors interact leading to destruction of beta cells and insulin deficiency.

  • Features of diabetes do not become evident until a majority of beta cells are destroyed.

  • These patients may alsohave other autoimmune disorders such as Graves’ disease,Hashimoto’sthyroiditis, and Addison’s disease.


Diabetes mellitus definition classification aetiopathogenesis

  • B. Idiopathic

  • Some individuals who have the clinical phenotype of type 1 DM lack immunologic markers indicative of an autoimmune process involving the beta cells.

  • These individuals are thought to develop insulin deficiency by unknown, nonimmune mechanisms.


Diabetes mellitus definition classification aetiopathogenesis

  • II. Type 2 diabetes

  • Environmental factors (such as obesity, nutrition, and physical activity) in Genetic susceptible patients leads to . a)Impaired insulin secretion b)Insulin resistance c)Excessive hepatic glucose & lipid production d)Abnormal fat metabolism.


Diabetes mellitus definition classification aetiopathogenesis

  • a)Impaired insulin secretion

  • In type 2 DM, insulin secretion initially increases in response to insulin resistance to maintain normal glucose tolerance.

  • Eventually, the insulin secretory defect progresses to a state of grossly inadequate insulin secretion.


Diabetes mellitus definition classification aetiopathogenesis

  • The reason(s) for the decline in insulin secretory capacity in type 2 DM is

  • 1)A second genetic defect—superimposed upon insulin resistance—leads to beta cell failure. 2)Glucose toxicity - Chronic hyperglycemia paradoxically impairs islet function. 3) Lipotoxicity - Elevation of free fatty acid levels and dietary fat also worsen islet function


Diabetes mellitus definition classification aetiopathogenesis

b)Insulin resistance

  • Insulin resistance, the decreased ability of insulin to act effectively on target tissues is a prominent feature of Type2 DM.


Diabetes mellitus definition classification aetiopathogenesis

  • Insulin binds to receptors on target site

  • Receptor autophosphorylation

  • Recruitment of intracellular signalling molecules

  • Insulin Receptor Substrate(IRS) and other protein complex initiate a cascade of phosphorylation and autophosphorylation reactions resulting in metabolic and mitogenic effects of insulin.


Diabetes mellitus definition classification aetiopathogenesis

  • Postreceptor defects in insulin-regulated phosphorylation/dephosphorylation plays the predominant role in insulin resistance.

  • The accumulation of lipid within skeletal myocytes, which may impair mitochondrial oxidative phosphorylation and reduce insulin-stimulated mitochondrial ATP production leading to insulin resistance.


Diabetes mellitus definition classification aetiopathogenesis

  • Insulin receptor levels and tyrosine kinase activity in skeletal muscle are reduced, but these alterations are most likely secondary to hyperinsulinemia and are not a primary defect.

  • Insulin resistance in Liver

    Failure to supressgluconeogenesis

    Fasting hyperglycemia.

.


Diabetes mellitus definition classification aetiopathogenesis

  • Insulin Resistance in liver

  • Decreased glycogen storage in postprandial state

  • Postprandial hyperglycemia


Diabetes mellitus definition classification aetiopathogenesis

  • Peripheral insulin resistance.

  • Decreased peripheral gluose usage.

  • Postprandial hyperglycemia.


Diabetes mellitus definition classification aetiopathogenesis

  • c)Excessive hepatic glucose & lipid production:

  • Insulin resistance in liver Excess production of glucose.

  • Insulin resistance in Adipose tissue

    Free Fatty Acid flux from adipocytes Increased lipid synthesis in hepatocytes.


Diabetes mellitus definition classification aetiopathogenesis

  • d)Abnormal fat metabolism:

  • The obesity accompanying type 2 DM, is thought to be part of the pathogenic process

  • The adipocytes secrete a number of biologic products.

  • The increased production of Resistin,TNFalfa, IL-6 by adipocytes are associated with insulin resistance.

