Diabetes Mellitus

Keith J Kaplan MD Department of Pathology Mayo Clinic

Definition
Chronic disorder of carbohydrate, fat, and protein metabolism. Characterized by hyperglycemia resulting from impaired carbohydrate (glucose) utilization resulting from a defective or deficient insulin secretory response. The chronic hyperglycemia is associated with dysfunction and failure of various organs, especially the eyes, kidneys, nerves, heart, and blood vessels.

Incidence
1-2%

of US adult population (13 million 5%) >50% in some native American groups 35,000 annual deaths in US alone Number 7 leading cause of death Type I (IDDM Insulin-dependent DM) 10 20% (Lifetime risk = 0.5%) Type II (NIDDM Non-insulin dependent DM) 80 90% (Lifetime risk = 5-7%)

Types of Diabetes Mellitus

Primary
Type I - IDDM Type II - NIDDM

Secondary
Chronic Pancreatitis

(most common)

(most common) Hormonal (steroids) Hemachromatosis Post-Surgical

Classification Primary DM
Clinical Onset TYPE I (IDDM) < 20 Years Normal weight Insulin Islet cell Abs Common 50% in twins HLA-D associated Autoimmunity Severe insulin def Insulitis early Beta cell depletion TYPE II (NIDDM) > 30 Years Obese Nl or Insulin No islet cell Abs Rare (HONK) 90-100% in twins No HLA association Insulin resistance Relative insulin def No insulitits Mild beta cell loss

Ketoacidosis Genetics Pathogenesis Islet Cells

Classification Secondary DM
secondary to pancreatic islet cell destruction
Chronic pancreatitis
Tumors (Pheochromocytoma, pituitary) Drugs (Corticosteroids, thiazides, others) Hemochromatosis Genetic diseases (lipodystrophy) Hyperglycemia

The Pancreas (Two for One) Exocrine Endocrine

Endocrine Pancreas Islets of Langerhans

Cell Type (%)
Beta (70%) Alpha (5%-20%) Delta (5%) PP (1% - 2%) EC D1

Hormone
Insulin Glucagon Somatostatin Panc Polypeptide Serotonin VIP

Alpha

Beta

Blood Glucose & Various Hormones

Hormone
Insulin Glucortocoids Glucagon

Action
Glucose Glucose Glucose Glucose

Diabetic Syndrome

Growth Hormone Glucose Epinephrine

Insulin Effects: A major anabolic hormone

Transmembrane transport of glucose &

AAs Glycogen formation in liver and muscle Glucose conversion to triglycerides Nucleic acid synthesis Protein synthesis All act to decrease blood glucose levels

Normal Insulin Metabolism

Preproinsulin Proinsulin

Insulin Release from -cells and prolonged with increased stimulation Insulin & C-peptide stored and released in secretory granules & released together Tyrosine kinase receptor modulates this activity phosphorylation

Insulin
is the only hormone that decreases blood glucose. Insulin travels to its target sites of liver, muscle, & fat cells. Glucose can enter these cells only with the aid of insulin. Insulin binds with a cellular receptor site to exert its effect.
Insulin

Insulin Action

Cellular Glucose Uptake

Insulin Requiring Striated Muscle Cardiac Muscle Fibroblasts Adipocytes Non-Insulin Requiring Blood Vessels Nerves Kidney Lens

Pathogenesis Type I DM
Severe lack of insulin caused by reduction in

-cell mass by 1 of 3 proposed mechanisms: Genetic susceptibility

HLA-DR3 or DR4 alleles in 80 95% of patients 50% concordance in identical twins (DQ linkage)

Autoimmunity Insulitis Islet cell antibodies (T-cell mediated) Association with autoimmune endocrine diseases Enviromental factors Viral mimicry (mumps, coxsachie B), toxins, cows milk

Normal Insulin Physiology

Glucose Granules Synthesis
Immediate Delayed

Insulin Insulin

(-) Blood Glucose

Primary Diabetes
Type I Diabetes (~15% - IDDM) Hyperglycemia Type II Diabetes (~85% - NIDDM) Blood Vessels Kidneys Eyes Nerves

Pathogenesis Type II DM
Genetic susceptibility 90% concordance in identical twin studies Link not yet identified Insulin resistance Metabolic Defects Deranged insulin secretion to meet needs Insulin resistance in peripheral tissues Decreased numbers of insulin receptors Post-receptor defects Obesity associated with insulin resistance/ insulin

