Diabetes 1. Why is Diabetes Important? 2 Source: 2004–2006 National Health Interview Survey...

Diabetes

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Why is Diabetes Important?

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Why is Diabetes Important?

Source: 2004–2006 National Health Interview Survey estimates projected to year 2007

Why is Diabetes Important?• Diabetes is probably the most important

endocrine disorder• A lot of people have diabetes and it causes a lot

of healthcare issues• Type 2 diabetes is increasing among children,

teens (10-19), and the elderly over 60• Percent of people with diabetes, by age group– 20-39 – 2.6%– 40-59 – 10.8%– 60 and older – 23.8%

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Type 2 Diabetes is Increasing in Children and Teens, Especially in

Certain Groups

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Type 2 Diabetes is Increasing in Children and Teens, Especially in Certain Groups

Source: SEARCH for Diabetes in Youth Study.NHW=Non-Hispanic whites; AA=African Americans; H=Hispanics; API=Asians/Pacific Islanders; I=American Indians

Chronic Complications of Diabetes Types 1 and 2

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Chronic Complications of Diabetes Types 1 and 2

1. Frequent infections- The high level of blood glucoseacts as a fuel for microorganisms

2. Diabetic retinopathy3. Diabetic nephropathy4. Arteriosclerosis/

vascular disease5. Diabetic neuropathy

• One in four hospitalized patients has diabetes• Problems two through five are

the most responsible for health issues among diabetes

8Porth, 2011, Essential of Pathophysiology, 3rd ed., Lippincott, p. 820

Diabetes MellitusTypes of Diabetes Mellitus

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Diabetes MellitusTypes of Diabetes Mellitus

A. Type 1:1. Beta cells of the pancreas are destroyed by autoimmune

attack.2. No insulin is produced.3. Must be treated with insulin injections in order to

replace what is not present

B. Type 2:1. Insulin resistance2. They have insulin but there is inadequate insulin secretion in order to control blood sugar3. May be treated with diet and exercise, oral medications, and/or insulin injections

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Lecture Outline

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Lecture Outline

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I. Insulin Pathways in Liver, Muscle and Fat

II. Pathophysiology of Diabetes Mellitus

II. Symptomatology of Diabetes Types 1 and 2

III. Insulin Therapy: Focus on Type 1

IV. Adverse Effects of Insulin

V. Pramlintide Therapy

VI. Pregnancy in Type I Diabetes

VII. Type 2 Diabetes: Pathophysiology and Presentation

VIII. Drugs Primarily Targeting Type II Diabetes

IX. Pregnancy in Type 2 Diabetes

X. Gestational Diabetes

Diabetes and Insulin TherapyDiagram

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Diabetes and Insulin TherapyDiagram

Insulin Pathways in the LiverDiagram

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Insulin Pathways in the LiverDiagram

Insulin Pathways in the LiverDescription

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Insulin Pathways in the LiverDescription

• This is a liver cell• Liver takes up glucose

– Can use it in the TCA cycle and make ATP– Can store it as glycogen (the storage form of glucose)

• When we eat and blood sugar is high, insulin is high, the liver takes in glucose and stores it as glycogen

• When we are fasting, blood sugar is getting low, insulin is low, and the pathway that is promoted by insulin is not going forward– Glycogen is being broken down and the liver can add glucose back to

the blood stream to nourish the body• The liver, under the guidance of insulin, controls blood glucose in

the body by breaking down glycogen or taking glucose out of the body– Insulin inhibits this pathway

• Therefore, this pathway does not go forward unless insulin is low

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Gluconeogenesis

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Gluconeogenesis

• The liver can make new glucose and add it to the bloodstream– Would want the liver to do this when glucose is

low– The pathway is inhibited by insulin• The pathway is not activated after eating when insulin

is high

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Synthesis of Triglycerides

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Synthesis of Triglycerides• Insulin also promotes the synthesis of triglycerides from fatty acids

– Triglycerides are the storage form of fat• Want to store fats after you have just eaten

– When fasting, triglyceride pathway is not being promoted, fats are broken down and made into acetyl-CoA

– Can be used to form ketone bodies• Ketone bodies get into the circulation and go throughout the body and then

are turned back into acetyl-CoA• The pathway for the synthesis of ketone bodies is inhibited by insulin

– Insulin is high after eating - can use glucose to fuel the body so insulin is inhibitory for the production of glucose

– The liver itself cannot use ketone bodies

• After not eating for a while, blood sugar would be low and ketone bodies would be present in the urine

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Insulin Pathways in the MuscleDiagram

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Insulin Pathways in the MuscleDiagram

Insulin Pathways in the MuscleDescription

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Insulin Pathways in the MuscleDescription

• Muscle cells take up glucose and can use it for fuel for the Kreb’s cycle

• Muscle cells store glycogen because they are energetic cells that need a lot of glucose– The glucose used by the muscle cells comes from the liver,

gluconeogenesis, and the muscle cell’s own storage• The difference between the muscle and the liver is that

in the muscle insulin must be present in order for glucose to be taken up by the muscle– Glucose can also be taken up by the muscle cell when the

cell is exercising

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Insulin Pathways in Fat TissueDiagram

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Insulin Pathways in Fat TissueDiagram

Insulin Pathways in Fat TissueDescription

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Insulin Pathways in Fat TissueDescription

• Glucose entry into fat cells is insulin-dependent• The fat cell is the storage place for triglycerides• The pathway of taking triglycerides into the fat is promoted

by insulin– In people with type 1 diabetes, insulin is not produced, so

triglycerides are not taken into the fat cells• This explains why people with type 1 diabetes often lose weight

before being diagnosed and gain weight when they go on insulin• If you just ate, triglyceride levels will be high and insulin will

be high– When insulin is high, the body does not want/need to be

breaking down fats because you have dietary fat– When insulin is lower, then you will break down the fats

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Glucose, Amino Acid, and Free Fatty Acid Utilization by Muscle, Liver, and

Fat Cells

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Glucose, Amino Acid, and Free Fatty Acid Utilization by Muscle, Liver, and Fat Cells

In the liver, what is the name of the pathway that generates new glucose

molecules from 3-carbon fragments?

