Pathophysiology & Diagnosis of Diabetes Mellitus

Presented by

Dr. Otis W. Kirksey

A.H. is a slender, 18 year old female, is referred to a the Diabetes clinic because a routine exam revealed glucosuria; a random plasma glucose ordered was 250 mg/dL. About 4 weeks before this visit, A.H. moved across the country to attend college. In retrospect, she has noted polydipsia, nocturia (3 times/night), fatigue, and a 12 lb weight loss over this period, which she attributed to the anziety associated with her move away from home and adjustment to her new environment. Her past medical history is remarkable for recurrent upper respiratory infections and 3 cases vaginal monilia over the past 6 months. Her family history is negative for diabetes, she is not taking any medications.

Her physical exam is unremarkable. Ht 5’5”, Wt. 50kg, FPG 280 mg/dL, A1C 14%,

Lecture ObjectivesUpon completion of this lecture series the student should be able to

Discuss the pathophysiolgical differences between type 1 diabetes and type 2 diabetes

Discuss the pathophysiolgical causes of secondary diabetes

Discuss the pathophysiolgical functions of insulin

Demonstrate understanding of normal carbohydrate metabolsim as well as the alterations which occur as a result of diabetes.

Recognize the common signs and symptoms associated with diabetes

Discuss criteria used to diagnosed diabetes

Differentiate between type 1 diabetes and type 2 diabetes in children

Definition of Diabetes Mellitus

Diabetes mellitus consists of a group of metabolic diseases characterized by

hyperglycemia resulting from defects in insulin secretion, insulin action or both.

Classification of Diabetes: Type 1

• Develops at any age, but most cases are diagnosed before the age of 30 years

• Affected individuals experience significant weight loss, and signs of hyperglycemia which appear abruptly

• Dependent on exogenous insulin to prevent ketoacidosis and sustain life

• Coma and death can result from delayed diagnosis and/or treatment

Classification of Diabetes: Type 2• Approximately 90% of patients with diabetes

have this type with disproportionate representation among the elderly and certain ethnic populations.

• Usually diagnosed in the 3rd or 4th decade of life

• Frequently asymptomatic at the time of diagnosis, but as many as 20% present with evidence of end organ damage.

• Approximately 80% are obese at time of diagnosis

• Endogenous insulin levels may be normal, increased, or decreased; the need for exogenous insulin is variable

• Insulin resistance is typically present with impaired glucose in the initial steps

• Not prone to ketosis

Classification of Diabetes: 2nd Diabetes

1. Maturity Onset Diabetes of the Young (MODY), glycogen synthase deficiency, and mitochondrial DNA markers

2. Pancreatic disorder such as, chronic pancreatitis, and pancreatectomy

3. Hormonal disorder such as Cushing syndrome, thyrotoxicosis, and acromegaly

4. Drug induced

Classification of Diabetes: Gestational

• Applies only in women in whom glucose intolerance develops or is first discovered during pregnancy

Glucose HomeostasisGlucose Homeostasis

Insulin Glucagon

CatecholaminesGrowth Hormone

Cortisol

70 – 140 mg/dl

Amylin

Physiologic Functions of Insulin• Primary role is to decrease blood glucose levels

• Stimulates the storage of glucose as glycogen in liver and muscle (Glycogenesis)

• Stimulates the synthesis of fatty acids and triglycerides

• Promotes the uptake of glucose by adipose tissue to provide glycerol for triglyceride synthesis

• Inhibits lipolysis and the resulting production of ketones

• Enhances the incorporations of amino acids into proteins

Physiologic Function of Glycogen and Other Counter Regulatory Hormones

• Glucogon acts only in the liver to maintain blood glucose levels

– Inhibits hepatic glycogen synthesis and stimulates glycogenolysis to release glucose

– Stimulates gluconeogenesis

• During prolonged fasting or starvation

– Facilitates ketogenesis by allowing oxidation of FFA’s to keytones

• Catecholamines, growth hormone and cortisol help to promote gluconeogenesis

Carbohydrate Metabolism in the Fed State

• Blood glucose concentrations rise after a meal

• There is a subsequent release of insulin in response to the increase blood glucose

Phase I occurs 10-20 minutes after stimulation, and is aimed at decreasing hepatic glucose production.

Phase II, continued response to long term glucose stimulation, allows glucose to enter peripheral cells

Fasting State Carbohydrate Metabolism• Falling blood glucose concentrations inhibit pancreatic insulin

and Amylin release and stimulate the release of glucagon.

