1. Diabetes: Insulin and Hypoglycemic Agents
Kurt Varner, Ph.D. and Robert Richards, M.D.

2. 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

4. 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

5. 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

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

7. 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

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

9. Structure of Insulin

10. Insulin - Mechanism of Action

11. 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

12. Treatment of Type 1 Diabetes
Insulin replacement

13. COMMONLY USED INSULIN PREPARATIONS
Type
Onset
(hr)
Peak
Duration (hr)
Usage
Rapid
Lispro (human analog) Lys to Pro in B chain
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: American Diabetes Association. Diabetes Care. 2003;26(suppl 1):S121-S124.

14. 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: American Diabetes Association. Diabetes Care. 2003;26(suppl 1):S121-S125.
Inhaled
Exubera

15. 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.

16. 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.

17. Treatment of Type 2 Diabetes

18. Type 2 Diabetes Mellitus

20. 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

21. 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

22. 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

23. 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: Lebovitz HE. In: Joslin’s Diabetes Mellitus. 1994:
23 NATIONAL DIABETES EDUCATION INITIATIVE™ FOR HEALTHCARE PROFESSIONALS

24. 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

25. 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.

26. 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.

27. 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: Zhou G et al. J Clin Invest. 2001;108:

28. 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)

29. 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).

30. 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

31. 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

32. 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

33. 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

34. 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)