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Diabetes: Insulin and
Hypoglycemic Agents
Kurt Varner, Ph.D. and Robert Richards, M.D.
3-05-2009
•LEARNING OBJECTIVES
•Compare Type 1 and Type 2 Diabetes
•List commonly use insulin preparations and their majaor adverse
effects
•List the three main classes of hypoglycemic agents
•Describe the mechanism of action of -glucosidase inhibitors their
adverse effects, drug-drug interactions and contraindications
•Explain the actions of sulfonylureas and meglitinides, drug-drug
interactions and contraindications
• Describe the actions of Metformin, its drug-drug interactions and
contraindications
•Explain the actions of Thiazolidinediones, their adverse effects,
drug-drug interactions and contraindications
Types of Diabetes
Diabetes Mellitus Type 1
Insulin Dependent Diabetes Mellitus (IDDM)
caused by destruction of pancreatic β cells
Diabetes Mellitus Type 2
Non-insulin Dependent Diabetes mellitus (NIDDM)
cause by insulin resistance
Type I vs Type II Diabetes
Type I
Type II
High
Plasma Glucose
High-very high
Low-Absent
1-20 years
Yes
No
Yes (diabetic coma)
10%
Insulin Levels
Age at Onset
Islet Antibodies
Obesity
Ketosis
Prevalence
High-normal
12+ years
No
Yes (60-90%)
Variable
90%
Usually Ineffective Oral Hypoglycemics
Required
Insulin Therapy
Effective
may be required
Consequences of Diabetes
Acute
Hyperglycemia
ketoacidosis
diabetic coma (hyperglycemia or hypoglycemia)
Chronic Complications of Diabetes
Retinopathy
Most common cause of
blindness in people
of working age
Nephropathy
16% of all new patients
needing renal replacement
therapy
Erectile Dysfunction
May affect up to 50% of
men with longstanding diabetes
Coronary and
cerebrovascular
Disease
2–4 fold increased risk
of coronary heart
disease and stroke; 75%
have hypertension
Foot Problems
15% of people with
diabetes develop
foot ulcers; 5–15% of
people with diabetic
foot ulcers need
amputations
Regulation of Insulin Secretion from the Pancreas
Glucose
Ca2+
GLUT-2
Depolarization
K+
Glucose
Ca2+
ATP
Insulin
Glucokinase
Glucose-6-Phosphate
Structure of Insulin
Insulin - Mechanism of Action
Normal Insulin Function: Fuel Storage
Glucose Storage
Gluconeogenesis
TG
Insulin
Insulin Insulin
Glucose and FFA Uptake
Glucose Uptake
Muscle
Pancreas
Gluconeogenic amino acid release to liver
Treatment of Type 1 Diabetes
Insulin replacement
COMMONLY USED INSULIN PREPARATIONS
Type
Onset
(hr)
Peak
(hr)
Duration
(hr)
Usage
Lispro (human analog) Lys to
0.2-0.5
0.5-2
3-4
Aspart
0.2-0.5
0.5-2
3-4
Glulisine
0.2-0.5
0.5-2
3-4
0.25-1
1-3
5-8
Meals/acute hyperglycemia
1.5-2
6-12
18-24
Basal Insulin and
overnight coverage
Basal Insulin and
overnight coverage- good
24 hr insulin coverage
Rapid
Pro in B chain
Meals/acute hyperglycemia
Good for acute diabetic
ketoacidosis
Short acting
Regular (human)
Intermediate
NPH (human)
Long-Acting
Glargine (human analog)
Gly to Asn in A chain, 2 extra
Arg in B chain
1-2
24
Detimir
2-4
11-14
Insulin Delivery Systems
Inhaled
Exubera
Split-Mixed regimen involving the
prebreakfast and presupper injection of a
mixture of regular and intermediate-acting
insulins
Divide evening dose into a presupper dose
of regular insulin followed by NPH or lente
insulin at bedtime
Basal/Bolus
Premeal short-acting insulin with
intermediate-acting insulin at breakfast
and bedtime
Continuous subcutaneous insulin
infusion.
Major Adverse Effect of Insulin Therapy: Insulin in the Absence of
Carbohydrate can Lead to Severe Hypoglycemia
1. First discerned at a plasma glucose level of 60 to 80 mg/dl (3.3
to 4.4 mM).
- Sweating, hunger, paresthesia (numbness) , palpitations, tremor,
and anxiety,
-principally of autonomic origin
2. At < 60 mg/dl
- Difficulty in concentrating, confusion, weakness, drowsiness, a
feeling of warmth, dizziness, blurred vision, and loss of
consciousness
- Neuroglycopenic symptom: occur at lower plasma glucose levels than
do autonomic symptoms.
Treatment of Type 2 Diabetes
Type 2 Diabetes Mellitus
Oral Drug Therapy for Type 2 DM
Acarbose
Miglitol
}
Inhibitors of CHO
absorption
Sulfonylureas
Repaglinide
Nateglinide
Biguanides
Thiazolidinediones
Incretin mimetics
DPP-4 inhibitors
}
}
}
Insulin secretagogues
Insulin sensitizers
Increase insulin release
Inhibitors of Intestinal Glucose Absorption:
Acarbose (Precose) and Miglitol (Glyset)
• Acts as an -glucosidase inhibitor: prevent cleavage of disaccharides
to monosaccharides in the intestine
•Delays carbohydrate absorption and reduced postprandial plasma
glucose.