• Glucagon stimulates glycogenolysis and gluconeogenesis to ensure a minimum blood glucose concentration ( at least 40 mg/dl) is maintained

Carbohydrate Metabolism in the Patient With Diabetes

• Due to the relative or absolute lack of insulin, blood glucose levels remain high after eating.

• Despite abnormally high glucose levels, low insulin levels promote glucagon release which accelerates hepatic glucose production

• Hyperglycemia is a result of excessive glucose production and under utilization

• Chronic exposure to hyperglycemia can cause irreversible inability of the beta cell to secrete insulin (GLUCOSE TOXICITY)

Signs and Symptoms

• When blood glucose concentrations exceed the renal threshold of 180 mg/dl, glucose spill into the urine. This leads to symptoms of:– polyuria

– polydipsia

– polyphagia

– weight loss

– blurred vision

– fatigue

– poor wound healing

– infections

Sites of Action by Therapeutic Options Presently Available to Treat Type 2 Diabetes

GLUCOSE ABSORPTION

BiguanidesBiguanidesThiozolidindionesThiozolidindiones

MUSCLEMUSCLE

PERIPHERAL GLUCOSE UPTAKEThiazolidinedionesThiazolidinediones

(Biguanides)(Biguanides)

PANCREAS

INSULIN SecretionINSULIN SecretionSulfonylureasSulfonylureasMeglitinidesMeglitinides

InsulinInsulin

ADIPOSE ADIPOSE TISSUETISSUE

LIVERLIVER

Alpha-glucosidase inhibitorsBiguanides

INTESTINEINTESTINE

Sonnenberg and Kotchen. Curr Opin Nephrol Hypertens 1998;7(5):551–5

Major Metabolic Defects in Type 2 Diabetes

• Peripheral insulin resistance in muscle and fat

• Decreased pancreatic insulin secretion

• Increased hepatic glucose output

Emerging Strategies

Haffner SM, et al. Diabetes Care, 1999

Sulfonylureas

Mechanism of Action

• Pancreatic Effects– Sulfonylurea agents sensitize beta cells to glucose,

increasing insulin secretion indirectly

– Glucagon release from the pancreas is inhibited

• Extrapancreatic Effects– Increasing insulin-receptor binding affinity

– Increasing insulin effect by postreceptor action

– Decreasing hepatic insulin extraction

ORAL SULFONYLUREAS

• First Generation

– Acetohexamide (Dymelor)

– Chlorpropamide (Diabenese)

– Tolazamide (Tolinase)

– Tolbutamide (Orinase)

• Second Generation

– Glipizide (Glucotrol, Glucotrol XL)

– Glyburide (Diabeta, Mironase, Glynase)

– Glimepiride (Amaryl)

SulfonylureasChemical Properties

• Structurally related to thiazide diuretics and sulfonamide antibiotics

• The second generation agents differ chemically from the first generation agents in that the side chain attached to the basic sulfonylurea structure is large and relative nonpolar. This change confers a more than 100-fold increase in hypoglycemic activity.

Pharmacokinetic properties:

• Chlorpropamide– The longest acting sulfonylurea (24-72 hours)

– Approx. 80% metabolized in the liver to inactive and weakly active compounds.

– Unchanged portion excreted in urine varies from 10-60%

– Average half-life is 36 hours

– Because of long half-life and variable renal excretion, should be used with caution in elderly and patients with renal impairment.

Pharmacokinetic properties:

• Glipizide – Intermediate acting with a duration of action of 12-24

hours.

– Half-life is about 2-4 hours

– Extensively metabolized by the liver to inactive products.

– Food delays the rate of absorption but not its bioavailability. Administer 30 minutes before meals.

Pharmacokinetic properties:

• Glyburide

– Duration of action is about 24 hours

– Half-life is approximately 1.5-4 hours

– Metabolized completely by the liver into inactive and weakly active compounds

– 50% of metabolites excreted in the urine, the remainder excreted via the biliary tract.

– Food does not delay the rate or extent or absorption.