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In the liver, what is the name of the pathway that generates new glucose molecules from 3-carbon fragments?

1. Glycogen breakdown2. Glycogen synthesis3. Gluconeogenesis4. Glycogenolysis –

glycogen breakdown

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Ways of Measuring the Effect of Insulin

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1. Urine testing for glucose or ketones: a) Urine testing for glucose is no longer recommended. b) Presence of ketones in the urine signifies fat breakdown

2. Blood Sugar: blood testing for glucose is the most accurate.a) Normal fasting BS – 80-110 mg/dlb) Normal 2-hr post prandial (2 hr PP) <160 mg/dl- The person drinks a bottle of glucose

- Come in, measure blood glucose, drink bottle of glucose solution, and then measure blood glucose again

3. Hemoglobin A1c : indicates about a 3-months average glucose level.a) Normal Hb A1c is about 5%.

Ways of Measuring the Effect of Insulin

Hemoglobin A1C

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Hemoglobin A1C

Glucose + protein (i.e., hemoglobin)

Glycosylated protein (i.e., hemoglobin A1C)

The Basis of Hemoglobin A1C

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The Basis of Hemoglobin A1C• If you take a protein (ex. albumin) and sit it in glucose,

some of the glucose molecules will hitch onto the proteins• In the bloodstream, the glucose molecules are also being

hitched onto proteins• Use hemoglobin because we know that the average

lifespan of a red blood cell is 120 days– The average age of a red blood cell is 60 days– The degree of glycolyslation is indicative of the average blood

sugar concentration over the last 60 days because the hemoglobin has been in the glucose for an average of 60 days• Shows how well the blood sugar has been controlled over the past 60

days• Normal is about 5%

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Rate of Daily Self-monitoring of Glucose among Diabetic Adults

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42MMWR November 2, 2007 / 56(43);1142

Rate of Daily Self-monitoring of Glucose among Diabetic Adults

Diabetic SymptomatologyPresenting Symptoms of Type 1

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Diabetic SymptomatologyPresenting Symptoms of Type 1

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1. Polyuria (frequent peeing) – the sugar in the urine acts similar exerts osmotic pressure, keeping the water in their urine

2. Polydipsia (frequent thirst)– dehydrated from peeing all of the time

3. Polyphagia (fat or muscle cells cannot take up adequate glucose because insulin is not present)

4. Possibly DKA.

Sources of Insulin

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Sources of Insulin

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I. Beef or pork: no longer manufactured.- Not used now because people developed allergies to

them

II. Human insulin is produced recombinately in yeast and is identical to that produced by the pancreas (in those of us who do not have type 1 diabetes).

III. Mutated human insulins (Lehne calls them “modified” insulins), produced recombinately in yeast, have different pharmacokinetic properties from unmutated human insulin.- This alters their pharmocokinetic properties

Insulin Strength and Dose

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Insulin Strength and Dose

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I. Insulin is measured in units: this is a biological measurement that tells how much a given quantity of insulin will lower blood sugar in a test animal.

II. Insulin preparations are in a concentration of 100 units/ml. Use an insulin syringe to inject. Some insulin come in a prefilled injection pen in addition to being available in a vial.

- ex. the flex pen is advertised heavily on television

•There is no set dose of insulin: each patient uses the amount that controls his/her blood sugar.

Types of Insulin

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INSULIN TYPE APPEARANCE ADDED

PROTEIN

PROFILE OF ACTION(hrs)*

ONSET PEAK DURA-TION

Short duration: rapid-acting

Lispro clear (pump use) none 0.2-0.5 1.5-2 3-5

Aspart clear (pump use) none 0.2-0.5 0.5-1

3-5

Glulisine clear (pump use) none 0.2-0.5 1-1.5 1.5-2.5

Short duration: slower acting

Regular clear (IV or SC) none 0.3-0.7 2-4 5-12

Intermediate-acting

NPH cloudy protamine 1-2 6-12 18-24

Insulin demetir Clear (not used IV)

None ~1.5 N/A ~16-24

Long-acting

Insulin glargine Clear (not used IV)

none 1.5 N/Ab 19-24

Types of Insulin

Categories of Insulin

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Categories of Insulin• Rapid-acting acts very quickly

– They are all modified insulins that have a different structure that makes them easier to be absorbed form the subcutaneous tissue

• Most insulin is injected subcutaneously• Short-duration• The mutant insulins are much more expensive but they can be injected

right before or right after eating, rather than 20 minutes before eating• Because NPH is bound to the protamine, it has a longer onset and

duration• Long-acting

• Some of these can be used in the insulin pump – The pump is warm and there used to be precipitation in the tubing, but now it

is okay

• THE ONLY INSULIN THAT IS USED IN AN IV IS REGULAR INSULIN --- this will be on the test!!!!!

