Download Pathophysiology & Diagnosis of Diabetes Mellitus

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 Objectives
Upon 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 Homeostasis
Insulin
Glucagon
Amylin
70 – 140 mg/dl
Catecholamines
Growth Hormone
Cortisol
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
LIVER
PANCREAS
ADIPOSE
TISSUE
MUSCLE
Biguanides
Thiozolidindiones
INTESTINE
INSULIN Secretion
Sulfonylureas
Meglitinides
Insulin
PERIPHERAL
GLUCOSE UPTAKE
Thiazolidinediones
(Biguanides)
GLUCOSE ABSORPTION
Alpha-glucosidase inhibitors
Biguanides
Sonnenberg and Kotchen. Curr Opin Nephrol Hypertens 1998;7(5):551–5
Emerging Strategies
Major Metabolic Defects in Type 2
Diabetes
• Peripheral insulin resistance
in muscle and fat
• Decreased pancreatic
insulin secretion
• Increased hepatic glucose
output
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
• Second Generation
– Acetohexamide
(Dymelor)
– Glipizide (Glucotrol,
Glucotrol XL)
– Chlorpropamide
(Diabenese)
– Glyburide (Diabeta,
Mironase, Glynase)
– Tolazamide (Tolinase)
– Glimepiride (Amaryl)
– Tolbutamide
(Orinase)
Sulfonylureas
Chemical 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 1060%
– 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
Decrease Binding
Phenylbutazone
Sulfonamides
Salicylates
Clofibrate
Increase Binding
Phenobarbital
Stoping drugs with
dereased protein
binding
Hypoglycemic ffects
Immediate, increase in
hypoglycemia, with
possible return to normal
levels or control with long
term treatment
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
Phenytoin
Thiazides
Estrogen
Nicotinic Acid
Potassium
Beta-adrenergic agonist
Glucocorticoids
Methylxanthines
Mechanism
Decrease insulin secretion
Decrease in peripheral response
to insulin
Increae hepatic glucose
production
Pharmacodynamic Interactions That
Increase The Hypoglycemic Effects of
Sulfonylureas
Drug
Mechanism
MAOIs
Methysergide
NSAIDs
Anabolic Steroids
Fenfluramine
Salicytes
Beta-adrenergic blockade
Centrally acting sympatholytics
Ethanol
Salicylates
Increased insulin secretion
Increase peripheral
resonse to insulin
Decrease in hepatic
glucose production
Common Adverse Effects of
Sulfonylureas:
• Gastrointestinal
– Anorexia
– Heartburn
– Nausea and Vomiting
– Abdominal distention
– Flatulence
• Morbilliform, maculopapular or urticarilial
rash
• Alcohol flushing
syndrome
(chlorpropamide
only)
• Hyponatremia
(chlorpropamide,
rarely tolbutamide
Rare Adverse Effects of
Sulfonylureas:
• Skin reactions
– Photosensitivity
• Hematologic
disorders
– Lichenoid eruptions
– Leukopenia
– Erythema multiforme
– Agranulocytopenia
– Exfoliative dermatitis
– Thrombocytopenia
• Hepatic disorders
– intrahepatic
cholestasis
(chlorpropamide)
– Hepatitis (glyburide)
– 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.
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
Adverse Effects
• 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
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 b-cell function
– Prevention of progression from impaired glucose
tolerance to type 2 diabetes
– Improvement in cardiovascular outcomes
Saltiel & 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 1025%
• 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
Pharmacokinetics of Available Insulin Products
Class
Preparation
Onset
hrs
Peak
hrs
Duration
hrs
Rapid Acting
Glulisine
Lispro
Aspart
.25 – 0.5
0.25 – 0.5
0.17 – 0.33
1–2
0.5 – 2.5
1–3
3–4
3 – 6.5
3–5
Short Acting
Regular
0.5 - 1
2–5
6 – 10
Intermediate
NPH
Lente
1 – 1.5
1 – 2.5
4 – 12
7 – 15
16 – 24
16 - 24
Long Acting
Glargine
Detemir
Ultralente
1 – 2 hr
3 – 4 hr
4 -6
No Peak
No Peak
8 -20
20 -24
Up to 24
24 – 28
Mixed Products
Humulin 70/30
Novolin 70/30
Humalog 75/25
30 -60
30 – 60
15 – 30
1.5 – 16
2 – 12
1 – 6.5
10 -16
10 -16
15 – 18
Oral Inhalation
Recombinant
Human insulin
0.17 – 0.33
0.5 – 1.5
6
Insulin Pharmacokinetics
• 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
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