Pancreatic Hormones & Antidiabetic Drugs

Dr. Meera Ababneh, Pharm.D, PhD

PancreasType of cells Approximate Percent of

Islet MassHormones secreted

Alpha (A) cell 20 Glucagon

Beta (B) cell 75 Insulin, C-peptide, proinsulin, amylin

Delta (D) cell 3-5 Somatostatin

G cell 1 Gastrin

F cell (PP cell) 1 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

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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.)

• Ketoacidosis—type 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.

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Diabetes Mellitus

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• 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.

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

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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)

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• 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

Incretin Mimetics

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• 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

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