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Profiles of Action of Various Insulins

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Profiles of Action of Various Insulins

54Lehne, 2009, Pharmacology for Nursing Care, 7th ed., Elsevier, p. 666

Profiles of Action of Insulin and Insulin Analogs

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56Hirsch, 2005, Insulin analogs, NEJM, 352:174-83

Profiles of Action of Insulin and Insulin Analogs

Insulin Mixtures

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Insulin Mixtures

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• 70/30 insulin lispro protamine/lispro

• 75/25 insulin aspart protamine/aspart

• 70/30 NPH/regular

• 50/50 NPH/regular

Insulin Administration

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Insulin Administration

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I. Subcutaneous: All preparations

II. Intravenous: Regular insulin only

III. Inhalation: Regular insulin only(The only available inhaled insulin formulation has been taken off the market.)

Constant Insulin Infusion Pump

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Constant Insulin Infusion Pump

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•A beeper-sized device containing a motor-driven syringe that the patient fills with a short-acting insulin (regular, lispro, aspart or glulisine).

•Tubing from the syringe is connected to a needle the patient implants in the subcutaneous space.

•The patient sets the device to deliver a basal level of insulin constantly, and can instruct it to deliver boluses to take care of meals.

•The pumps are becoming very sophisticated

Which insulin can be used IV?

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Which insulin can be used IV?

1. Lispro2. Demitir3. Regular4. NPH

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Lispro

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The Goal of Insulin Therapy

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The Goal of Insulin Therapy

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• Euglycemic (normoglycemic) control: defined as blood sugar control that approximates that of a person without diabetes (normalization of blood sugar).

• Virtually all newly diagnosed Type 1 diabetic patients are placed on this type of therapy because of the evidence that it decreases complications of diabetes.

Effect of Intensive vs. Conventional Insulin Therapy

on Development of Complications

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The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N. Eng. J. Med., 329: 1993, p. 981

Effect of Intensive vs. Conventional Insulin Therapy on Development of Complications

Effect of Intensive vs. Conventional Insulin Therapy

on Development of ComplicationsDescription

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Effect of Intensive vs. Conventional Insulin Therapy on Development of Complications

Description• Compares the blood sugar testing with the goal of

normal glucose values with the old method of urine testing and the fixed insulin regimen (conventional therapy)– The graphs showed retinopathy in patients

• More patients in the conventional treatment has retinopathy than in the new treatment

• This trial revolutionalized the treatment of diabetes• The goal to control the blood sugar as though the

person is not diabetic has been shown with both type I and type II (more so type I) to reduce the complications associated with diabetes

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Strategies for Insulin Therapy

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Strategies for Insulin Therapy

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1. Multiple insulin injections.

2. Constant insulin infusion pump.

• With each strategy, patients must test their blood sugar 4-10 times per day, and make adjustments in their insulin dose based on their blood sugar measurements.

Strategies for Multiple Insulin Injections

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Strategies for Multiple Insulin Injections

Shade, et al, Intensive Insulin Therapy, Excerpta Medica, 1983, p. 133.

The Choice of Insulin Strategy is Based on Patient Preference

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The Choice of Insulin Strategy is Based on Patient Preference

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• The pump may be harder to use and require more patient motivation and commitment.

• Either strategy requires an intelligent patient with a good knowledge of their own disease.

• Children and elderly patients may have problems related to their stage of development or comorbidities.

Comparison of Pump and Multiple Insulin Injections

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The pump and multiple insulin injections both produce similar results when used optimally. The choice between the two is based on patient preference.

Comparison of Pump and Multiple Insulin Injections

Insulin Use Across the Lifespan

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Insulin Use Across the Lifespan

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• Children need close supervision but most prefer to prick their own fingers and give their own injections as soon as they are able.

• Adolescents may rebel against the dietary restrictions and the need for continual monitoring.

• Elderly may have difficulty with seeing test strips or manipulating syringes because of retinopathy or neuropathy.

• Cognitive decline in the elderly may necessitate someone else taking responsibility for the insulin regimen.

Individualization of Insulin Protocols

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Individualization of Insulin Protocols

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•Each patient’s regimen is shaped by their lifestyle, their blood sugar measurements, and their diet—but for type 1 diabetes, each patient’s goal should be euglycemia.

•For type 2, the goal may be able to be a little bit above normal because the data supporting the benefit of euglycemia are not as strong in type 2 diabetics as in type 1 diabetics

•Patients are instructed in a basic insulin regimen and given instructions on what to do in case of particular blood sugar measurements—this is called a sliding scale.

Example of a Sliding Scale

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Example of a Sliding Scale

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Fasting blood sugar Dose of regular insulin before breakfast

60-80 20 units

80-100 25 units

100-120 30 units

120-130 35 units

130-140 40 units

Adverse Effects of InsulinHypoglycemia

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Adverse Effects of InsulinHypogylcemia

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Hypoglycemia: means low blood sugar

Two sets of symptoms

A. CNS symptoms: headache, confusion, drowsiness, and fatigue followed by coma, seizures, and possibly death.

B. Peripheral symptoms: tachycardia, sweating, nervousness, all caused by activation of the sympathetic nervous system.

Treatment for Hypoglycemia

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Treatment for Hypoglycemia

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•If conscious: p. o. sugar, i.e. a sugar cube, cake icing, glucose tablets, etc.

•If unconscious: IV dextrose (glucose), 50 g.

•If confronted with an unconscious diabetic patient, it is safest to assume that the problem is hypoglycemia and administer IV dextrose immediately.

Problematic Drug Interactions for Diabetics

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Problematic Drug Interactions for Diabetics

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•Beta-blockers may mask the sympathetic symptoms of hypoglycemia.

•Other drugs that affect blood sugar or insulin resistance may increase or decrease the activity of insulin.

