Course Content

Ideals in Brief

Imagine taking that first bite into an indulgent piece of cheesecake and savoring the smooth, creamy texture of the filling along with the subtle crunch of the graham cracker crust.  After a few more bites, the sweetness and joy of the cheesecake overpowers the senses to the point the troubles of the day, seem to melt away.  Even though the scrumptious and decadent cheesecake has become the best part of the day at that very moment, the body is working diligently to utilize the sudden surge of sugar or glucose that just arrived.  Normally, as glucose levels begin to rise when food is ingested, the endocrine system, particularly the pancreas, match those levels by secreting insulin into the bloodstream.  This would allow the cells of the body to absorb glucose, which will later be used for energy for every day metabolic process.  However, with a patient suffering from diabetes, this integral balancing act of glucose within the body is disrupted.  In fact, that sudden spike of sugar from the cheesecake described above can have dire consequences for diabetics, especially if their blood sugar is not already managed effectively.  With diabetes being ranked number seven in the leading cause of death in the United States by the Centers of Disease Control and Prevention (CDC), it is vital for pharmacists and pharmacy technicians to not only understand the complexities of diabetes, but to recognize how important their roles are in the overall medication treatment management for patients dealing with diabetes.

This continuing education article will begin by providing an overview of the anatomy and physiology of the endocrine organs involved in managing blood glucose levels.  From there, it will provide an explanation of the different types of diabetes including their respective symptoms and treatment options.  Finally, reviewing how diabetes can complicate other chronic conditions such as cardiovascular disease and the overall devastating effects diabetes has on patients.  

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“More than 29 million Americans are living with diabetes, and 86 million are living with prediabetes” (CDC)

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Before going into how diabetes affects the body it is very important to understand how the body normally regulates blood glucose levels.  Referring to the example of eating the cheesecake earlier, any time the body consumes a meal, blood glucose levels begin to rise.  The basis behind eating is to provide the body nutrients and energy to sustain life and glucose cannot be used as energy without entering the cells. In the simplest terms, for glucose to enter the cells, the pancreas needs to secrete a hormone called insulin that essentially activates glucose receptors known as GLUT4 (glucose transporter type 4) of the cells which in turn, allow them to absorb glucose. 

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Although this brief description provides a good foundation, there are more extensive processes involved within the endocrine system for normal regulation of blood glucose. 

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Pancreas Anatomy and Physiology

Since it has already been mentioned, the journey will begin with the endocrine gland, the pancreas. The pancreas is derived from the Greek words pan (all) and kreas (flesh) and can be described as flat-pear shaped organ that lies transversely on the posterior abdominal wall behind the stomach.

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The pancreas gland exhibits both endocrine and exocrine functions. In adults, the exocrine functions outnumber the endocrine. Their functions are outlined in the table below:

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There is importance in knowing that both functions of the pancreas serve in maintaining the glucose homeostasis and nutrient storage of the body.  The Acinar cells, which makes up the exocrine functions, produces the digestive enzymes that makes up the pancreatic juices.  The islets of Langerhans, which makes up the endocrine functions and only account for 1 to 2 percent of pancreatic tissue, secrete insulin and glucagon into the bloodstream for blood glucose regulation.

Metabolism Control

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With the endocrine and exocrine functions of the pancreas, the pancreas has an essential role in controlling the metabolism of the body. Comprehending this concept is necessary to grasp where the signs and symptoms of the different types of diabetes are derived from and how the mechanism of actions of the treatments currently available, work in reducing blood glucose levels in diabetics. 

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To start, adequate glucose levels are required for “optimal body growth and development and for the function of the central nervous system, for which glucose is the major source of energy” (Robert Utiger).  Metabolism regulation allows energy to be used immediately or to be stored away within the liver or in adipose cells during times of fasting. 