Drugs That Effect Protein Binding of Sulfonylureas

Type of Interaction

Hypoglycemic ffects

Decrease Binding Phenylbutazone Sulfonamides Salicylates Clofibrate

Immediate, increase in hypoglycemia, with possible return to normal levels or control with long term treatment

Increase Binding Phenobarbital Stoping drugs with dereased protein binding

Decreased (but may prolong drug elimination half-life)

Drugs That Effect The Metabolsim of Sulfonylureas

• Decreased hepatic metabolism:

– Phenylbutazone

– Chloramphenicol

– Dicumerol

• Increased hepatic metabolism:

– Chronic alcoholism

– Phenobarbitol

– Rifampin

Pharmocodynamic Interactions That Decrease the Hypoglycemic Effect of Sulfonylureas

Drug Mechanism

PhenytoinThiazides

Decrease insulin secretion

EstrogenNicotinic AcidPotassium

Decrease in peripheral responseto insulin

Beta-adrenergic agonistGlucocorticoidsMethylxanthines

Increae hepatic glucoseproduction

Pharmacodynamic Interactions That Increase The Hypoglycemic Effects of Sulfonylureas

Drug MechanismMAOIsMethysergideNSAIDs

Increased insulin secretion

Anabolic SteroidsFenfluramineSalicytes

Increase peripheralresonse to insulin

Beta-adrenergic blockadeCentrally acting sympatholyticsEthanolSalicylates

Decrease in hepaticglucose production

Common Adverse Effects of Sulfonylureas:

• Gastrointestinal

– Anorexia

– Heartburn

– Nausea and Vomiting

– Abdominal distention

– Flatulence

• Morbilliform, maculo-papular or urticarilial rash

• Alcohol flushing syndrome (chlorpropamide only)

• Hyponatremia (chlorpropamide, rarely tolbutamide

Rare Adverse Effects of Sulfonylureas:

• Skin reactions

– Photosensitivity

– Lichenoid eruptions

– Erythema multiforme

– Exfoliative dermatitis

• Hepatic disorders

– intrahepatic cholestasis (chlorpropamide)

– Hepatitis (glyburide)

• Hematologic disorders

– Leukopenia

– Agranulocytopenia

– Thrombocytopenia

– Aplastic anemia

– Hemolytic anemia

Dosing of Sulfonylureas

• Chlorpropamide

– 0.1-0.5gm QD

– Caution in elderly and patients with renal impairement.

• Glyburide

– 5-20mg QD or BId

– Caution elderly and patients with renal impairement. Doses > 10mg should be divided

Dosing of Sulfonylureas

• Micronized Glyburide

– 1.0-12mg QD

– Daily doses > 6mg should be divided

• Glipizide

– 2.5-40mg QD or BID

– Daily doses > 15mg should be divided

• Glipizide Extended-Release

– 5-20mg QD

Dosing of Sulfonylureas

• Glimepiride

– Initially 1-2mg QD with breakfast or first main meal;

– After reaching a dose of 2mg increase by up to 2mg at 1-2 week intervals if needed

– The maximum recommended dose is 8 mg daily

Prandin (Repaglinide)

Mechanism of action - a nonsulfonylurea which increases insulin release from the pancreas.

Different from sulfonylureas, dosed prior to meals in order to prevent increase in blood glucose after meals

Clinical Efficacy of Meclinides

• Monotherapy

– Lowers HbA1c 2.1% for those not previously treated with insulin secretagogues

– Lowers HbA1c 1.7% for those previously treated with insulin secretagogues

– Combination with metformin

• Additional 1% reduction in HbA1c

Adverse Effects

• Gastrointestinal

– Diarrhea, constipation, vomiting

• Hypoglycemia (16%)

• Use cautiously in patients with liver impairment

Drug Interactions

• Metabolized by microsomal enzymes

– levels may be elevated by: ketoconazole, itraconazole and erythromycin

– levels may be decrease by: rifampicin, barbituates, and carbamazepine

Dosing

• HbA1c < 8% 0.5mg tid ac

(Individuals not previously treated)

• HbA1c > 8% 1-2 mg tid

(Individuals previously treated)

• Increase dose at one week intervals

• Maximum dose 16 mg daily, or 4mg/dose

Biguanides

Metformin (Glucophage) is an antihyperglycemic agent, marketed in 1995 in the USA for oral treatment of patients with Type 2 diabetes not adequately controlled by diet alone

Metformin:Mechanism of Action

Decreases glucose production in the liver, increases insulin sensitivity and increases glucose uptake into the cells. It does not effect glucagon

Decreases glucose absorption in the stomach

Has no effect on pancreatic insulin secretion, but does require the presence of insulin to be effective

It has slightly favorable effect on serum lipids and promotes weight loss

Clinical Efficacy of Metformin

• Lowers fasting blood glucose approximately 60%

• Lowers HbA1c 1 to 2%

• Decreases Triglycerides (16%)

• Decreases LDL (8%)

• Decreases Total Chol (5%)

• Increases HDL (2%)

• Lowers endogenous insulin levels

Adverse Effects• Hypoglycemia is rare

• Unpleasant GI effects - a metallic taste, diarrhea, nausea, vomiting, and anorexia

• Metformin should be temporarily (48 hours after) withheld in patients undergoing radiologic studies involving parenteral administration of iodinated contrast materials

Lactic Acidosis- The occurrence appears to be rare with currently recommended doses.

