Transcript PANCREATIC HORMONES

XIV. PANCREATIC HORMONES
Diabetes mellitus - 16 million in U.S., half unaware, 650,000
new diagnoses/year
Occurs most often in adults
But is most prevalent chronic disorder in teenagers — 127,000
A. Hormones
1. Insulin - secreted by ß-cells
2. Glucagon - secreted by -cells
3. Both hormones regulate blood glucose levels
XIV. PANCREATIC HORMONES
A. Regulation of release
1. Gastrointestinal nutrients and hormones — glucose, amino
acids, fatty acids, ketone bodies and gastrointestinal
hormones stimulate secretion.
2. Autonomic mechanisms -Norepinephrine and epinephrine inhibit secretion
Selective ß-receptor stimulation stimulates release
Cholinergic stimulation (e.g., vagus) stimulates release
3. Hormones
a) glucagon
b) somatostatin
4. Glucose — increase in blood glucose increases release
decrease in blood glucose decreases release
XIV. PANCREATIC HORMONES
B. Mechanism of release
Leads to
depolarization
Glucose
Closes
Potassium
channel
Glucose
transporter
R
Glucose
Decreases
potassium
conductance
Calcium
channels
ATP
Ca+
Metabolism
Insulin
granules
Insulin
XIV. PANCREATIC HORMONES
C. Role in metabolic processes
1. Review
Glucagon
Glucose
Glycogen
synthetase
R
Gluco-1phosphatase
Glycogen
Energy
utilization
Gluconeogenesis
Lipase
Urea
excretion
Protein
Lipid
Amino
Acids
Free
Fatty
Acids
Ketone
Bodies
Liver
XIV. PANCREATIC HORMONES
C. Role in metabolic processes
2. Insulin effects
Increases
Glucose
Decreases
Glycogen
synthetase
Insulin
R
Glycogen
Gluco-1phosphatase
Energy
utilization
Gluconeogenesis
Lipase
Urea
excretion
Protein
Free
Fatty
Acids
Ketone
Bodies
Liver
Lipid
Amino
Acids
XIV. PANCREATIC HORMONES
C. Role in metabolic processes
3. Insulin deficiency
Hyperglycemia
Increases
Decreases
Insulin
Glycogen
synthetase
R
Glycogen
Gluco-1phosphatase
Gluconeogenesis
Lipase
Urea
excretion
(Azoturia)
Protein
(Ketonemia
and Acidosis)
Energy
utilization
Free
Fatty
Acids
Ketone
Bodies
Liver
Amino
Acids
Lipid
Hyperlipemia
XIV. PANCREATIC HORMONES
D. Types of diabetes mellitus
1. Insulin-dependent diabetes mellitus (IDDM, Type I)
a) Characteristics:
Severe form
Usually in juveniles
Occasionally in adults
Insulin virtually absent
Plasma glucagon elevated
b) Etiology
Pancreatic B cell unresponsive to insulin stimuli
Damaged pancreatic B cells
Autoimmune response
Environmental insult
Genetic defect
XIV. PANCREATIC HORMONES
D. Types of diabetes mellitus
2. Non-insulin-dependent diabetes mellitus (NIDDM, Type II)
a) Characteristics:
Milder than IDDM
Usually adults, occasionally juveniles
Heterogenous group
b) Etiology
Subnormal levels of insulin
Tissue insensitivity to insulin
Pancreatic B cell unresponsive to insulin
Hyperglycemia impairs B cell response
XIV. PANCREATIC HORMONES
E. Replacement therapy in IDDM
1. Preparations of insulin are divided into three catagories
according to promptness, duration and intensity of action.
2. Fast-acting — zinc insulin
3. Intermediate acting — Isophane insulin suspension is a modified
protamine zinc insulin suspension
4. Long-acting -- Hagedorn insulin-zinc-protamine complex
5. Humalog Mix 25 (Canada)
6. Velosulin BR
5. New modes of treatment - infusion pumps and inhalers
XIV. PANCREATIC HORMONES
F. Insulin side effects
1. Hypoglycemia — insulin requirement reduced, failure to eat,
unaccustomed exercise, or insulin overdose
can all cause hypoglycemia
a) A rapid fall in blood glucose
b) A slow fall in blood glucose
Treatment of hypoglycemia is to administer fruit juice or
glucose; if not available, then glucagon
2. Other adverse reactions — mostly allergic reactions, but usually
subside after chronic administration
XIV. PANCREATIC HORMONES
G. Treatment of NIDDM
1. Diet
2. Insulin -- most patients treated with insulin and diet
3. Oral hypoglycemic agents:
Used when diet control insufficient
Used with insulin to lower dosage of insulin.
Not when insulin requirements exceed 200 units/day.
XIV. PANCREATIC HORMONES
G. Treatment of NIDDM
3. Oral hypoglycemic agents (cont.)
a) Sulfonylureas (first generation)
1) Agents - acetohexamide (Dymelor), chlorpropamide (Diabinese),
tolazamide (Tolinase), tolbutamide (Orinase)
2) Mechanism of action -- stimulate ß-cells to secrete insulin
3) Adverse effects -- associated with cardiovascular disease, hypoglycemia
Effectiveness questioned
b) Sulfonylureas (second generation)
a) Agents - glyburide (Diabeta, Micronase) and glipizide (Glucotrol) and
Glimepride (1996)
b) Mechanism of action:
Stimulate insulin release from ß cells (K channel blockers)
Release glucogon and somatostatin
Inhibit hepatic gluconeogenesis
Enhance insulin receptor sensitivity
c) Adverse effects - less than with first generation
XIV. PANCREATIC HORMONES
G. Treatment of NIDDM
c) Biguanides
Phenformin introduced in 1957
Metformin (Glucophage) available in 1994
Mechanism of action -increases the utilization of glucose by decreasing cellular respiration
decreases glucose levels by inhibiting gluconeogenesis
inhibits intestinal absorption of glucose
Adverse effects -- phenformin produced fatal lactic acidosis,
metformin much less so
Contraindications — hepatic disease or past history of lactic acidosis
XIV. PANCREATIC HORMONES
G. Treatment of NIDDM
d) Thiazolidinediones (antihyperglycemic)
Troglitazone (Rezulin) - marketed in 1997
Ciglitazone, Pioglitazone (Actos) - FDA approval pending,
Rosiglitazone (Avandia)
Action - reduce plasma glucose, insulin and lipid levels
in insulin-rresistant animal models
Mechanism of action - increases synthesis of insulin
transporters
Toxicity - troglitazone implicated in acute liver failure, FDA
recommends other in this class carry warning label
rosiglitazone elevates LDL
rosiglitazone may be fetotoxic
XIV. PANCREATIC HORMONES
G. Treatment of NIDDM
e) Alpha-glucosidase inhibitors
Acarbose (Precose)
Mechanism of action - reduces intestinal absorption of starch
dextrin, and disaccharides — postprandial reduction
in plasma glucose
Side effects - malabsorption, flatulence and abdominal
bloating
XIV. PANCREATIC HORMONES
H. Glucagon
1. Physiological actions
a) Insulin and glucagon are mutual antagonists
Glucagon mobilizes fuel -- increases [glucose] plasma
Increased glucose leads to increase in insulin and
decrease in glucagon
b) Following a meal, decreased glucagon secretion.
c) Starvation (decrease in blood glucose) causes increase in
glucagon secretion
2. Regulation of secretion -- glucose is primary stimulus.
Increased plasma glucose decreases glucagon secretion and vice
versa
3. Therapeutic use -- used to treat insulin-induced hypoglycemia