•No effect on lipid profiles
•Tends not to cause weight gain
•GI side effects include flatulence (80%), diarrhea (27%) and nausea
(8%) . Titrating the dose of drug slowly reduces GI side effects.
•Additive effect when used in combination with sulfonylureas and
metformin
Sulfonylureas: Mechanism of Action
GLUT2
Na+
-
K+
Sulfonylureas
KIR K+
Na+
K+
K+
Pancreatic
ß cell
Insulin granules
Vm
Ca2+
↑ Ca2+
Voltage-gated
Ca2+ channel
Sulfonylureas: Mechanism of
Action
SULFONYLUREAS
Oral administration and bind to plasma proteins
Actions can be enhanced by alcohol
~50% of new onset Type II diabetic can reach appropriate glycemic control
First Generation: less potent but longer half lives
Acetohexamide rapidly metabolized, but active metabolite 4-7 hrs
Chlorpropamide (24-48 hours)
Tolazamide (4-7 hrs)
Tolbutamide (4-7 hrs)
2nd Generation: 100x more potent, but shorter half-life (3-5 hrs)
Glyburide (glibenclamide) (may cause hypoglycemia)
Glimeperide
Glipizide
Insulin Secretagogue: Repaglinide and Nateglinide
- Chemically Unrelated to Sulfonylureas but same mechanism
of action
-Rapid absorption with half-life of 1 hr.
- Can be taken right before meal
-Less likely to cause hypoglycemia
-Metabolized by liver. Caution in pts. with insufficiency.
Repaglinide approved for mild to moderate liver failure
Nateglinide for moderate liver failure.
Biguanides: Insulin Sensitizers
In medieval Europe, a plant locally known as Goat’s Rue
(Galega officinalis) was used to treat symptoms of diabetes.
The plant contained the compound guanidine.
In the 1950’s, the biguanide Phenformin was introduced for
treating type 2 diabetes in the U.S.. It was withdrawn from the
market due to cases of fatal lactic acidosis.
2nd Generation Biguanide
Metformin: Mechanism of
Action
METFORMIN
• Major mechanism of action:  AMP-dependent kinase.
- Inhibits conversion of acetyl CoA to malonyl CoA, by acetylCoA carboxylase, the rate-limiting step in lipogenesis. Net result
is a faster rate of fatty acetyl-CoA influx into the mitochondria
where it undergoes oxidation to ketone bodies
- Increases expression or activity of glycolytic enzymes and
GLUT-4, decreases activity of gluconeogenic enzymes
- Net: hepatic glucose production and  glucose uptake in
muscle and adipose.
• Can reduce plasma glucose levels by 25% and decrease hemoglobin
A1c by 1-2%. Also lowers plasma triglyceride levels
• Does not lead to hypoglycemia when used alone i.e. is antihyperglycemic
• Adherence to prescribing guidelines is crucial to minimize risk of
metabolic acidosis. (reason why phenformin taken off the market)
METFORMIN (cont.)
CONTRAINDICATIONS
Parenteral radiographic contrast administration: may cause acute renal
failure and lactic acidosis in patients on metformin. Must withhold
metformin just prior to and for 48 hours after the completion of the
procedure.
Metabolic acidosis, lactic acidosis and diabetic ketoacidosis
Metformin is substantially eliminated by the kidney and is absolutely
contraindicated for use in patients with renal failure or renal impairment
(creatinine ≥1.5 in men, or ≥ 1.4 in women).
Thiazolidinediones: Pioglitazone, Rosiglitazone
• Activate nuclear receptors: peroxisome proliferatoractivator receptors (PPAR-g).
•Increases gene expression in muscle, liver and fat to
increase insulin sensitivity.
•Seem to have additional beneficial effects on blood vessels
to reduce hypertension and atherosclerosis
•Can be used as monotherapy or in combination with
metformin or sulfonylureas
PPARg: Sites of Metabolic
Action
Insulin Sensitivity
Insulin Sensitivity
 Glucose output
Thiazolidinediones: Pioglitazone
• Some metabolites pharmacologically active
• Excreted primarily in the feces
• Half-life: plasma half-life is 3 to 7 hours
• 16 to 24 hours for metabolites
• Extensively (>99%) bound to albumin
• No evidence of drug-induced hepatotoxicity
• Should not be used in patients who experienced
jaundice while taking troglitazone
Can worsen or cause heart failure. Also cause
edema, decrease hematocrit
Thiazolidinediones: Rosiglitazone (Avandia)
•
Some evidence of drug-induced hepatotoxicity
- Rosiglitazone linked to fatal ischemic heart disease
- Don’t use in class 3 or 4 failure.
- Can worsen or cause heart failure. Also cause edema,
decrease hematocrit
NEW CLASSES OF HYPOGLYCEMICS
Amylin: 37-aa peptide produced by β cells and co-secreted with insulin.
Inhibits glucagon secretion, delays gastric emptying and suppress
appetite.
Pramlintide: Modified amylin peptide used with insulin to prevent
postparandial hyperglycemia . Must be injected.
Incretin: Glucagon-like peptide (GLP-1 released from the gut to augment
glucose-dependent insulin secretion from pancreas).
- same effects as amylin plus increases Beta cell number
Incretin is rapidly broken down by dipeptidyl peptidase-4 enzyme
(DPP-4)
Exenatide; Incretin mimetic (injected)
Sitagliptin: DPP-4 inhibitorb (oral)
Vildagliptin: DPP-4 inhibitor (oral)