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To fathom the functionality of the pancreas has on metabolism, let’s refer to that delicious cheesecake example from earlier.  When a meal is consumed, the carbohydrates are turned into glucose thus increasing the blood glucose levels in the body.  Like clockwork, the pancreas begins to release insulin secretions up to 10x the amount of glucose in the blood; doing so will stimulate the absorption of glucose into the liver and muscle cells and triglycerides into adipose cells.  Simultaneously, the liver will stop release its glucagon storage and fatty acids and amino acids are stored into the liver and peripheral tissues.  As one could imagine, insulin also inhibits lipolysis (the breakdown of fat). 

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After a few hours after eating that delicious cheesecake, the blood glucose levels reach their pre-meal values as insulin levels taper off and glucagon levels retain the glucose needs of the body.  Also, lipolysis converts fatty acids as fuels for muscle cells and glycerol is converted into glucose in the liver. 

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As the period of fasting continues, i.e. 12-14 hours, glucose production from the liver continues to sustain the needs of the body.  At the same time, glucose levels are maintained by glycogenolysis (the conversion of glycogen to glucose) and gluconeogenesis (creating glucose from amino acids and glycerol). The body enters the catabolic state that is presented with decreased insulin secretion, increased glucagon secretion, and nutrient mobilization from the stores in the liver, muscle, and adipose cells.

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If fasting were to continue, fatty acids released from adipose cells are converted to keto acids (beta-hydroxybutyric acid and acetoacetic acid; known as ketone bodies) in the liver.  Eventually, the brain will use keto acids in addition to glucose for energy. Keto acids through gluconeogenesis continues to sustain the body and therefore, reduces the need for amino acids produced by the breakdown of muscle.  “Starvation is characterized by low serum insulin concentrations, high glucagon concentrations, and high serum free fatty acid and keto acid concentrations” (Robert Utiger) Seeing how normal glucose regulation occurs within the body, it makes it easier to understand the effects from an imbalance or improper management of blood glucose levels in diabetes

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Although insulin and glucagon are the primary hormones involved in glucose homeostasis and metabolism, there are other hormones worth noting:
 

Source: https://dtc.ucsf.edu/types-of-diabetes/type2/understanding-type-2-diabetes/how-the-body-processes-sugar/blood-sugar-other-hormones/

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By looking at graph below, it provides a clear representation of how the body balances the blood glucose levels as an individual consumes meals throughout the day. Later, clarity will be provided on how diet, exercise, and pharmacotherapy all fit together when managing the body’s blood sugar levels.

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Brief History of Diabetes

The first case of diabetes dates to 1552 BC when Hesy-Ra, an Egyptian physician “documented frequent urination as a symptom of a mysterious disease that also caused emaciation ([a] condition of wasting away)” along with those “people known as ‘waste tasters’ [who] diagnosed diabetes by tasking the urine of people suspected of having it [diabetes]” (Krisah McCoy).  As disturbing as these practices may be, they led to scientists using chemical tests to determine the presence of glucose in urine.  These findings contribute to the origin of the name since diabetes means to “siphon” and mellitus refers to “honey.” An in depth view of these and other tools will be described.

Type 1, Insulin-Dependent Diabetes Mellitus (IDDM) Pathology

By definition, diabetes “is a chronic (long term) condition marked by abnormally high levels of sugar (glucose) in the blood (Steven Ehrlich).  Patients suffering from type 1 diabetes mellitus (T1D) do not produce enough insulin for their cells to absorb the glucose consumed from meals.  According to the CDC, of the 29 million Americans diagnosed with diabetes, T1D accounts for 5% of those cases in adults or 1 in 500 people (CDC).  T1D was once thought as juvenile diabetes, but it is more widely accepted as autoimmune diabetes.  This is due to the body’s immune system mistaken the islets of Langerhans (where insulin is created) as a foreign entity and attacking it.  This immune attack led by the T-Cells invade the pancreas and destroys the beta cells to the point where little to no insulin is produced. 

