PHAR 308: Flashcards 22 - Diabetes and Treatments

What is the role of the pancreas in the body?

Acts as an endocrine and exocrine organ for hormones and secretion of digestion enzymes

How many types of diabetes are there?

10 different types, each has their own circumstances but this course focuses on T1 and T2 diabetes

What is insulin and glucagon secretion like when in a fasting state? HOw does this impact the blood glucose levels in the body?

Insulin is secreted in small concentrations to maintain blood glucose levels less that 100 mg/dL

Glucagon is secreted in to maintain blood glucose for cells to use for energy.

What is insulin and glucagon secretion like after a meal is consumed? How does this impact the blood glucose levels in the body?

insulin levels rise and the glucagon levels drop to ensure that there is not hyperglycemia and to increase sugar uptake into the storage tissues (liver, skeletal muscle, fat)

What is the pathophysiology of Diabetes Mellitus?

Hyperglycemia when the patient is fasting and/or abnormal glucose management following a meal

What is the normal pattern of insulin secretion after a meal is consumed?

Glucose levels increase leading to an increase in insulin secretion

What is the pattern of insulin secretion after a meal is consumed for T1D patients?

As glucose levels rise, the insulin levels stay the same

What is the pattern of insulin secretion after a meal is consumed for Y2D patients?

Glucose levels rise and insulin levels slowly rise after a long delay

What is insulin resistance?

A delay in insulin secretion or a non-responsive target receptor in the tissue

insulin fails to stimulate target tissues

Result: hyperglycemia and beta cell burnout as they will continue to produce insulin in response to hyperglycemia

What are the main contributors to Type 1 diabetes and what are the primary avenues of treatment for this disorder?

Not highly contributed to by insulin resistance

Treatment: exogenous insulin, stimulate endogenous insulin

What are the main contributors to Type 2 diabetes and what are the primary avenues of treatment for this disorder?

Contributed to by insulin resistance

Treatment: Change lifestyle, ease insulin resistance with drugs, supplement insulin (if resistance is minimal)

What is the structure of the insulin hormone?

a peptide hormone with an A and B chain

Changes to the B chain can lead to different structures in the blood to confer stability of the molecule 

What are some of the stimulants leading to insulin secretion from the beta cells

Increased levels of glucose, AA, fatty acids and ketone bodies in the blood

Beta Adrenergic receptor stimulation, parasympahetic activation, GLP-1 stimulation, GIP etc.

What are some inhibitors to insulin release?

Low blood glucose

somatostatin

alpha - adrenergic recetor agonists

What is the pathway for insulin release from the beta cell?

1. Glucose from the plasma enters the cell via facilitate diffusion with the Glut-2 transporter

2. Glucose is turned into pyruvate which the mitochondria converts to ATP

3. A rising level of ATP in comparison to ADP leads to blockage of the K/ATP channel preventing K⁺ from exiting the cell

4. Depolarization of the cell due to increased K⁺ levels activates the VGCC transporter allowing Ca²⁺ to enter the cell 

5. Calcium will act on insulin-vesicles in the cell to activate exocytosis of the hormone into the blood 

6. In parallel, ATP converted to cAMP will activate a secondary pathway to increase gene transcription of the cell 

When insulin binds to the insulin receptor, what are the major downstream effects?

1. Glucose transport (uptake)

2. Glycogen Synthesis

3. Lipid Synthesis

4. Protein Synthesis

5. Mitogenesis (cell division)

What are the actions of insulin on carbohydrate metabolism?

• Increase glucose uptake

• Increase glycogen synthesis and decrease glycogenolysis  

• Increase glycolysis and decrease gluconeogenesis 

• Increase glucose oxidation 

What are the actions of insulin on lipid metabolism?

Increase fatty acid transport

Increase triglyceride synthesis (storage) 

Decrease lipolysis 

What are the actions of insulin on protein metabolism?

Increase AA transport

Increase protein synthesis

Decrease protein degradation

How does low insulin levels lead to Ketoacidosis?

Low levels of insulin leads to increased production of Ketone bodies which decrease blood pH and can lead to a coma and death

Results from extremely low insulin levels

How does low insulin levels lead to Muscle Wasting?

When basal insulin levels are low the body will not be anabolic — instead protein degradation occurs due to a lack of insulin maintaining the tissue  

What are this point of insulin therapy?

To subcutaneously administer exogenous insulin to the body to supplement the lack of endogenous insulin

Allows for cells to uptake glucose and reduce the effects of hyperglycemia in the body

What are differences between insulin therapy and the endogenous release of insulin?

1. Absorption kinetic are different — not able to replicate the natural rise and fall of insulin levels in response to changes in blood glucose

2. Injected insulin enters the peripheral circulation leading to a global impact, normally the insulin is released into the portal circulation for activity on the liver first.

How do insulin formulations differ from the endogenous molecule?