  • Adiponectin and Leptin secreted by adipocytes increase insulin sensitivity and are decreased in obesity.


Diabetes mellitus definition classification aetiopathogenesis

  • III. Other specific types of diabetes

  • A. Genetic defects of Beta cell function characterized by mutations :

  • I. (MODY 1) : Mutation in Hepatocyte nuclear transcription (HNF) 4 alfa.

  • This transcription network plays a role in the early development of the pancreas.

  • In the pancreas these genes influence expression of, among others, the genes for insulin, the principal glucose transporter (GLUT2), and several proteins involved in glucose and mitochondrial metabolism.


Diabetes mellitus definition classification aetiopathogenesis

  • MODY2:

  • MODY 2 is due to any of several mutations in the GCK gene on chromosome 7 for glucokinase.

  • Glukokinase serves as the glucose sensor for the beta cell.

  • These loss-of-function mutations result in a glucokinase molecule that is less sensitive or less responsive to rising levels of glucose.


Diabetes mellitus definition classification aetiopathogenesis

  • 3. HNF-1alfa (MODY 3)

  • MODY 3 is caused by mutations of the HNF1α gene, a homeobox gene on chromosome 12.

  • HNF1α is a transcription factor important for differentiation of beta cells.

  • Mutations of this gene lead to reduced beta cell mass or impaired function


Diabetes mellitus definition classification aetiopathogenesis

  • 4. Insulin promoter factor-1 (IPF-1; MODY 4) MODY 4 arises from mutations of the IPF1homeobox gene on chromosome 13.

  • IPF1 is a transcription factor vital to the development of the embryonic pancreas.

  • Even in adults it continues to play a role in the regulation and expression of genes for insulin, GLUT2, glucokinase, and somatostatin


Diabetes mellitus definition classification aetiopathogenesis

  • 5. HNF-1 . (MODY5):

  • HNF1β is involved in early stages of embryonic development of several organs, including the pancreas.

  • Most of those who develop diabetes show atrophy of the entire pancreas, with mild or subclincal deficiency of exocrine as well as endocrine function (MODY 5).


Diabetes mellitus definition classification aetiopathogenesis

  • 6. NeuroD1 (MODY 6)

  • MODY 6 arises from mutations of the gene for the transcription factor referred to as neurogenic differentiation .

  • NeuroD1 promotes transcription of the insulin gene as well as some genes involved in formation of beta cells and parts of the nervous system  


Diabetes mellitus definition classification aetiopathogenesis

  • 7.MitochondrialDNA:

    Point mutations in mitochondrial DNA have been found to beassociated with diabetes mellitus and deafness.

  • 8. Subunits of ATP-sensitive potassium channel : Mutations in subunits of the ATP-sensitive potassium channel subunits are the major causes of permanent neonatal diabetes.


Diabetes mellitus definition classification aetiopathogenesis

  • 9. Proinsulin or insulin conversion:

    Genetic abnormalities that result in the inability to convertproinsulin to insulin and the resultant carbohydrate intolerance have been identified


Diabetes mellitus definition classification aetiopathogenesis

  •   B. Genetic defects in insulin action

  •     1. Type A insulin resistance:

  • Individuals with the type A insulin resistance syndrome have an undefined defect in the insulin-signaling pathway


Diabetes mellitus definition classification aetiopathogenesis

  •  2. Leprechaunism

    and 3. Rabson-Mendenhall syndrome

    are two paediatric syndromes that

    have mutations in the insulin receptor gene with subsequentalterations in insulin receptor function and extreme insulinresistance.


Diabetes mellitus definition classification aetiopathogenesis

  • C. Diseases of the pancreas :

  • Any process that diffusely injures the pancreas can cause diabetes pancreas:

  • pancreatitis, pancreatectomy, neoplasia, cystic fibrosis, hemochromatosis, fibrocalculouspancreatopathy.


