Pancreatic Hormones & Antidiabetic Drugs
Dr. Meera Ababneh, Pharm.D, PhD
Pancreas
Type of cells Approximate Percent of Islet Mass Hormones secreted
Alpha (A) cell Beta (B) cell Delta (D) cell G cell F cell (PP cell)
20 75 3-5 1 1
Glucagon Insulin, C-peptide, proinsulin, amylin Somatostatin Gastrin Pancreatic polypeptide (PP)
Pancreas Gland
Insulin : storage and anabolic hormone of the body Islet amyloid polypeptide (IAPP, or amylin): modulates appetite, gastric emptying, and glucagon and insulin secretion Glucagon: hyperglycemic factor that mobilizes glycogen stores Somatostatin: a universal inhibitor of secretory cells Gastrin: stimulates gastric acid secretion Pancreatic peptide: facilitates digestive processes by a mechanism not yet clarified.
Pancreatic Endocrine Function
Insulin:
Promotes cell use of glucose and carbohydrate storage (mostly in skeletal muscle) Constantly secreted by the pancreas in response to blood glucose levels Stimulates glycogen synthesis in the liver Facilitates entry of amino acids into the cell
Incretins also stimulate insulin secretion.
Pancreatic Endocrine Function
Glucagon:
Increases circulating glucose levels Stimulates glycogenolysis in liver, which allows glucose to enter circulation Also helps in converting amino acids to glucose
Healthy Response
Eat meal, peak glucose at about 30 minutes Phase 1: stored insulin released upon ingestion of meal Glucose continues to rise, reaching above 100mg/dl 20 minutes later Phase 2: beta cells secrete more insulin 1-2 hours later, glucose levels reach around 85 mg/dl
1-6
Insulin promotes synthesis
Endocrine effects of insulin (1)
Effect on liver:
Reversal of catabolic features of insulin deficiency Inhibits glycogenolysis Inhibits conversion of fatty acids and amino acids to keto acids Inhibits conversion of amino acids to glucose Anabolic action Promotes glucose storage as glycogen (induces glucokinase and glycogen synthase, inhibits phosphorylase) Increases triglyceride synthesis and very-low-density lipoprotein formation
Endocrine effects of insulin (2)
Effect on muscle:
Increased protein synthesis
Increases amino acid transport Increases ribosomal protein synthesis Increased glycogen synthesis Increases glucose transport Induces glycogen synthase and inhibits phosphorylase
Endocrine effects of insulin (3)
Effect on adipose tissue: Increased triglyceride storage Lipoprotein lipase is induced and activated by insulin to hydrolyze triglycerides from lipoproteins
Glucose transport into cell provides glycerol phosphate to permit esterification of fatty acids supplied by lipoprotein transport Intracellular lipase is inhibited by insulin
Diabetes Mellitus
Disorder of pancreatic endocrine function resulting in:
Deficient secretion of insulin Insulin resistance
The excess production of insulin causes the down regulation (decrease) in the number of receptors and the target cells cannot synthesize enough receptor protein to keep up, further contributing to the problem.
Combination of both
Types of DM
Type 1
Autoimmune disorder (coxsackie virus implicates as trigger) Destruction of beta cells Cessation of insulin production
Type 2
Insulin resistance Obesity Genetic link
Type 3
specific causes of an elevated blood glucose
Type 4
Gestational diabetes (GDM)
Diabetes Mellitus
Symptoms of diabetes: Increased blood glucose levels Glycosuria Polyuria Polydipsia Polyphagia Diabetic neuropathy
Diabetes Mellitius (symptoms cont.)
Ketoacidosistype 1 diabetics
The breakdown of fat produces an increase in ketone bodies in the blood. This condition is called ketosis. As the ketone level increases, metabolic acidosis (ketoacidosis) occurs.
Amputation
Inadequate circulation to the extremities, coupled with soft-tissue infections that resist healing, may lead to necrosis (gangrene) and the need for amputation.
1-16
Diabetes Mellitus
Blood glucose monitoring:
A healthy fasting blood glucose level is between 70 and 110mg/dL. Glucose meters:
Used to test blood glucose levels several times a day
Glycolated hemoglobin (HbA1c):
Used to evaluate 3 months of glucose levels Hemoglobin that has glucose attached to it. Because RBCs do not require insulin to uptake glucose, glucose enters the RBC and readily binds to hemoglobin without the help of enzymes.
39-17
Treatment of Diabetes Mellitus
Immediate therapy is to correct metabolic imbalance.
