diabetes: insulin and hypoglycemic agents 3-05-2009 kurt varner, ph.d. and robert richards, m.d
TRANSCRIPT
Diabetes: Insulin and Hypoglycemic Agents
3-05-2009
Kurt Varner, Ph.D. and Robert Richards, M.D.Kurt Varner, Ph.D. and Robert Richards, M.D.
•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
Diabetes Mellitus Type 1Diabetes Mellitus Type 1
Insulin Dependent Diabetes Mellitus (IDDM)Insulin Dependent Diabetes Mellitus (IDDM)
caused by destruction of pancreatic caused by destruction of pancreatic ββ cells cells
Diabetes Mellitus Type 2Diabetes Mellitus Type 2
Non-insulin Dependent Diabetes mellitus (NIDDM)Non-insulin Dependent Diabetes mellitus (NIDDM)
cause by insulin resistancecause by insulin resistance
Types of Diabetes
Type I Type I Type IIType II
HighHigh Plasma GlucosePlasma Glucose High-very highHigh-very high
Low-AbsentLow-Absent Insulin LevelsInsulin Levels High-normalHigh-normal
1-20 years1-20 years Age at OnsetAge at Onset 12+ years12+ years
YesYes Islet AntibodiesIslet Antibodies NoNo
NoNo ObesityObesity Yes (60-90%)Yes (60-90%)
Yes (diabetic coma)Yes (diabetic coma) KetosisKetosis VariableVariable
10%10% PrevalencePrevalence 90%90%
Type I vs Type II Diabetes
Oral Hypoglycemics
Insulin TherapyRequired
Usually Ineffective Effective
may be required
Consequences of DiabetesConsequences of Diabetes
Acute Acute
Hyperglycemia Hyperglycemia
ketoacidosis ketoacidosis
diabetic coma (diabetic coma (hyperglycemia or hypoglycemiahyperglycemia or hypoglycemia))
Chronic Complications of Diabetes
RetinopathyRetinopathyMost common cause of Most common cause of
blindness in people of blindness in people of working ageworking age
NephropathyNephropathy16% of all new patients 16% of all new patients
needing renal replacement needing renal replacement therapytherapy
Erectile DysfunctionErectile DysfunctionMay affect up to 50% of May affect up to 50% of
men with long-men with long-standing diabetesstanding diabetes
Coronary and Coronary and cerebrovascular cerebrovascular
DiseaseDisease2–4 fold increased risk 2–4 fold increased risk
of coronary heart of coronary heart disease and stroke; 75% disease and stroke; 75%
have hypertensionhave hypertension
Foot ProblemsFoot Problems15% of people with 15% of people with diabetes develop diabetes develop
foot ulcers; 5–15% of foot ulcers; 5–15% of people with diabetic people with diabetic
foot ulcers need foot ulcers need amputationsamputations
Insulin
Glucose
Glucose
GLUT-2
Glucose-6-Phosphate
GlucokinaseATP
K+
Ca2+
Ca2+
Depolarization
Regulation of Insulin Secretion from the Pancreas
TG
Normal Insulin Function: Fuel Storage
Insulin InsulinInsulinGlucose
Glucose Uptake
Muscle
Pancreas
Glucose Storage
Gluconeogenesis
Glucose and FFA Uptake
Gluconeogenic amino acid release to liver
Type Onset(hr)
Peak (hr)
Duration (hr)
Usage
Rapid
Lispro (human analog) Lys to Pro in B chain
0.2-0.5 0.5-2 3-4 Meals/acute hyperglycemia Good for acute diabetic ketoacidosis
Aspart 0.2-0.5 0.5-2 3-4
Glulisine 0.2-0.5 0.5-2 3-4
Short acting
Regular (human) 0.25-1 1-3 5-8 Meals/acute hyperglycemia
Intermediate
NPH (human) 1.5-2 6-12 18-24 Basal Insulin and overnight coverage
Long-Acting
Glargine (human analog) Gly to Asn in A chain, 2 extra Arg in B chain
Detimir
1-2
2-4
24
11-14
Basal Insulin and overnight coverage- good 24 hr insulin coverage
COMMONLY USED INSULIN PREPARATIONS
Continuous subcutaneous insulin infusion.
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
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.
Oral Drug Therapy for Type 2 DM
Acarbose
Miglitol
Sulfonylureas
Repaglinide
Nateglinide
Biguanides
Thiazolidinediones
Incretin mimetics
DPP-4 inhibitors
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Insulin secretagogues
Insulin sensitizers
Inhibitors of CHO absorption
} 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
Na+
Na+
K+
K+
K+
K+
GLUT2
Ca2+
Voltage-gated Ca2+ channel
KIR
Pancreatic ß cell
Insulin granules
↑ Ca2+
-
Sulfonylureas-
Vm
Sulfonylureas: Mechanism of ActionSulfonylureas: Mechanism of Action
SULFONYLUREASOral 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.
METFORMIN • Major mechanism of action: AMP-dependent kinase.
- Inhibits conversion of acetyl CoA to malonyl CoA, by acetyl-CoA 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 anti-hyperglycemic
• 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 proliferator-activator receptors (PPAR-).
•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
PPARPPAR: Sites of Metabolic : Sites of Metabolic ActionAction
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)