Lecture 15 - Antidiabetic Drugs Flashcards
What is Diabetes Mellitus?
A syndrome with a deficient secretion of insulin, insulin resistance, or a combo of the two
What is Diabetes Insipidus?
A rare disorder that occurs when a person’s kidneys pass and abnormally large volume of urine that is insipid (dilute and odorless). Caused by deficiency of antidiuretic hormone (ADH, vessopressin)
What do alpha pancreatic hormones do?
Secrete glucagon
What do Beta pancreatic hormones do?
Secrete insulin and amylin (inhibit glucagon secretion)
What are intestinal hormones called?
Incretins
- secreted by endocrine cells in the small intestine
- GIP - gastric inhibitory protein, glucose-dependent insulinotropic peptide
- GLP-1 - glucagon like protein-1
Insulin (anabolic hormone) - function
- Helps muscle, fat and liver cells absorbs glucose from blood, decreases blood glucose levels
- Stimulates glycogen synthesis in the liver and muscle tissue, reduce glucose production
Incretins - function
- Sense the glucose levels in the GI tract
- Stimulate and increase insulin secretion
Glucagon - Function
- Increases circulating glucose levels
- Stimulates gluconeogenesis in liver, which allows glucose to enter the circulation
- Aids in converting amino acids to glucose
Describe the negative feedback loop between glucose blood level and insulin secretion
- Stimulus raises blood glucose level (eating)
- high blood glucose level is detected by insulin-secreting cells of the pancreas
- Pancreas secretes the hormone insulin causing liver cells to take up glucose and store it as glycogen
- Most body cells also take up more glucose, glucose levels decline, glucagon secreted, insulin release stops
- Return to homeostatic blood glucose level until the next meal
How is insulin released from the cell?
- Glucose enters the cell through GLUT2 and causes an increase in ATP
- ATP increase is sensed by membrane-bound receptors (SUR)
- ATP-K+ channels close causing depolarization
- Ca2+ channels open
- Increased cellular Ca2+ triggers release of insulin and amylin through exocytosis
How does glucagon increase blood glucose level?
Stimulates the liver to convert stored glycogen into glucose (glycogenolysis) and gluconeogenesis
What happens in the cell after insulin binds?
- Tyrosine kinase activation
- signaling molecules (IRS, PI3K, PDK1, AKT, AS160, etc –> Proliferation, cell survival, proliferation
- GLUT4 transporters are translocated
- Glucose uptake –> metabolism (glycolysis) and storage (glycogenesis)
Criteria for diagnosing diabetes medillus
A repeated blood glucose of 126 mg/dl or more after fasting or 200 mg/dl or higher 2 hours after eating or random sampling during the day, accompanied by other symptoms
Symptoms and complications of diabetes medillus
- High blood glucose levels
- Hyperinsulinemia
- Glycosuria
- Polyuria
- Polydipsia (excessive thirst and fluid intake
- Polyphagia
- Ketoacidosis due to lack of enough insulin to turn sugar into energy
- Diabetic neuropathy
- Hypertension, stroke, cardiovascular disease
Type 1 vs Type 2
Etiology
Type 1 - Autoimmune destruction of pancreatic beta-cells
Type 2 - Insulin resistance w/ inadequate beta-cell function to compensate
Type 1 vs Type 2
Insulin levels
Type 1 - Absent or negligible
Type 2 - Typically higher than normal
Type 1 vs Type 2
Insulin action
Type 1 - absent or negligible
Type 2 - Decreased
Type 1 vs Type 2
Insulin resistance
Type 1 - not part of the syndrome but may be present
Type 2 - Yes
Type 1 vs Type 2
Age of onset
Type 1 - typically < 30 years
Type 2 - typically > 40 years
Type 1 vs Type 2
Acute complications
Type 1 - Ketoacidosis, wasting
Type 2 - Hyperglycemia (can lead to seizures and coma)
Type 1 vs Type 2
Chronic complications
Both - Neuropathy, retinopathy, nephropathy, peripheral vascular disease, coronary artery disease
What is hyperinsulinemia?
High levels of insulin due to overproduction from the beta cells trying to compensate for insulin resistance –> leads to type 2 diabetes
Insulin resistance causes
Obesity, physical inactivity, hormones, and genetic factors
Drug classes of parenteral treatment in DM
- Insulins
- Amylin analogs
- Incretin mimetics (GLP-1 receptor agonists)
Drug classes of oral treatments in DM
- Secretagogues (Kir 6.2 channel inhibitors)
- Glucose absorption inhibitors (alpha-glucosidase inhibitors)
- Biguanides (Metformin)
- Insulin sensitzers (PPARy receptor activator)
- Peptidase inhibitors
- Sodium-glucose co-transporter 2 (SGLT2) inhibitors
What is the source of insulin?
Originally obtained from dogs, pork, or beef organs. Today it is produced only though recombinant DNA technology
What are recombinant insulin analogs?
Amino acids have been switched or replaced, making different molecules that are still recognized by the receptor, but gains new features
Pramlintide
Amylin analog
Reduces prandial glucose, decreases prandial glucagon, delays gastric emptying, and induces weight loss
What is the function of amylin?
Reduces postprandial glucagon secretion and hepatic glucose production. Also delays gastric emptying and mediates satiety
GLP-1 and Incretin Mimetics - Role in blood sugar regulation
GLP-1 is released in response to food intake. It stimulates the release of insulin from beta cells and inhibits the release of glucagon
GLP-1 and Incretin Mimetics - Influence on appetite
GLP-1 acts on the brain to reduce appetite and increase feelings of fullness. It slows the emptying of the stomach which prolongs the feeling of fullness
GLP-1 and Incretin Mimetics - Degradation
GLP-1 has a half life of 1-5 min
- rapidly degraded by dipeptidyl peptidase-4
GLP-1 and Incretin Mimetics - Therapeutic potential
GLP-1 receptor agonists - Extenatide, Semaglutide, Liraglutide
What are secretagogues?
A substance that induces or causes the secretion of another substance (eg gastrin and histamine increase gastric acid secretion of drugs that promote insulin secretion)
Sulfonylureas and meglitinides - Mechanism of action
Secretagogue
- Enter beta cells and cause release of insulin
- inhibit K+ channels and therby open Ca2+ channels
- Do not have insulin like activity so cannot be used in type 1
Diazoxide
A potassium channel activator which inhibits insulin release to treat hypoglycemia
Clucose absorption inhibitors
Miglitol (alpha-glucosidase inhibitor) and Acarbose (beta-amylase inhibitor)
- Interrupt carbohydrate digestion from diet
- glucose absorption delayed but not eliminated
- keep blood glucose levels from peaking after meals
Metformin
Biguanide
- lowers postprandial glucose levels by decreasing liver glucose production and intestinal glucose absorption
- enhances glucose utilization by other tissues by increasing insulin sensitivity
Thiazolidinediones (Pioglitazone and Rosiglitazone)
Insulin sensitzers
- Lowers blood sugar by decreasing insulin resistance, increases sensitivity to insulin
- Activate the PPARy receptors –> increases insulin sensitization and enhances glucose metabolism
Interfering with the incretin pathway
What do dipeptidyl peptidase-4 inhibitors do?
- Stimulate insulin secretion
- Decresed glucagon secretion
Canagliflozin, dapagliforzin, and empagliflozin
Sodium-glucose co-transporter 2 inhibitors
- work in kidneys by inhibiting glucose reabsorption
- contraindication with type 1 DM or severe kidney disease
