Diabetes: Insulin and Hypoglycemic Agents 3-05-2009 Kurt Varner, Ph.D. and Robert Richards, M.D.

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

Structure of Insulin

Insulin - Mechanism of Action

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

Treatment of Type 1 DiabetesTreatment of Type 1 Diabetes

Insulin replacement

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

Insulin Delivery SystemsInsulin Delivery Systems

ExuberaInhaled

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.

Treatment of Type 2 Diabetes

Type 2 Diabetes Mellitus Type 2 Diabetes Mellitus

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

Sulfonylureas: Mechanism of Sulfonylureas: Mechanism of ActionAction

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: Mechanism of Metformin: Mechanism of ActionAction

2nd Generation Biguanide

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)