The B chain is usually what is different

Changes to the B chain which generates hexamers can generate different PK through altering the stability of the molecule 

What is the PK of the recombinant insulin?

Administration is SC or IV

Half life can different based on formulation

Cleared by the kidney (60%) and liver (40%)

What are some of the ADRs which are related to the use of recombinant insulin for diabetics?

Weight gain, Temporary visual disturbances, lipoatrophy at the injection site, allergic reactions to the injection (local), hypoglycemia and in rare cases, diabetic coma due to hypoglycemia

What is glucagon?

Often identified as the “antagonist” of insulin 

29 AA peptide hormone 

Increases glucose levels in the blood during fasting by inducing glycogenolysis, gluconeogenesis and lipolysis

Inhibits glycolysis and glycogenesis 

Impacts heart (chronotropic and inotropic)

What are incretins?

Hormones release from SI epithelium in response to food which stimulates Beta cells of the pancreas to secrete insulin into the blood 

What are the two forms of incretins?

1. Glucose-dependent Insulinotropic Peptide (GIP)

2. Glucagon-Like Peptide-1 (GLP-1)

What is the metabolism of incretins?

Dipeptidyl Peptidase-IV (DPP-IV) Enzyme catabolizes the incretins

How does Incretin secretion relate to diabetes?

Individuals with T2D typically have  reduced incretin secretion 

What are the four groups of Insulin Secretagogues?

1. Incretin analogues

2. Gliptins

3. Sulfonylureas

4. Meglitinides

However, there must be functioning Beta cells present to have effective treatment from these drugs

What are some examples of Incretin Analogues?

Semaglutide, Liraglutide, Exenatide

What is the Pharmacodynamics, Mechanism of Action and Pharmacokinetics for Incretin Analogues?

PD/MOA: will bind and activate the GLP-1 receptor on pancreatic B cells which stimulates insulin secretion, will increase feeling of satiation and slow SITT

PK: resistant to DPP-IV degradation and will be eliminated similar to large endogenous plasma protein. Half life ~ 1 week  

What are some ADRs of Incretin Analogues?

Nausea, vomiting, diarrhea (related to decrease SITT) and reactions at the injection site 

What are some examples of Gliptins?

Sitagliptin, Saxagliptin

What is the Pharmacodynamics, Mechanism of Action and Pharmacokinetics for Gliptins?

PD/MOA: Acts a competitive inhibitor to the DPP-IV enzyme to prevent the breakdown of incretins so insulin is secreted 

PK: Orally administrated and will peak 1-3 post dosing before removal via renal fltration 

What are the ADRs of Gliptins?

Increases in upper respiratory tract infections as there is a decrease in Tcells (related to DPP-IV), headaches, allergic and hypersensitivity reactions

What are some examples of Sulfonylureas?

Glyburide, Glipzide

What is the Pharmacodynamics, Mechanism of Action and Pharmacokinetics for Sulfonylureas?

To promote the release of insulin by blocking the K/ATP channel leading to beta cell depolarization 

Absorption in the GI tract and will be bound to proteins before metabolism in the liver and renal excretion 

What are the ADRs of Sulfonylureas?

Hypoglycemia, weighht gain, allergic reactions, anemia

What are some examples of Meglitinides?

Repaglinide, Nataglinide

What is the Pharmacodynamics, Mechanism of Action and Pharmacokinetics for Meglinitides?

PD/MOA: closes K/ATP channel of beta cells to stimulate insulin exocytosis

PK: Absorbed fromt he GI tract and will peak after 1 hour

What are some ADRs of Meglinitides?

Hypoglycemia 

What are the three classes of drugs which are used to traet insulin resistance.

Biguanides

Thiazolidinediones

Amylin Analogues

What is an example of a Biguanide and what is it’s mechanism of action?

Metformin

Will decrease hepatic gluconeogenesis to promote glucose uptake by skeletal muscle and adipose tissue

Increases feelings of satiation

What is the PK and ADR of metformin?

Oral administration leads to a long half life (6hr) then removed by the kidney 

ADR: GI distress, increases plasma lactate as it oxidizes fatty acids 

What is an example of a Thiazolidinedione and what is it’s mechanism of action?

Rosiglitazone and pioglitazone

Activate the PPAR-γ in fat tissue which stimulates the storage of fats 

Leads to lowered blood glucose by improving the insulin sensitivity of cells

What are some ADRs of Thiazolidinediones

Weight gain, fluid retention and possible hepatotoxicity 

What is an example of an Amylin analog and what is it’s MOA?

Pramlintide

Binds to the hypothalamus to inhibit the secretion of glucagon and delays gastric emptying

What are some ADRs of Amylin Analogs

Headaches, nausea, vomiting and GI effects

What are some other Antihyperglycemic Drugs?

1. D2 Dopamine Receptor Agonists

2. Bile Acid Sequestrants

3. Gliflozins — increase renal excretion of glucose

4. Alpha Glucosidase Inhibitors to decrease breakdown of polymers into glucose monomers