•Oral drugs for diabetes

To maintain euglycemic control, what measures must a diabetic patient use to measure his/her

blood sugar?

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To maintain euglycemic control, what measures must a diabetic patient use to measure his/her blood sugar?

1. Urine testing2. Home blood sugar

testing once a day3. Home blood sugar

testing 4-6 times per day

4. Hemoglobin A1C testing

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Amylin AThe Basis for a Drug for Type 1 and

Type 2 Diabetics

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Amylin AThe Basis for a Drug for Type 1 and Type 2 Diabetics

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•What is amylin?•Amylin is a small protein that is made in the beta cells of the pancreas (just like insulin) and stored in secretory granules along with insulin.

• When insulin is secreted, amylin is secreted along with it.

•Until recently, we didn’t know the function of amylin.

•BUT in type 1 DM, the beta cells die so there is no amylin!, just like they do not have any insulin

Functions of Amylin

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Functions of Amylin

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1. Potentiates the action of insulin on target cells.

2. Inhibits the secretion of glucagon (a pancreatic hormone that is made in alpha cells of the pancreas that opposes insulin).

3. Delays gastric emptying and thereby blunts postprandial blood glucose peaks because the food does not get into the intestines all at once, but rather does it slowly

4. Increases satiety and promotes weight loss.

Secretion Profile of Amylin and Insulin in Healthy Adults

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98

Symlin® prescribing information

Secretion Profile of Amylin and Insulin in Healthy Adults

Pramlintide (Symlin®)An Amylin Agonist

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Pramlintide (Symlin®)An Amylin Agonist

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• A small protein very similar to amylin.

• Inject subcutaneously before meals (cannot be mixed with insulin).

• For injection, a 30 unit (0.3 ml) insulin syringe is used and a conversion chart tells what volume to draw up.

Conversion of Symlin Dose to Insulin Unit Equivalents

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Conversion of Symlin Dose to Insulin Unit Equivalents

Starting a Type 1 Patient on Pramlintide

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Starting a Type 1 Patient on Pramlintide

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•Because pramlintide potentiates the does of insulin, it decreases their previous dose of short-acting insulin by half.

•Start pramlintide at 15μg before major meals.

•If nausea occurs, continue that dose until it subsides (several days); then increase in 15 μg increments to 60 μg, each time waiting for nausea to subside.

•After a stable dose is achieved at which there is no nausea, adjust the insulin dose to achieve euglycemic control.

Problems with Pramlintide

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Problems with Pramlintide

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1. Delayed absorption and lower peak levels of po drugs due to delayed gastric emptying (take them one hour before injecting pramlintide).

2. Should not be used with other drugs that delay gastric emptying or slow GI motility.

3. Potentiates insulin’s ability to cause hypoglycemia, increasing the risk of hypoglycemia

4. Nausea and vomiting are prominent side effects that may abate with continued use.

Mean Plasma Glucose Concentration in Type 1 DM Patients

on Regular Insulin Compared with Pramlintide plus Regular Insulin

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108Symlin® prescribing information

Mean Plasma Glucose Concentration in Type 1 DM Patients on Regular Insulin Compared with Pramlintide plus Regular Insulin

Possible Problems for Pregnant Diabetics

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Possible Problems for Pregnant Diabetics

1.Increased incidence of birth defects.- This is possibly because insulin is a

growth factor

2. Premature labor that may be related to the maturation of the placenta

3. Fetal macrosomia (big body) and organomegaly (big organs)

Infants of Diabetic Mothers

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Infants of Diabetic Mothers

1. Glucose crosses the placenta.

2. Fetal pancreas responds to hyperglycemia by secreting high levels of insulin.- If the mother’s glucose is high, the baby’s pancreas will pour out insulin to decrease glucose, but it cannot because the glucose comes from the mother

3. Insulin stimulates fat deposition in infant, causing macrosomia.

4. Insulin stimulates glycogen deposition in infant, causing organomegaly.

5. Fetal hyperinsulinemia continues after delivery. - But when maternal glucose supply is cut off, this results in perinatal

hypoglycemia because the glucose is no longer present

Pregnant Patients with Pre-existing Type 1 DM

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Pregnant Patients with Pre-existing Type 1 DM

1. Insulin requirements decrease at first and then continually increase as the pregnancy progresses.

2. With ideal control, fetal outcomes approach those of nondiabetic mothers.

3. Infants may require Caesarean section because of macrosomia and also should be monitored closely for hypoglycemia after birth.

4. Gestational and type 2 DM will be discussed later.

Type 2 Diabetes

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Type 2 Diabetes

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•Part of a syndrome that includes insulin resistance.

•People develop worsening insulin resistance over their lifetime and type 2 diabetes may be the result.

•However, if people with insulin resistance take care of themselves and/or avoid weight gain, they can delay the onset or prevent type 2 diabetes.

What is Insulin Resistance?Diagram

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118

Nestler, J.E., Assessment of insulin resistance. Scientific American Science and Medicine, 1: 1994, p. 59.

What is Insulin Resistance?Diagram

Insulin Resistance

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Insulin Resistance

• The artificial pancreas machine was set to maintain their plasma insulin and glucose at 80mg– The insulin directed the cells to take up the glucose

• For the normal people, the machine had to give a lot of glucose to maintain insulin, but for the hypertensives, the machine did not have to give as much glucose– The insulin was having greater effects on the controls than

on the hypertensives• The hypertensive patients had insulin resistance and insulin did

not work as well as in normal people

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Explanation of Insulin Resistance Slide

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Explanation of Insulin Resistance Slide• Two groups were compared – hypertensives and people

without hypertension.• The subjects were hooked up to an “artificial pancreas” in the

hospital. The machine can be set to maintain constant insulin and glucose levels in the subject.