Maintenance therapy is directed at regulating blood glucose levels:
Diet control Exercise Medications
Diabetes Treatment
Parenteral administration:
Insulin, amylin analog, incretin mimetics
Oral antidiabetics
Secretagogues, glucose absorption inhibitors, biguanides, insulin sensitizers, peptidase inhibitors
*insulin and secretagogues are hypoglycemics: decrease normal or elevated glucose levels
1-19
Insulin
Source:
Insulin was originally obtained from pork or beef organs.
Today it is produced only through synthesis:
Recombinant DNA technology
Insulin available today comes in different onsets and durations of actions.
Insulin preparation
Rapid-acting Short-acting Intermediate-acting Long-acting Insulin delivery systems
Extent and duration of action of various types of insulin
Insulin
Dosage:
It is usually administered 30 to 60 minutes before meals.
The long-acting recombinant DNA insulins are dosed once daily. Insulin is administered with a specifically calibrated syringe.
Insulin pens are an alternative for delivering a precise dose.
Insulin
Changes in insulin requirements:
Colds, fevers, surgery, and stress all increase glucose levels, which increases insulin need.
Heavy exercise can lower the insulin need.
Drugs can affect glucose levels, requiring changes to the insulin dose.
Allergic reactions may necessitate change to another species of insulin. Lipodystrophy is a disappearance of subcutaneous fat at the site of insulin injection.
Insulin
Adverse effects:
Blurred vision Hypoglycemia Hunger Headache Fatigue Anxiety Nervousness Confusion Paresthesia
Amylin Analogs (sc admin)
Amylin:
It is the hormone co-secreted by the beta cells with insulin. Without enough amylin, blood glucose levels rise. Slows gastric emptying and suppresses glucagon secretion, satiety signal
Pramlintide (Symlin):
Mimics amylin to control glucose levels Adverse effects include vomiting, decreased appetite, headache, and dizziness
39-28
Incretin Mimetics
Incretins:
Hormones secreted from the duodenum, due to glucose stimulation Increase insulin secretion
GIP (gastric inhibitory peptide) GLP-1 (glucagon-like peptide-1)
Exenatide(Byetta) and liraglutide(Victoza):
Incretin mimetic Adverse effects include nausea, diarrhea, headache, and dizziness
39-29
Oral Antidiabetic Drugs
Used in the management of type 2 diabetes Approved for treatment when diet and exercise have not achieved target glycemic control
Oral Antidiabetic Drugs
Secretagogues
Substances that induce or cause the secretion of another substance Enter beta cells and cause the release of insulin Do not have insulin-like activity, so should not be used in type I diabetes
Secretagogues
Sulfonylureas:
Two generations Reduce fasting plasma glucose
Nonsulfonylureas:
Stimulate insulin secretion Quicker onset of action than sulfonylureas
Both types must be taken 1 to 30 minutes before each meal.
Secretagogues
Adverse effects:
Hypoglycemia GI irritation Nausea Diarrhea Weakness Fatigue Dizziness
Glucose Absorption Inhibitors
Interrupt carbohydrate digestion from diet Glucose absorption delayed but not eliminated Keep blood glucose levels from peaking after meals Taken with each meal
Glucose Absorption Inhibitors
Adverse effects:
GI flatulence Diarrhea
Abdominal pain
Do not cause hypoglycemia unless used in combination with secretagogues or insulin
Antihyperglycemic: Biguanides
Decrease blood glucose levels after meals by decreasing liver glucose production and intestinal glucose absorption Enhance glucose use by other tissues in the body No direct effect on insulin secretion
Biguanides
Adverse effects:
Diarrhea Nausea Vomiting Lactic acidosis (rare), life-threatening black box warning
Contraindication:
Alcohol potentiates the action of metformin on lactic acid metabolism
Insulin Sensitizers: Thiazolidinedione
Enhance peripheral cell response to insulin Allow glucose to be used more efficiently Decrease insulin resistance and increase insulin sensitivity of fat, skeletal muscle, and liver cells
Insulin Sensitizers
Adverse effects:
Fluid retention
Weight gain
Headache
Fatigue Diarrhea Contraindicated liver and cardiovascular disease states.
Dipeptidyl Peptidase-4 Inhibitors
DPP-4 in intestine
Breaks down GLP-1
Inhibitor leads to:
Stimulation of insulin secretion Decreased glucagon secretion
Adverse effects:
Nasopharyngitis Upper respiratory infections Headache