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In addition to these signs and symptoms, type 1 diabetes mellitus causes several complications to other organ systems within the human body.  The following complications listed below stress the importance of diagnosing diabetes early and constant managing of the patient’s blood glucose levels:

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​After learning the signs, symptoms, and complications of Type 1 Diabetes Mellitus, there are several risk factors health care professionals need to know which are outlined below:

• Family History

• Genetics

• Geography: incidence of Type 1 Diabetes tends to increase to countries away from the equator.  People in Finland and Sardinia have the highest incidence of Type 1; 2 to 3 times higher rates in the United States and 400 times more than the people living in Venezuela

• Age: Can appear at any age but appears at two noticeable peaks:  children between the ages of 4 to 7 years of age and 10 to 14 years of age.

•  Exposed to certain viruses: Epstein-Barr, Coxsackie, mumps, and cytomegalovirus

• Early exposure to cow’s milk

• Low Vitamin D levels

• Drinking water containing nitrates

• Have a mother who had preeclampsia during pregnancy

• Being born with jaundice

• Early (before 4 months) or late (after 7 months) introduction of cereal and gluten into a baby’s diet

Source: http://www.mayoclinic.org/diseases-conditions/type-1-diabetes/basics/risk-factors/con-20019573

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Type 2, Non-Insulin-Dependent Diabetes Mellitus (NIDDM) Pathology

From diagnosis to pathology, there are several similarities between Type 1 and Type 2 Diabetes Mellitus (T2D).  In fact, from what has been learned so far about T1D, almost all the signs and symptoms are seen in T2D.  However, there are distinct differences between the two types.

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Starting with the body’s state of insulin, in T1D, the patient’s pancreas is unable to produce insulin due to the autoimmune attack on the beta cells.  In T2D, the body’s pancreas can produce not enough insulin and or the insulin it does secrete, turns to be ineffective.  In other words, the body is resistant to its own insulin.  For this reason, T2D is often referred to as insulin-resistance Diabetes Mellitus. 

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There may be insulin circulating through the bloodstream, but the receptor cells are not able be activated by them.  To add to the variance, T2D is “characterized by hyperglycemia, insulting resistance, and relative insulin deficiency” (Olokoba). As for the epidemiology of T2D, it is estimated that 366 million people had diabetes mellitus in 2011 and that number is rise to 552 million by 2030 (Olokoba).            

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With these differences between the two types of diabetes mellitus, the course of treatment may vary slightly; keeping in mind the medication treatment management will be geared specifically for every patient. 

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Gestational Diabetes

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Gestational diabetes mellitus (GDM) is defined as “diabetes diagnosed during pregnancy that is not clearly overt diabetes” (Kampman et al).  According the latest CDC report, the prevalence of gestational diabetes in the United States may be as high as 9.2% (Barbor). In fact, “the prevalence is higher amongst African American, Hispanic American, Native American, Pacific Islander, and South or East Asian women than in Caucasion women”(Kampann, et al)

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So how does gestational diabetes develop in the first place?  To answer this question, one must know what happens during pregnancy regarding the changes in hormone levels.  In a normal pregnancy, the maternal tissues become progressively insensitive to insulin which is believed to be caused by estrogen and cortisol being released in the placenta along with other factors including obesity and specifically to the pregnancy itself (Kampmann et al).  Under a normal pregnancy, insulin-mediated whole-body glucose disposal decreases by 50% and in order to maintain an euglycemic (normal glucose levels) state, the woman must increase her insulin secretion by 200%-250% (Kampmann).  If the pregnant woman is unable to secrete adequate amounts of insulin, gestational diabetes can develop.   

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Diabetic Ketoacidosis (DKA)