• All biguanides inhibit lactate metabolism, therefore increased concentrations due to renal impairment can cause lactic acidosis

Symptoms of Lactic Acidosis

• Weakness

• Fatigue

• Generalized muscle pain

• Dizziness

• Lightheadedness

• Anemia

Drug Interactions

• Cimetidine increases serum concentrations of metformin

• Metformin can decrease absorption of vitamin B12 and folic acid causing deficiency of these vitamins

Dosage

• 500 mg bid with morning and evening meals is usually the starting dose.

• The usual dose is 850 mg bid

• Maximum dose is 850 tid

Monitoring Parameters

• Serum glucose levels

• GI side effects

• Serum LFTs

• Serum creatinine

Contraindications

Renal dysfunction Avoid in males with SrCr >1.5 or 1.4 in females

Cardiovascular failure

CHF (requiring pharmacology)

Dehydration

48 hours after the use of radiographic contrast dye

recent myocardial infarction

Alcoholism or binge drinking

metabolic acidosis

Liver Disease

Pregnancy

Known Hypersensitivity

Alpha Glucosidase Inhibitors

• Arcarbose - approved in 1995– do not mistake with aldose reductase inhibitors

• Mechanism of action - blocks enzyme alpha glucosidase in the small intestines and reduces the absorption of carbohydrates.

• Causes a blunted rise in postprandial blood glucose

Clinical Efficacy of Alpha-Glycosidase Inhibitors

• Lowers blood glucose 40 mg%

• Lowers HbgA1c by 0.5 to 1%

• Include postprandial monitoring to determine therapeutic benefit

Acarbose: Pharmacokinetics

• Systemic absorption is about 35%, mostly as metabolites and is influenced by microbial flora.

• Plasma protein binding is concentration dependent with low binding occurring at higher concentrations and up to 98% bound at low concentrations

• T1/2 is about 2 hours

• Abdominal pain

• Diarrhea

• Elevated hepatic enzyme

• Flatulence

• Elevation of LVTs (rare)

– Associated with doses > 300

– Elevated serum transaminase levels at doses higher than 100 mg TID

– Reversible with discontinuation of medication

Adverse Effects

Dosage

• Acarbose

• Mglitol

• Dosing should start low

– 25 mg tid (with first bite of food

– Titrate, every 4-8 weeks

– Maximimum

• 300mg/day > 130 lbs

• 150mg/day 130 lbs

Contraindications

• Known hypersensitivity

• inflammatory bowel syndrome

• diabetic ketoacidosis

• colonic ulceration

• partial intestinal obstruction

Thiazolidinediones: Mechanism of Action

• Decrease insulin resistance at peripheral sites and in the liver

• Increase insulin-dependent glucose disposal and decreased hepatic glucose output

• Dependant on presence of insulin

• Increases action at receptor and post-receptor level in hepatic and peripheral tissues

Thiazolidinediones:Rationale for Type 2 Diabetes Therapy

• Proven characteristics

– Target insulin resistance, a core defect

– Improve glycemic control

– Do not cause hypoglycemia

– Improve lipid profile (pioglitazone and troglitazone)

• Potential benefits

– Preservation of pancreatic -cell function

– Prevention of progression from impaired glucose tolerance to type 2 diabetes

– Improvement in cardiovascular outcomesSaltiel & Olefsky. Diabetes 1996;45:1661–9

Sonnenberg and Kotchen. Curr Opin Nephrol Hypertens 1998;7(5):551–5

Clinical Efficacy of Thiazolidinediones

• Rosiglitazone lowers HbA1c 1.5%

– Combination metformin produces additional 1.2%

• Pioglitazone lowers HbA1c 1.6-2.6%

– Combination with oral sulfonylurea: add ional 1.3%

– Combination with metformin: additional 0.8%

– Combination with insulin additional 1%

• Requires 2-11 weeks for maximum response

Adverse Effects

• Anemia

• Edema

• Weight Gain

Liver dysfunction

• Idiosyncratic hepatocellular toxicity

• Reported rate is 1 in 57,000 patients

• The risk of serious liver events appears to peak between two and seven months after initiation of therapy and then declines

• Liver enzymes should be monitored regularly

Liver dysfunction

LVTs should be measured before starting therapy and every 2 months for the first year, then periodically

Drug Interactions

• Use with caution with any drug known to be metabolized by one of the P450 isoenzymes

Dosing• Pioglitizone

– Monotherapy – 15-30 mg once daily without regards to meals. The dose may be increased in increments to 45mg.