• The machine was set to maintain a plasma insulin level of 80 μU/ml and a plasma glucose of 80 mg/dl

• Dextrose (glucose) was delivered through an IV line to maintain the plasma glucose at 80 mg/dl.

• The normal subjects required higher quantities of dextrose via IV to maintain their blood sugar at 80 mg/dl than the hypertensive patients did.– Because their insulin was working better, whereas the hypertensives

had insulin resistance

Explanation of Insulin Resistance Slide (cont.)• The reason the normal subjects required more IV glucose

was that the infused insulin was promoting glucose removal from the bloodstream– The removed glucose was being stored in the liver as glycogen or

was entering fat and muscle cells.– Because it was removed from the bloodstream, in order for the

subjects’ blood sugar to remain at 80 mg/dl, the machine replaced the removed glucose with the dextrose infusion.

• In this experiment, the insulin infusion was more effective at causing glucose to be removed from the bloodstream in normal subjects than in the hypertensive subjects.

• The hypertensive subjects had insulin resistance.

Known Mediators of Insulin Resistance

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Known Mediators of Insulin Resistance

I. Acute:A. Cortisol increases insulin resistanceB. Growth Hormone increases insulin resistanceC. Epinephrine - increaseD. Hyperinsulinemia - increaseE. Hyperglycemia - increase

II. Chronic:A. Receptor-mediated: Fewer insulin receptors on each

cell (common in obesity)- as you gain weight, the number of insulin receptors on cells decreases, and if you lose weight the number increases

B. Postreceptor: Second messenger system doesn’t workproperly

Insulin Receptor Activation

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Insulin Receptor Activation

Porth, 2007, Essential of Pathophysiology, 2nd ed., Lippincott, p. 703

Insulin Receptor ActivationDescription

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Insulin Receptor ActivationDescription

• When insulin binds to the receptor, the signaling proteins cause a number of effects within the cell– In post-messenger resistance, there is most likely

something wrong inside of the cell– When insulin binds to its receptor, GLUT-4 becomes

available to transport insulin

• If there is a post-receptor problem, there will most likely be a problem in glucose and fat transport

129

The “Metabolic Syndrome”

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The “Metabolic Syndrome”

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•A.K.A “syndrome X” or “diabesity”

• Central obesity, hypertension, poorly regulated blood glucose, and dyslipidemia

• A recent article states that ~1 in 3 Americans has the metabolic syndrome.

• Not everyone with the metabolic syndrome develops type 2 DM, but such people are at increased risk when compared to people without the metabolic syndrome.

• Lifestyle changes can delay or prevent type 2 DM.

Progression of Insulin Resistance to Type 2 DM and Beyond

Diagram

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133

InsulinSensitivity

InsulinSecretion

Normal glucosetolerance Diabetic

NonobeseNormal

ObeseNormal

Obese,ImpairedGlucose

Tolerance

Obese,DiabeticHyper-insulin-

emic

Obese,DiabeticHypo-insulin-

emic

HIGH

NORMAL

LOW

Adapted from Nestler,JE, Assessment of Insulin Resistance,Science & Medicine, 1: 1994, p.58.



Description

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Progression of Insulin Resistance to Type 2 DM and BeyondDescription

• A normal person who is not fat has normal insulin sensitivity or secretion

• If the same person is fat, sensitivity decreases (resistance increases) and the pancreas secretes more insulin– The pancreas continues to increase the secretion of insulin in order to

control the blood sugar• Fasting blood glucose is normal, but if given a glucose load (drink), the blood

sugar will be too high– This is referred to as impaired glucose intolerance

» Normally are fine, but if they has a lot of glucose, the pancreas cannot compensate• As the person ages, the secretion of insulin drops. It is still greater than

normal, but it is not enough to control the fasting blood sugar. The person now has diabetes– The obese, diabetic hyperinsulinemic person can usually be treated with oral

medications• The obese, hypoinsulinemic person may have to receive insulin because they

do not have enough• With this bar graph, you can go forward and backward!

– This is a good thing because the person can go back to normal (from obese, impaired)• Do not think that you can go all the way from obese, diabetic,

hypoinsulinemic to normal 135

Commonalities of Type 2 Diabetes

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Commonalities of Type 2 Diabetes

1. Pancreatic secretion of insulin is not sufficient to control blood sugar.- Insulin secretion may be very high, higher than in a

normal person, but it cannot control the glucose because of the resistance

2. Receptor-mediated and postreceptor insulin resistance.- could be due to mutations on the proteins/receptors

3. Gluconeogenesis is not appropriately inhibited by insulin.

Type 2 DM is Composed of Multiple Vicious Cycles

Diagram

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139

Type 2 DM is Composed of Multiple Vicious Cycles

Vicious Cycles of Diabetes

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Vicious Cycles of Diabetes • The type 2 people have several cycles that are

working against them to make type 2 diabetes worse– Obesity – downregulation – resistance –

hyperglycemia – resistance– High insulin – downreg. – resistance– Insulin – increased deposition of fat – obesity –

downreg. – resistance– Decrease in pancreatic responsiveness –

hyperglycemia– Gluconeogenesis – hyperglycemia

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Presentation of Type 2 DM

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Presentation of Type 2 DM

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1. Most Type 2 patients are older and/or obese.- The age of onset is decreasing due to obesity

2. Present with complications of diabetes: fungal infections, UTI, vascular disease, etc.

3. Blood sugar may not be high enough for symptoms of polydipsia, polyuria, or polyphagia.

4. Evidently the amount of insulin present prevents ketosis and DKA.

Overview of Treatment for Type 2

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Overview of Treatment for Type 2

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1. Diet and exercise is the cornerstone treatment - Diet is even more important in type 2 than in type

1

2. Oral agents.

3. Insulin for those whose diabetes cannot be controlled with oral agents.

4. Home glucose monitoring is used for patients in all stages of type 2.

Diet and Exercise

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Diet and Exercise

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• They are the cornerstone of treatment.