Diabetic ketoacidosis (DKA) is characterized by hyperglycemia, ketoacidosis, and ketonuria.  This complication occurs more frequently in T1D over T2D.  To comprehend DKA, refer to the steps the body takes when unable to transfer glucose from the bloodstream to inside all the cells and tissues.  When the body recognizes the lack of glucose, the liver releases its stores of glucose via gluconeogenesis and glycogenolysis to compensate.  In addition, the body turns to adipose cells (fat) and amino acids (proteins) to burn to release glucose.  Ketones are a by-product of this process.  The two most common ketone bodies are acetoacetic and beta-hydroxybutyrate.  The next compensation tactic the body initiates is to expel excessive ketones and glucose out of the body through urination.  This is vital since the rising levels of these ketones the pH of the blood dramatically to very acidic levels; if this goes untreated, DKA is fatal.  The downside to the kidneys doing this is how it causes polyuria to the point of dehydration.  The urine being voided from the body is insipid, meaning it is diluted and odorless.  To elaborate further on just how much urine the body is voiding with DKA, normal daily urine output is 1-2 quarts of urine a day.  With DKA however, the kidneys can pass as much as 20 quarts of urine a day.  This ultimately results in severe dehydration that requires administrating intravenous electrolytes. 

Signs and Symptoms of Diabetic Ketoacidosis:

• Malaise, generalized weakness, and fatigability

• Nausea and vomiting, abdominal pain, decreased appetite, anorexia

• Rapid weight loss (especially with patients recently diagnosed with T1D)

• Decreased perspiration

• Altered conscience

• Fever

• Coughing

• Chills

• Chest pain

• Dyspenea

• Arthralgia

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Diabetic Insipidus (DI)

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Diabetes Insipidus, commonly referred to as “death by dehydration,” is “part of a group of hereditary or acquired polyuria and polydipsia disease”(Kalra et al).  It is also classified as a hereditary or acquired condition when the pituitary gland is unable to secrete arginine vasopression, or Anti-Diuretic Hormone (ADH).  It is a rare disease with only a prevalence of 1:25000 that can occur at any age and gender.  The pituitary gland utilizes ADH to maintain water balance in the human body; a life-saving feature since the body is 70% water. There are two types of DI.  The first being central DI where the pituitary is unable to secrete ADH due to tumors while the other version is called nephrogenic diabetes insipidus which is when the kidneys no longer response effectively to ADH. Urine production for both cases can be as much as 12 L per day.  It is clear why DI is referred to as “death by dehydration.”

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Diagnostic Tests and Screening

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Just like with any condition, early detection and constant monitoring are essential to the overall treatment plan for all types of diabetes.  In this section, it will cover the most common diagnostic tools used for the applicable type of diabetes.  Health care professionals including pharmacists and pharmacy technicians should familiarize themselves with each of these diagnostics tools to better assist their patients dealing with diabetes:

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With these tests, it is important to know the numbers behind them:

aGlucose values are in milligrams per deciliter, or mg/dL.

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Medication Treatments:

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There have been great strides made in improving both the medications and drug delivery systems used for diabetes mellitus.  Ever since the first insulin injection in 1921 after being discovered by Canadian physician, Frederick Banting and medical student, Charles Best, to the first FDA approved inhaled insulin, Exubura®, all health care professionals including pharmacists and pharmacy technicians must be abreast on all the new medications including their mechanism of actions, in order to provide the utmost best care for their patients.  In this section, it will review the different mechanism of actions (MOA) of the most common drugs used today including the different drug delivery systems.

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Starting with the different MOA of oral/injectable non-insulin antihyperglycemic drugs:

• ​Insulin Secretagogues – Directly Acting

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The first set of medications are classified as insulin secretagoges, or more simply put, they are drugs that stimulate insulin release from the beta cells within the pancreas

• ​Sulfonylurea MOA: to close ATP-Sensitive K-channels in the beta cell plasma membrane, and so initiate a chain of events which results in insulin release (Ashcroft)

• Meglitinides MOA: These work similarly to sulfonylurea as they stimulate the release of insulin from the pancreatic beta cells but attach to the sulfonylurea receptor of the beta cell.   

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Insulin Sensitizers- Directly Acting

• Peroxisome proliferator-activated receptor gamma (PPARy) – Thiazolidinediones (TZD) MOA: These drugs work on reducing insulin resistance and improving beta cell function. They are ligand-dependent transcription factor and a member of the nuclear receptor superfamily that regulate adipocyte differentiation.

• Biguanides MOA: These decrease hepatic glucose production, decrease intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization.