– Combination

• Insulin – Start with 15 or 30 mg

• If hypoglycemia occurs or if blood glucose concentration is 100mg/dl or less, Insulin dose should be decreased 10-25%

• Metformin

• Sulfonylureas

Incretins

• Pramlintide – amylin analog

– Dose (Type 1)• 15mcg tid (just before meals• Must decrease insulin dose by 50%• Maintenance dose 30 – 60 mcg

– Dose (Type 2)• 60 mcg tid

– Side Effects include hypoglycemia, nausea, vomiting. May delay oral drug absorption

• Exenatide (Type 2)– Dose

• 5mcg bid (before morning and evening meal)• Maximum dose 10 mcg bid

– Side effects include nausea, vomiting, diarrhea, increased hypoglcyemia with sulfonylureas

– May delay absorption of oral drugs, separate by one hour

Insulin

• Indicated in:– all patients with type 1

– certain type 2 patients

– Gestational Diabetes

– patients with parenteral nutrition who require high caloric supplements

– diabetic ketoacidosis

– hyperosmolar nonketotic acidosis

– certain patients with secondary diabetes

Forms of Insulin

• Biosynthetic - recombinant DNA origin utilizing E. Coli (Lilly)

• Biosynthetic - recombinant DNA origin utilizing bakers yeast (Novo Nordisk

Forms of Insulin

• Biosynthetic - recombinant DNA origin utilizing E. Coli (Lilly)

• Biosynthetic - recombinant DNA origin utilizing bakers yeast (Novo Nordisk

Class Preparation Onsethrs

Peakhrs

Durationhrs

Rapid Acting GlulisineLisproAspart

.25 – 0.50.25 – 0.5

0.17 – 0.33

1 – 2 0.5 – 2.5

1 – 3

3 – 4 3 – 6.53 – 5

Short Acting Regular 0.5 - 1 2 – 5 6 – 10

Intermediate NPH Lente

1 – 1.51 – 2.5

4 – 12 7 – 15

16 – 2416 - 24

Long Acting GlargineDetemir

Ultralente

1 – 2 hr3 – 4 hr

4 -6

No PeakNo Peak

8 -20

20 -24Up to 2424 – 28

Mixed Products Humulin 70/30Novolin 70/30

Humalog 75/25

30 -60 30 – 6015 – 30

1.5 – 162 – 12

1 – 6.5

10 -16 10 -16

15 – 18

Oral Inhalation Recombinant Human insulin

0.17 – 0.33 0.5 – 1.5 6

Pharmacokinetics of Available Insulin Products

• Ultra short-acting (Insulin lispro - Humalog)– has faster onset , shorter duration of action

than regular insulin

– allows patients with diabetes to to inject insulin immediately before eating instead of giving their insulin 30-60 minutes before meals

Insulin Pharmacokinetics

Problems and Complications

• Hypoglycemia

• Lipodystrophies

– atrophy

– hypertrophy

Dosing

• Usual dose is between 0.5-1.0 units/kg/day

• There is no formula

Combination Therapy: Oral agent plus insulin

• Rationale– Combination of two agents with different mechanisms of action– More convenient and may be safer

• Sulfonylurea + Insulin– BIDS therapy: bedtime insulin/daytime sulfonylurea– Useful in patients early in course of disease

• Metformin + Insulin– Improves insulin sensitivity

• Alpha glucosidase inhibitor (acarbose) + Insulin– Decreases postprandial glycemia

• Thiazolidinediones + Insulin– Improves insulin resistance, improves insulin action in peripheral

tissues– Reduces insulin requirement

Dosing Methods

2/3 of total daily dose in the morning and 1/3 in the evening using a 70/30 mixture of intermediate and regular insulin

Combination Regimens

• BIDS (Bedtime Insulin Daytime Sulfonylureas