• Diet lowers blood sugar and helps with weight loss.

• Exercise lowers blood sugar without need for insulin and burns calories to help with weight loss

• These strategies may be sufficient for mild cases.

Therapy for Type 2 Diabetes Must Address Defective Metabolic

Processing Pathways

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149

Therapy for Type 2 Diabetes Must Address Defective Metabolic Processing Pathways

Drugs for Type 2 DM to Increase the Secretion of Insulin – Sulfonylurea

Drugs

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Drugs for Type 2 DM to Increase the Secretion of Insulin – Sulfonylurea Drugs

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I. Most have a chemical structure called sulfonylurea.

II. Stimulate “nonphysiologic” secretion of insulin independent of blood glucose concentrations. They can cause hypoglycemia.

- if you have not eaten, insulin will go up

III. Block an ATP-dependent potassium channel, preventing repolarization of the beta cell when the beta cell is depolarized and is secreting insulin

Mechanism of Action of the Sulfonylurea-like Drugs

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Mechanism of Action of the Sulfonylurea-like Drugs

153Porth, Pathophysiology: Concepts of Altered Health States, 7th ed., 2005, Lippincott, Williams & Wilkins, p.990.

Drugs which Increase Insulin Secretion by Inhibiting ATP-sensitive

K+ Channels

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Drugs which Increase Insulin Secretion by Inhibiting ATP-sensitive K+ Channels

•1st generation sulfonylureas:AcetohexamideChlorpropamide

TolazamideTolbutamide

•2nd generation sulfonylureas are the ones that are usedGlipzideGlyburide – the only one that is safe for pregnancyGlimepiride

• Meglitinides (non-sulfonylurea, short acting) are used for meal control• Take them right before you eat and increase the secretion of insulin right before

the meal and then they are metabolized quicklyRepaglinideNateglinide

More on MeliglitinidesRepaglinide and Nateglinide

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More on MeliglitinidesRepaglinide and Nateglinide

• Meliglitinides have been shown to interact with gemfibrozil, a lipid-lowering drug and with antifungals like ketoconazole and itraconazole, at the level of cytochrome P450 enzymes.

•Metabolism of repaglinide and nateglinide may be delayed so that they reach higher plasma levels and have prolonged activity.

•Hypoglycemia may result.

Adverse Effects and Contraindications of Sulfonylurea-

Like Drugs

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Adverse Effects and Contraindications of Sulfonylurea-Like Drugs

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1. Hypoglycemia due to the non-physiologic secretion of insulin regardless of the blood glucose levels

2. Hepatotoxicity (elevated liver enzymes).

3. Patients with liver disease may metabolize these drugs more slowly, which will produce longer half-lives and higher peak concentrations.

4. Elderly patients with impaired renal function might also have slowed elimination.

5. N and V, rashes. (universal adverse effects)

6. Contraindicated in type 1, since the patient does not have insulin.

7. Contraindicated in pregnancy because of concerns about teratogenicity (except for glyburide).


Processing Pathways

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Addressing the Cycle

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Addressing the Cycle

• Work by increasing insulin secretion– However, this will lead to the increased deposition

of fat• This is a big problem, because then it increases the

vicious cycle of obesity

– These drugs are not used as often because there are better drugs

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Drugs That Affect Insulin Resistance

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Drugs That Affect Insulin Resistance

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Two Chemical Classes:

A. Biguanides

B. Thiazolidinediones (glitazones)

BiguanideMetformin

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BiguanideMetformin

• Very widely used and good

• Decreases glucose production by the liver, increases glycogen synthesis, increases glucose utilization by fat and muscle, and inhibits lipolysis.

• Insulin also does these

• We don’t know how metformin does these things, but it does not do them by binding to the insulin receptor.

• Can be used as monotherapy or in combination with a sulfonylurea or a glitazone.

Adverse Effects of Metformin

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Adverse Effects of Metformin

• May cause lactic acidosis in patients with any degree of renal impairment, which slows elimination of metformin and causes increased blood levels.• This is very serious

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Beneficial Effects of Metformin

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Beneficial Effects of Metformin

• When used alone, it will not cause hypoglycemia because it does not affect the amount of insulin, it just makes its secretion more effective

• When used as monotherapy, will not cause weight gain.

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Patients with Renal Impairment?

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Patients with Renal Impairment?

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•People that should not be given metformin

•Elderly.

•Diabetic.

•Patients receiving contrast for radiologic procedures, such as angiography. Metformin must be withheld for several days prior to the procedure.

•This is because the contrast causes renal impairment and may lead to lactic acidosis

Other Problems with Metformin

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Other Problems with Metformin

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•Hepatic dysfunction may predispose the patient to lactic acidosis.

•Nausea

•Vomiting

•Rashes

•Metallic taste•One of the reasons that people stop taking metformin

Thiazolidinediones(glitazones) Mechanism of Action

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Thiazolidinediones(glitazones) Mechanism of Action

I. Pioglitazone

II. Rosiglitazone (Avandia)

• They interact with PPAR-gamma, a transcription factor important in differentiation of fat and muscle cells.