Relationship Between Obesity and Type II DM

Obesity is a cause of insulin resistance, which

is defined as a diminished biologic response (such as glucose transport) to insulin. Obesity is associated with hyperinsulinemia in the face of a normal or elevated blood glucose (the constellation of laboratory findings consistent with insulin resistance)

Type II DM and Obesity

Depends on family history, weight

distribution, and duration of obesity NIDDM is up to 10 times more likely in an obese person with a diabetic parent than in an equally obese subject with a negative family history Morbidly obese not necessarily diabetic

Fasting Insulin Levels and BMI

25 20 Fasting 15 Insulin (mU/l) 10 5 0 22 24 26 28 30 32 34 36 BMI

Metabolic Derangements
Disordered metabolism
Carbohydrates

fuel is broken down Fats increased lipolysis of stored fat Protein catabolism increased
Polyuria, polydipsia, polyphagia triad

osmotic diuresis polyuria Loss of water polydipsia Poorly defined mechanism polyphagia
Hyperglycemic

Metabolic Derangements
Ketoacidosis
Stimulated

by increase in glucagon Excessive breakdown of fat triglycerides fatty acids ketone bodies (in liver) Ketone bodies normally metabolized in muscle Lack of insulin ketonemia and ketonuria
Coma
DKA

IDDM HONK NIDDM

Pathogenesis of Complications
Non-enzymatic glycosylation Attachment to amino group of proteins Leads to AGEs (Advanced glycosylation end products) Accumulate on proteins in blood vessels & BMs Trapping of LDL/Cholesterol in vessels (atherosclerosis) Laboratory measurement glycosylated

hemoglobin levels (HbA1C) indicate level over several weeks

Pathogenesis of Complications
Intracellular hyperglycemia with disturbances

of PolyolSorbitol Pathway
Hyperglycemia may increase intracellular glucose Hyperosmolarity results in water influx osmotic cell injury (cataracts) Damage to Schwann cells (demyelination of nerves) & retinal capillary pericytes (microaneurysms) ? sorbitol/fructose

Pathogenesis of Complications
Increased Intracellular Glucose - Polyol Pathways Non-Insulin Requiring Cells Nerves Fructose Lens Sorbitol Kidneys Blood Vessels Glucose Osmolality Ion Pump Impairment + Osmolality

Pathogenesis of Complications
Increased Intracellular Glucose - Polyol Pathways Non-Insulin Requiring Cells Schwann Cells Retinal Pericytes
Sorbitol Sorbitol

Neuropathy Retinal Microaneurysms Lens Opacities

Lens

Fructose Sorbitol

Pathology - Atherosclerosis
75% under age of 40 have severe

atherosclerosis Complicated atherosclerosis ulceration, calcification, thrombosis ~50% with dyslipidemia, HDL Accelerated atherosclerosis
Platelet adhesiveness Thromboxane A2 Prostacyclins

Large vessel disease AMI, gangrene, CVA

Vascular Pathology in Diabetics

AMI Most common cause of death Renal failure Second most common cause

of death Gangrene of lower extremities Hyaline arteriosclerosis

Pathology Microangiopathy
BM thickening in capillaries of skin, skeletal muscle,

retina, glomeruli and renal medulla PAS+ thick BM Vessels become permeable to plasma proteins Secondary to AGEs Nephropathy, retinopathy, neuropathy Hypertension

Pathology Nephropathy
Microangiopathy leads to one or more of the

following: Diffuse or nodular diabetic glomerulosclerosis Renal arteriosclerosis & atherosclerosis Necrotizing renal papillitis

Pathology Nephropathy
Diffuse glomerulosclerosis less specific Nodular glomerulosclerosis more specific Insudative lesions accumulation of plasma proteins Fibrin cap between glomerular endothelium & GBM Capsular drop between parietal epithelial cell & Bowmans capsule Arteriolosclerosis both afferent & efferent arterioles

resulting in hypertension

Pathology - Retinopathy
Proliferative Retinopathy Non-Proliferative Cataracts Glaucoma