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Insulin Secretagogues- Indirectly Acting via Incretin pathway

• Glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 MOA: Peptide hormones secreted from endocrine cells in the small intestines.  Both activate insulin secretions; GLP-1 also inhibits glucagon secretion and slows gastric emptying.

• Dipeptidyl peptidase 4 inhibitor (DPP4i) MOA: By working via the incretin levels (GLP-1 and GIP), these drugs inhibit glucagon release.  Doing so will increase insulin secretion, decrease gastric emptying, and decrease blood glucose levels.

• Analog of Human Amylin (injection) MOA: Amylin is collocated with insulin in secretory granules and cosecreted with insulin by the beta cells in response to food intake.

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Excretion Enhancers:

• Sodium Glucose Co-Transporter-2 (SGLT-2) MOA: These class of drugs block SGLT-2 protein which is involved in 90% of the glucose reabsorption in the proximal renal tubular in the kidney.  By doing this, it results in increased renal glucose excretion and lower blood glucose levels

• Alpha-Glucosidase Inhibitors (AGi) MOA: To start, alpha-glucosidase is one of the enzymes responsible for breaking down carbohydrates to smaller particles like glucose, in order for the carbohydrates to be absorbed.  AGi work by competitive and reversible inhibition of these intestinal enzymes.  This slows the digestion of carbohydrates and delay glucose absorption.  Ultimately, it results in a smaller and slower rise in blood glucose levels after meals.

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In summary for these non-insulin anti-hyperglycemic medications:

Now let’s explore the insulin anti-hyperglycemic medications MOA medications

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When it comes to the insulins, it is important to differentiate the different onset of times and duration of actions for they play a pivotal role in maintaining proper blood glucose levels.  Also, proper administration of these medications is crucial to prevent both hyperglycemia and hypoglycemia (more prevalent). Another important note is how patients must purchase syringes, alcohol swabs, sharps containers, and pen needles along with pickup their medications.

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Most insulins come in vials as shown below and the strength is represented by u(units)/mL [ 100u/mL is the most common but always make a habit to double check the strength]. Vial insulins have a beyond use date of 28 days except for Lantus® being 3 months.

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For convenience purposes, insulin can also come in pre-filled syringes.  Keep in mind, patients need to purchase pen needles to use their pens.  Examples include the following:

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If round the clock administration of insulin is required for the patient, an insulin pump is necessary for maintaining proper blood glucose levels.  Whole insulin vials are placed inside the pumps where the insulin is later pushed through tubing and a needle that is embedded into the patient. 

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Important note, insulin-regular (Humulin® R or Novolin® R) is the only insulin that can be mixed into an IV admixture.  Once mixed, the beyond use date is 24 hours in room temperature and up to 14 days in the refrigerator (Rocchio).

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Finally, many insulin regimens utilize a sliding scale for dosing.  A sliding scale is based on how much insulin to administer based on the current blood glucose reading; this is specific to the medications, condition of the patient, and hospital protocol.

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Necessary Lifestyle Changes When Living with Diabetes

Being diagnosed with either of the types of diabetes results in having to make dramatic changes in one’s lifestyle. With the cheesecake example for the beginning, diet along with proper exercise must take precedence to prevent further complications associated with diabetes.  In fact, lifestyle intervention changes at the prediabetic stage have proved successful at reducing the incidence of T2D by 28.5% to 58% (Alouki et al).  On top of diet and exercise, diligently monitoring one’s blood glucose levels and adhering to the set medication therapy are vital for survival and preventing unnecessary medical expenses. 

The Future of Diabetes Treatments

Medications, diagnostics, and nutrition continue to advance to provide diabetic patients renewed hope in managing and treating diabetes.  With diabetes causing paradigm shifts in one’s life, potentially forever, continued support from family, friends, and health care providers all contribute to improving patient outcome and enhance the efficacy of care.  That being said, health care providers, especially pharmacists and pharmacy technicians, need to stay on top of the changes occurring in medical treatments for diabetes mellitus.