• In some way, this improves insulin sensitivity, thus decreasing insulin resistance and decreasing blood sugar

• These drugs are sometimes called “insulin sensitizers”.

Thiazolidinediones (glitazones)Uses and Advantages

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Thiazolidinediones (glitazones)Uses and Advantages

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•May be used as monotherapy, or combined with a sulfonylurea, metformin, or insulin.

•Will not cause hypoglycemia when used alone because they do not affect insulin secretion

•Resumption of ovulation in anovulatory patients.•Ex. people with polycystic ovary syndrome (need to be aware of this in some people, because some diabetics may not want to ovulate)

Thiazolidinediones (glitazones)Adverse Effects

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Thiazolidinediones (glitazones)Adverse Effects

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•Both pioglitazone and rosiglitazone cause edema which may worsen heart failure

•Half-lives of both may be prolonged in patients with hepatic disease.

• A previous member of this class (troglitazone) was removed from the market because of hepatotoxicity. This is probably not a concern with current drugs.

•Possible cytochrome P450 interaction with birth control pills (probably not rosaglitazone).

•The person may need to get a higher dose or use an alternative method of contraception

Safety of Rosiglitazone (Avandia)

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Safety of Rosiglitazone (Avandia)• Although both rosiglitazone and pioglitazone have been

shown to cause increased fluid retention and to exacerbate heart failure, a good bit of data suggests that rosiglitazone is worse in this regard than pioglitazone.– Rosiglitazone may be associated with increased cardiac

morbidity and mortality due to heart failure• The FDA has issue the following recommendations.– Restrict the use of the diabetes drug rosiglitazone (Avandia) to

patients with Type 2 diabetes who cannot control their diabetes on other medications and are unable to take pioglitazone

– GSK (the marketer) will develop a plan for restricted access to rosiglitazone

• Stay tuned


Processing Pathways

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Oral Drug Combinations

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Oral Drug Combinations

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Glipizide/metformin 2 dosages

Glyburide/metformin 2 dosages

Rosiglitazone/metformin 3 dosages(Presumably will also have restricted access)

Pioglitazone/metformin 2 dosages

The Problem with Oral Drug Combinations

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The Problem with Oral Drug Combinations

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•With combinations, the likelihood of hypoglycemia may be increased.

•This is especially true with combinations of metformin with a sulfonylurea-like drug.

Alpha-Glucosidase InhibitorsAscarabose and Miglitol

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Alpha-Glucosidase InhibitorsAscarabose and Miglitol

• These drugs prevent the absorption of sugars in the intestine by inhibiting the enzymes that degrade disaccharides (sucrose or lactose) to monosaccharides (glucose, galactose, and fructose).

•Lactose – glucose and galactose•Those with lactose intolerance do not have the enzyme that breaks lactose into glucose and galactose, enzyme stays in the intestine, exerts osmotic pull, leads to a lot of gas

•Sucrose – glucose and fructose?

• Disaccharides cannot be absorbed by the intestine.

• Since the disaccharides stay in the intestine, they provide increased food for bacteria, which produce a lot of gas and cramping

• The disaccharides also increase the osmotic pressure of bowel contents, increasing the liquidity of the stool.

•The drugs lead to lactose and sucrose intolerance, causing the symptoms of lactose intolerance

Alpha-Glucosidase InhibitorsSide Effects and Use

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Alpha-Glucosidase InhibitorsSide Effects and Use

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Side Effects Diarrhea

Flatulence

•Antidiabetic activity is modest—these drugs are adjuncts to other treatment, not primary treatment.

• Used in type 1 and type 2.

Effects of Classes of Diabetes Drugs

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Effects of Classes of Diabetes Drugs

195Porth, 2011, Essential of Pathophysiology, 3rd ed., Lippincott, p. 814

Exenatide (Byetta®)

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Exenatide (Byetta®)

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1. A peptide drug that is an analog of a hormone called GLP-1 (a GLP-1 agonist).

2. Potentiates glucose-sensitive insulin secretion.- When your blood sugar is high, the pancreas secretes insulin and this drug

will potentiate it so that it secretes more insulin- When the blood sugar is low, it will not do anything, so it will not cause

hypoglycemia

3. Slows gastric emptying.

4. Approved for use with metformin, sulfonylureas or glitazones.

5. Not approved for type 1 (depends on pancreatic insulin secretion for effectiveness)- Because type 1 does not have a pancreas that can secrete insulin

Exenatide (Byetta®)Administration and Interactions

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Exenatide (Byetta®)Administration and Interactions

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• Administered by subcutaneous injection 1 hour before breakfast and/or the evening meal. It is supplied in pre-filled injection pens.

• May cause hypoglycemia when administered with a sulfonylurea but not with metformin.

• When initiating exenatide therapy, the dose of sulfonylurea should be reduced.

•Not approved for use with nateglinide, repaglinide, or insulin.

Exenatide (Byetta®)Side Effects

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Exenatide (Byetta®)Side Effects

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• Not to be used with alpha-glucosidase inhibitors.

• Can delay onset of activity or lower the absorption of oral drugs (take them one hour before injection).

• Nausea, vomiting, and diarrhea were the most frequent adverse events.

• Pregnancy category C (evidence of fetal harm in animals)

Liraglutide (Victoza) a New GLP-1 Agonist

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Liraglutide (Victoza) a New GLP-1 Agonist

• Similar to exenatide, a peptide drug that must be injected.

• Could be expected to behave very similarly to exenatide.

• Unlike exenatide (at least to date) liraglutide caused thyroid tumors in animals.

