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 High Plasma Glucose High-very high Low-Absent Insulin Levels High-normal 1-20 years Age at Onset 12+ years Yes Islet Antibodies No Obesity Yes (60-90%) Yes (diabetic coma) Ketosis Variable 10% Prevalence 90% Usually Ineffective Oral Hypoglycemics Effective Required Insulin Therapy may be required

Consequences of Diabetes Acute Hyperglycemia ketoacidosis diabetic coma (hyperglycemia or hypoglycemia)

Chronic Complications of Diabetes Coronary and cerebrovascular Disease 2–4 fold increased risk of coronary heart disease and stroke; 75% have hypertension Retinopathy Most common cause of blindness in people of working age Nephropathy 16% of all new patients needing renal replacement therapy Foot Problems 15% of people with diabetes develop foot ulcers; 5–15% of people with diabetic foot ulcers need amputations Erectile Dysfunction May affect up to 50% of men with long-standing diabetes

Regulation of Insulin Secretion from the Pancreas Glucose Ca2+ GLUT-2 K+ Depolarization Glucose Ca2+ ATP Glucokinase Insulin Glucose-6-Phosphate

Structure of Insulin

Insulin - Mechanism of Action

Normal Insulin Function: Fuel Storage Glucose Storage Gluconeogenesis TG Glucose and FFA Uptake Insulin Glucose 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 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 Glulisine 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 DeWitt DE, Hirsch IB. JAMA. 2003;289:2254-2264. American Diabetes Association. Diabetes Care. 2003;26(suppl 1):S121-S124.

Insulin Delivery Systems The various insulin delivery systems each have their advantages and disadvantages. Although the pen injector may be a suitable alternative for a patient who is unable to use a syringe or has needle phobia, the American Diabetes Association cautions that this delivery system should not be viewed as a routine option for patients with diabetes. In addition to increased expense, jet injection may traumatize the skin. Insulin pump therapy (continuous subcutaneous insulin infusion, or CSII) should be administered by a skilled professional. Patients need to be selected carefully and educated thoroughly. They should be strongly motivated to improve glucose control and to assume substantial responsibility for their own care. Some clinicians reserve CSII for patients in whom 3 to 4 daily injections fail to achieve euglycemia; others administer CSII to motivated patients whose daily schedule makes conventional therapy less effective. Clinical studies of inhaled insulin suggested that glucose control is similar to that obtained with a subcutaneous insulin regimen. The risk of hypoglycemia was not increased. Other insulin delivery systems being investigated include buccal tablets and an oral aerosol spray that is absorbed through the buccal muscosal lining and in the oropharyngeal regions. DeWitt DE, Hirsch IB. JAMA. 2003;289:2254-2264. American Diabetes Association. Diabetes Care. 2003;26(suppl 1):S121-S125. 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 Sulfonylureas Repaglinide Nateglinide Biguanides Thiazolidinediones Incretin mimetics DPP-4 inhibitors Inhibitors of CHO absorption } 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 - Sulfonylureas GLUT2 Na+ K+ K+ Na+ KIR K+ Vm K+ - Pancreatic ß cell Ca2+ Voltage-gated Ca2+ channel ↑ Ca2+ Insulin granules

Sulfonylureas: Mechanism of Action For many years, the sulfonylureas were the only class of antidiabetic drugs approved as oral agents in the United States. Sulfonylureas increase the secretion of insulin from the pancreatic b cells in response to glucose and other stimuli, thereby lowering blood glucose levels by increasing plasma insulin concentrations. Secondary effects of sulfonylurea therapy may include improvement in hepatic and peripheral insulin sensitivity. DeFronzo RA. Diabetes. 1988;37:667-687. Lebovitz HE. In: Joslin’s Diabetes Mellitus. 1994:508-529. 23 NATIONAL DIABETES EDUCATION INITIATIVE™ FOR HEALTHCARE PROFESSIONALS

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.

Metformin: Mechanism of Action 2nd Generation Biguanide Metformin: Mechanism of Action Metformin: Mechanism of Action Metformin is the only agent in the biguanide class of antidiabetics available in the United States for the treatment of type 2 diabetes. Metformin does not stimulate insulin secretion. Instead, it inhibits glucose production by hepatocytes and stimulates glucose uptake by skeletal muscle, in both instances via activation of AMP-activated protein kinase (AMPK). The precise steps by which AMPK activation has an effect on glucose production and uptake remain to be elucidated. AMPK activation also may account for metformin’s salutory effects on triglyceride levels. Metformin’s activation of AMPK results in reduced acetyl-CoA carboxylase activity, increased fatty acid oxidation, and decreased expression of lipogenic enzymes. DeFronzo RA et al. J Clin Endocrinol Metab. 1991;73:1294-1301. Zhou G et al. J Clin Invest. 2001;108:1167-1174.

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-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 Slide I.14 PPARg: Sites of Metabolic Action Insulin Sensitivity PPARg: Sites of Metabolic Action PPARg ligands have direct effects on adipose tissue and probably on skeletal muscle, pancreas, and liver. The prevailing belief, however, is that PPARg ligands exert most of their metabolic effects via their action on adipose tissue, where they stimulate the synthesis of fat and inhibit lipolysis. An indirect effect of PPARg that occurs via adipose tissue is alteration of various cytokines, notably decreased tumor necrosis factor-a and increased adiponectin (also known as adipocyte complement-related protein). Both of these cytokines have been implicated as negative or positive regulators of, respectively, insulin sensitivity. Decreased serum concentrations of free fatty acids (FFA) results from increased fat synthesis and decreased lipolysis in adipose tissue. This is thought to decrease the delivery of FFA to skeletal muscle and to improve insulin sensitivity. Decreased serum FFA also improves b-cell function. 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)