Ocular complications
Retinopathy 4th leading cause of blindness in US Non-proliferative retinal hemorrhages, exudates,

edema, venous dilatation, microangiopathy Proliferative neovascularization and fibrosis; blindness especially when it involves macula Cataracts, glaucoma Neovascularization of iris anterior chamber hemorrhage Mononeuropathy of cranial nerves diplopia

Pathology Neuropathy
Microangiopathy & Polyol Disturbances Peripheral Sensory & motor function of

lower extremities Autonomic Bladder & bowel function

Pathology Pancreatic
Reduction in size & number of islets (I > II) Increase size & number in newborns (GDM) Beta cell degranulation by EM (I) Fibrosis of islets (I & II) Amyloid replacement of islets (II > I) Lymphocytic infiltration Insulitis (II > I)

Infections
Mucormycosis of nasal sinuses

cavernous sinus thrombosis Staph, strept skin infections furuncles (boils), caruncles Candidiasis of vagina & oral cavity

Clinical
Type I (IDDM) 15% <20 y/o Normal Weight Insulin Islet Cell Abs Ketoacidosis Type II (NIDDM) 85% >30 y/o Obesity Nl/ Insulin No islet cell abs No ketoacidosis (HONK)

Type I Diabetes Clinical

Under 20 years of age Polyuria Polydipsia Polyphasia Ketoacidosis

Diabetic Ketoacidosis (DKA)

Type of Diabetes Age of Patient Acidosis Glucose Ketosis CNS Rx Type I - IDDM Younger Yes 400-800 mg/dl Yes Lethargy Insulin, Fluids

Diabetic Ketoacidosis
Insulin Fat Breakdown (Ketone Bodies) Ketoacids Acidosis

Laboratory Findings pH Glucose (600-800) HCO3 Ketones

Type II Risk Factors

Positive family history Obesity >20% BW or BMI > 27 kg/mL Age > 45 Previous IGT or IFG HDL < 35 mg/dl Triglycerides > 250 mg/dl

Type II Diabetes Clinical

Routine blood/urine testing

asymptomatic adult (>40y/o) Usually obese Unexplained weakness or weight loss May have polyphagia/polydipsia

Hyperosmolar Non-Ketotic Coma (HONK)

Type of Diabetes Age of Patient Acidosis Glucose Ketosis CNS Rx Type II - NIDDM Older Yes > 1000 mg/dl No to Slight Coma Fluids, +/- insulin

Hyperosmolar Non-Ketotic Acidosis (HONK)

Glucose Osmotic Diuresis Metabolic Acidosis Coma

Laboratory Findings pH Glucose (>1000) HCO3No Ketosis

DKA and HONK

DKA glucose pH HCO3 Osmolality Ketones Dehydration > 300 (x=475) < 7.3 < 18 (x=9) < 320 3+ 1-2 + Non-ketotic > 600 (x=1166) > 7.3 > 15 (x=22) > 320 1+ 3+

Hypoglycemic Coma
Glucose < 60 tremor, tachycardia,

sweating, hunger Glucose < 40 intellectual and psychomotor impairment Glucose < 20 confusion, seizures, loss of consciousness

Criteria for Diagnosis of Diabetes Mellitus

Expert Committee on the Diagnosis &

Classification of Diabetes Mellitus (1999) Fasting blood glucose 126 mg/dL on at least 2 occasions
Test should be performed after an 8-hour fast Normal fasting glucose < 110 mg/dL

Symptoms of hyperglycemia (e.g. polyuria,

polydipsia, polyphagia, unexplained weight loss with a casual blood glucose 200 mg/dL

Criteria for Diagnosis of Diabetes Mellitus

Formal oral glucose tolerance tests not

generally recommended for routine clinical use

If used, 75-g glucose load recommended 2-hour postload glucose level of 200 mg/dL

Gestational diabetes screening 50-g glucose load If 1-hour 140 mg/dL then Complete 100-g 3-hour oral GTT Need 2 of 3 Fasting: 105, 1 hour: 190, 2 hour: 165, 3 hour: 145 mg/dL

HBA1C
HgB + Glucose Labile GHgB Pre-GHgB Amadori Reaction Stable GHB or HBA1C

Treatment

Effects of Insulin
Carbohydrate Uptake of Glucose by Cells Liver Glycogen Pyruvate Fat
Breakdown of Fat Formation of Fat FFA

ADA - Goals of Therapy

FPG < 120mg/dl & HBA1C < 7%