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DPP-4 Inhibitors

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DPP-4 Inhibitors• Can be taken orally• DPP-4 is an enzyme that degrades several hormones secreted

by the GI tract, including GLP-1

• These hormones, collectively called incretins, increase insulin secretion and decrease glucagon secretion in response to elevations in blood glucose.

• DPP-4 inhibitors would be expected to have similar activity to exanatide (Byetta). But whereas Byetta must be injected because it is a protein that would be destroyed in the digestive tract, DPP-4 inhibitors are small molecules that remain effective when taken by mouth.

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DPP-4 InhibitorsSitagliptin (Januvia) and Saxagliptin

(Onglyza)

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DPP-4 InhibitorsSitagliptin (Januvia) and Saxagliptin (Onglyza)• Used in Type 2 DM only (depends on pancreatic insulin

secretion for effect).• Monotherapy (with diet and exercise)

• Can be combined with metformin, a glitazone or glimepiride (sitagliptin) or glyburide (saxagliptin).

• When taken alone, will not cause hypoglycemia.• Sitagliptin - renal excretion of unchanged drug (adjust for

renal impairment)• Saxagliptin – both hepatic metabolism and renal excretion.

Cytochrome P450 inhibitors slow metabolism (lower dose)• Once daily dosing

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Pramlintide (Symlin®)

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Pramlintide (Symlin®)

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• Also approved for type 1 diabetes• Approved for type 2 patients who require insulin with or

without concurrent therapy with a sulfonylurea or metformin (not a glitazone).

• Initial dose for type 2 patients is 60 μg to be increased to 120 μg when nausea subsides.

• Insulin dose should be cut by half when initiating therapy.

• After a stable dose of pramlintide (60 or 120 μg) is achieved, insulin dose should be titrated for optimal blood glucose control.

• Other issues with pramlintide are the same as for type 1.

Insulin for Type 2 DM

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Insulin for Type 2 DM

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• Can be used alone or in addition to oral agents.

• Use is similar to that for type 1

•Newer evidence suggests that tight control of type 2 may be dangerous because the risk of hypoglycemia is great and not as beneficial as it is for type 1. Most clinicians will tolerate somewhat higher blood sugars in type 2 patients.

DKA and HHNC

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DKA and HHNC

Lehne, 2009, Pharmacology for Nursing Care, 7th ed., Elsevier, p. 682

HHNC is more common in type 2. DKA is more common in type 1. In HHNC, the pathway to ketone formation is not activated so there is no acidosis.

Diabetic Ketoacidosis

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Diabetic Ketoacidosis

• Out of control states of diabetes

• DKA– There is an abundance of glucose but no insulin so

the glucose cannot go into the cells– The body responds by breaking down triglycerides

into fatty acids and then into ketones• The formation of ketones creates the ketoacidosis and

gives off the fruity smell

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HHNC

• HHNC (hyperosmolar, hyperglycemic non-ketotic coma)– There is an abundance of glucose but it is not being

used, which leads to the hyperglycemia• With too much glucose, osmotic diuresis occurs (glucose acts

as a diuretic, like mannitol)– This leads to a loss of water, dehydration, and hemoconcentration

• In HHNC, a lot of fluid is pulled into the vasculature and death may occur via cerebral edema

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Acute Complications of Diabetes

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Acute Complications of Diabetes

• Diabetic ketoacidosis (DKA) is more common in type 1

• Hyperglycemic hyperosmolar non-ketotic (HHNC) coma is more common in type 2.

• Treat both with an intravenous insulin infusion (regular insulin). Bring the blood sugar down slowly with frequent bedside blood sugar checks.

• Ketonemia (ketones in the blood) of DKA may resolve more slowly than the hyperglycemia. If so, give D5W to keep the sugar up and do something with the ketones?*

• Death may be due to cerebral edema caused by fluid shifts.

• Hypoglycemia may result from too rapid insulin administration.

What is first line treatment for type 2 diabetes?

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What is first line treatment for type 2 diabetes?

1. Oral agents2. Insulin3. Pramlintide4. Diet and exercise

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Oral a

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Diet &

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25%25%25%25%

Pregnancy in Type 2 Diabetics

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Pregnancy in Type 2 Diabetics

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•Most oral diabetes drugs should not be used in pregnancy (except glyburide) because they might be teratogenic

•They may be teratogenic.

•They may not control blood glucose well enough to avoid complications in the infant.

•Glyburide or insulin are the choices for pregnant type 2 diabetics.

Gestational Diabetes

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Gestational Diabetes

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•Gestational diabetes is almost always type 2 diabetes that develops in a pregnant women because of the hormones

•Hormones of pregnancy synthesized by the placenta increase insulin resistance.

•If the woman had some degree of baseline insulin resistance (most likely due to pregnancy), she can be pushed over into the category of frank diabetes.

Gestational DiabetesComplications

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Gestational DiabetesComplications

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•The pregnancy and infant are at risk for complications of a diabetic pregnancy, as mentioned before.

•Organomegaly, macrosomia

•After delivery, the placenta is delivered, insulin resistance returns to baseline and is again successfully compensated for by increased insulin secretion.

•The mother is at risk for development of type 2 later in life.

•There is some baseline resistance that could get worse if she gains weight or as she gets older

Gestational DiabetesTreatment

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Gestational DiabetesTreatment

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• Gestational diabetics may be successfully treated with strict diet.

• If not, treat with intensive insulin therapy.

• Recent data confirms that gestational diabetes should be treated aggressively for good outcome of the pregnancy.

Diabetes 1. Why is Diabetes Important? 2 Source: 2004–2006 National Health Interview Survey...

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