Diabetes mellitus definition classification aetiopathogenesis

  • D. Endocrinopathies—

  • Several hormones (e.g. growth hormone, cortisol, glucagon,

    epinephrine) antagonize insulin action.

  • Diseases associatedwith excess secretion of these hormones can cause diabetes.

    (e.g. Acromegaly, Cushing’s Syndrome, Glucagonoma and Phaeochromocytoma).

  • These forms of hyperglycaemia

    typically resolve when the hormone excess is removed.


Diabetes mellitus definition classification aetiopathogenesis

  • E. Drug- or chemical-induced DM:

  • Many drugs can impair insulin secretion.

  • These drugs maynot, by themselves, cause diabetes but they may precipitate

    diabetes in persons with insulin resistance.

  • Vacor, pentamidine, canpermanently destroy pancreatic beta cells.

  • Nicotinic acid, glucocorticoids, can impair insulin action.


Diabetes mellitus definition classification aetiopathogenesis

  • F. Infections—

  • Certain viruses have been associated with beta–celldestruction.

  • Congenital rubella, cytomegalovirus, coxsackie, adenovirus and mumps have beenimplicated in inducing the disease.


Diabetes mellitus definition classification aetiopathogenesis

  • G. Uncommon forms of immune-mediated diabetes —

  • "stiff-person syndrome and anti-insulin receptor antibodies.

  • The “stiff person syndrome” is an autoimmune disorder of the central nervoussystem, characterized by stiffness of the axial muscles withpainful spasms (87). Affected people usually have high titresof the GAD autoantibodies and approximately one-half will

    develop diabetes.

  • Anti–insulin receptor antibodies occasionally found in patients withsystemic lupus erythematosus and other autoimmune diseases can cause diabetes by

    binding to the insulin receptor.  


Diabetes mellitus definition classification aetiopathogenesis

  • Other genetic syndromes sometimes associated with diabetes—

  • Many genetic syndromes are accompanied by an increasedincidence of diabetes mellitus.

  • These include thechromosomal abnormalities of Down’s syndrome,Klinefelter’s syndrome and Turner’s syndrome, Wolfram's syndrome, Friedreich's ataxia, Huntington's chorea, Laurence-Moon-Biedl syndrome, myotonic dystrophy, porphyria, Prader-Willi syndrome.


Diabetes mellitus definition classification aetiopathogenesis

  • IV. Gestational diabetes mellitus (GDM)

  • Gestational diabetes is carbohydrate intolerance resulting inhyperglycaemia of variable severity with onset or first

    recognition during pregnancy.

  • It does not exclude thepossibility that the glucose intolerance may antedatepregnancy but has been previously unrecognized.


Diabetes mellitus definition classification aetiopathogenesis

  • Insulin resistance related to the metabolic changes of late pregnancy, and

  • The increased insulin requirements may lead to IGT .  


Screening diagnosis

Screening & Diagnosis

  • SCREENING FORDIABETES:

  • Recommendations:

  • The ADA recommends screening of all individuals >45 years every 3 years.

  • screening individuals at an earlier age if they are overweight [body mass index (BMI) > 25 km/m2] and have one additional risk factor for diabetes


Diabetes mellitus definition classification aetiopathogenesis

Risk Factors for Type 2 Diabetes Mellitus

  • Family history of diabetes (i.e., parent or sibling with type 2 diabetes)

  • Obesity (BMI 25 kg/m2)

  • Habitual physical inactivity

  • Race/ethnicity (e.g., African American, Latino, Native American, Asian American, Pacific Islander)

  • Previously identified IFG or IGT

  • History of GDM or delivery of baby >4 kg (>9 lb)

  • Hypertension (blood pressure 140/90 mmHg)

  • HDL cholesterol level <35 mg/dL (0.90 mmol/L) and/or a triglyceride level >250 mg/dL (2.82 mmol/L)

  • Polycystic ovary syndrome or acanthosisnigricans

  • History of vascular disease


Diabetes mellitus definition classification aetiopathogenesis

  • ● To screen for diabetes/pre-diabetes, either

  • An FPG test or 2-h OGTT (75-g

    glucose load) or both are appropriate.

