Diabetes mellitus

Diabetes mellitus

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  Diabetes Mellitus andit’s complications Dr. Abhra Ghosh
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  Diabetes Mellitus -Definition A chronic disease primarily due to disorder of carbohydrate metabolism, cause of which is deficiency or diminished effectiveness of insulin, resulting in hyperglycemia and glycosuria. Secondary changes may occur in the metabolism of proteins, fats, water and electrolytes and in tissues/organs sometimes with grave consequences
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  Types of DiabetesMellitus Classified into 4 general categories: 1. Type 1 diabetes [aka. Juvenile diabetes*] (due to autoimmune β-cell destruction, usually leading to absolute insulin deficiency) 2. Type 2 diabetes (due to a progressive loss of adequate β-cell insulin secretion frequently on the background of insulin resistance) 3. Gestational diabetes mellitus (diabetes diagnosed in the second or third trimester of pregnancy that was not clearly overt diabetes prior to gestation)
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  4. Specific typesof diabetes due to other causes, e.g., monogenic diabetes syndromes (such as neonatal diabetes and maturity-onset diabetes of the young*), diseases of the exocrine pancreas (such as cystic fibrosis and pancreatitis), and drug- or chemical-induced diabetes (such as with glucocorticoid use, in the treatment of HIV/AIDS, or after organ transplantation) Types of Diabetes Mellitus
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  Recent advances –Excerpts* 1. Immune markers of IDDM: • GAD – Glutamic acid decarboxylase is of potential significance • Anti-GAD antibodies is seen in Type I diabetes with age of onset >35 years • So, anti GAD helps in differentiating Type 1 and Type 2 DM
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  Recent advances –Excerpts* 2. Genes of DM – MODY • Few genes have been discovered – MODY1 (HNF4⍺) MODY2 (GCK) MODY3 (HNF1⍺) MODY5 (HNF1β) • Contributes to 2-5% of diabetes • Inheritable • Mutation of these genes increase the susceptibility to NIDDM
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  Clinical features • Polyuria •Polydipsia • Polyphagia • Generalized weakness, tiredness • Loss of weight • Dehydration • Hypercholesterolemia • Acidosis
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  Type 1 diabetesmellitus - Pathogenesis Exposure to a virus or toxin start the process of β cell destruction Infiltration of the β cells by lymphocytes - insulitis Cells are destroyed – decrease in production of insulin When the insulin secretory capacity falls below a threshold, symptoms of type 1 diabetes appear
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  Type 2 diabetesmellitus - Pathogenesis Points to remember – • Metabolic alternations observed in T2D are milder • Reason is – Though inadequate, there is insulin secretion in T2DM • Acute complications are less compared to T1DM
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  Type 2 diabetesmellitus - Pathogenesis Obesity Increase in secretion of proinflammatory cytokines, leptins, decreased secretion of adiponectin Decrease in insulin receptor by internalization Insulin resistance and hyperinsulinemia Exhaustion of beta cells of pancreas Decrease in insulin secretion  T2DM
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  Metabolic changes Intestine Amino acidsChylomicrons Glucose Release into Adipose tissue Lipo. lipase Accumulation in blood Protein synthesis Neoglucogenesis Amino acids from muscle breakdown Mobilization of TAG Glycerol + FA Liver Acetyl CoA Ketone bodies VLDL
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  Progression of T2DM Insulin resistance Hyper insulinemia Impaired glucose tolerance Decline inbeta cell func T2DM Microvascular complications Macrovascular complications
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  Diagnosis The ADA recommendsthat the following people be screened for diabetes: • Anyone with a body mass index higher than 25 (23 for Asian Americans), regardless of age • Anyone older than age 45 • Women who have had gestational diabetes • Anyone who has been diagnosed with prediabetes
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  • Random bloodsugar test – ≥ 200mg/dL • Fasting blood sugar test – <100 mg/dL - Normal 100 to 125 mg/dL - Prediabetes >126 mg/dL - Diabetes • Oral glucose tolerance test – 140 mg/dL - Normal 140 to 199 mg/dL - IGT >200 mg/dL - Diabetes Diagnosis
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  Glycated hemoglobin (A1C)test: • Below 5.7%  normal • 5.7% to 6.4%  prediabetes • 6.5% or higher on two separate tests  diabetes • An A1C level of less than 7%  common treatment target for adult diabetic Diagnosis
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  Treatment • Weight reduction •Exercise • Dietary modification • Drugs – Oral hypoglycemic agents • Insulin
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  Complications Complications due toDM Acute 1. Diabetic ketoacidosis 2. Coma Chronic Involvement of small vessels 1. Retino, nephro, neuropathy 2. Diabetic gangrene 3. Skin lesions Involvement of large vessels 1. Atherosclerosis 2. Myocardial infarction 3. Stroke
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  Increased influx throughpolyol pathway Toxic aldehydes Inactive alcohols Aldose reductase Increased glucose Sorbitol NADPH NADP+ GSH GSSG
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  Intracellular production ofAGE precursors • Excess glucose causes alteration of proteins involved in gene regulation • AGE diffuses out of cells and modify extracellular matrix proteins • AGE binds with albumin  bind with AGE receptors  production of inflammatory markers
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  PKC activation Hyperglycemia ↑ DAG ↑PKC Vascular occlusion ↑ Vascular permeability ↑ Collagen formation Capillary occlusion Proinflamma tory gene expression ↑ ROS formation
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  Increased hexosamine pathwayactivity Fructose – 6 – phosphate Glucosamine – 6 – phosphate GFAT UDP – N – acetyl glucosamine Attach with serine and threonine residues of transcription factors Altered gene expression and vascular pathology
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  Inhibition of glyceraldehyde– 3 – phosphate dehydrogenase ↑ Glucose ↑ Glucose – 6 - phosphate ↑ Fructose – 6 – phosphate Glyceraldehyde – 3 phosphate 1,3 - bisphosphoglycerate ROS from mitochondria Poly ADP ribose ↓ GADPH PKC pathway AGE pathway Hexosamine pathway Polyol pathway
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  DKA
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  Complications in T1DMvs T2DM