  • (B) An OGTT may be considered in patientswith IFG to better define the risk

    of diabetes.


Diabetes mellitus definition classification aetiopathogenesis

  • Immunolical markers: In contrast to type 2 DM, a long asymptomatic period of hyperglycemia is rare prior to the diagnosis of type 1 DM. A number of immunologic markers for type 1 DM are becoming available (discussed below), but their routine use is not recommended now.


Diabetes mellitus definition classification aetiopathogenesis

  • Diagnosis of Diabetes:

  • ADA Criteria for the diagnosis of diabetes

  • 1. Symptoms of diabetes and a casual plasma glucose 200 mg/dl (11.1 mmol/l).

    OR

  • 2. FPG 126 mg/dl (7.0 mmol/l).

    OR

  • 3. 2-h plasma glucose 200 mg/dl (11.1 mmol/l) during an OGTT. (75gm)


Diabetes mellitus definition classification aetiopathogenesis

  • WHO Criteria for diagnosis of diabetes mellitus

  • Diabetes:

    Fasting > 7.0 (> 126)

    Or2-h post glucose load > 11.1 (> 200)

    or both

  • Impaired Glucose Tolerance (IGT):

    Fasting (if measured) < 7.0 (< 126)

    & 2-h post glucose load > 7.8 (> 140) & < 11.1(<200)

  • Impaired Fasting Glycaemia (IFG):

    Fasting > 6.1 (> 110) & < 7.0 (< 126)and (if measured)

    2-h post glucose load < 7.8 (< 140


Diabetes mellitus definition classification aetiopathogenesis

  • Some investigators have advocated the hemoglobin A1C (A1C) as a diagnostic test for DM.

  • Though there is a strong correlation between elevations in the plasma glucose and the A1C , the relationship between the FPG and the A1C in individuals with normal glucose tolerance or mild glucose intolerance is less clear, and thus the use of the A1C is not currently recommended to diagnose diabetes.


Iii detection and diagnosis of gdm

III. DETECTION AND DIAGNOSIS OF GDM

Recommendations:

  • ● Screen for diabetes in pregnancy using

    risk factor analysis and, if appropriate,use of an OGTT.

  • The OGTT should be done in the morning after anovernight fast of 8–14 h.


Diabetes mellitus definition classification aetiopathogenesis

  • ●Risk assessment for GDM should be undertakenat the first prenatal visit.

  • Womenwith clinical characteristics consistentwith a high risk for GDM (those withmarked obesity, personal history of GDM,glycosuria, or a strong family history ofdiabetes) should undergo glucose testingas soon as possible.

  • An FPG _126mg/dl or a casual plasma glucose _200mg/dl meets the threshold for the diagnosisof diabetes

  • High-risk women not found to haveGDMat the initial screening and average-riskwomen should be tested between 24 and28 weeks of gestation.


Diabetes mellitus definition classification aetiopathogenesis

  • Testing should followone of two approaches:

  • ● One-step approach: perform a diagnostic100-g OGTT

  • ● Two-step approach: perform an initial

    screening by measuring the plasma orserum glucose concentration 1 h after a50-g oral glucose load (glucose challengetest) and perform a diagnostic100-g OGTT on that subset of womenexceeding the glucose threshold valueon the glucose challenge test.


Diabetes mellitus definition classification aetiopathogenesis

When the two-step approach is used, a glucosethreshold value _140 mg/dl identifies80% of women with GDM, and theyield is further increased to 90% by usinga cutoff of _130 mg/dl.

  • criteria for the 100-g OGTTare as follows: _95 mg/dl fasting, _180mg/dl at 1 h, _155 mg/dl at 2 h, and_140 mg/dl at 3 h. Two or more of theplasma glucose values must be met or exceededfor a positive diagnosis.


Thank you

THANK YOU


  • Login