Lecture #10: Pancreatic Hormones and Metabolic Regulation
I. INTRODUCTION
1. The pancreas arises from the embryonic foregut.
a. The EXOCRINE pancreas excretes enzymes and bicarbonate to the duodenum.
b. The ENDOCRINE pancrease secretes its hormones to the circulation.
2. The importance of pancreas realized by its association with diabetes (thirst, hunger, & ¯weight).
a. copious urination by diabetics.
b. frequent cases of ketoacidosis and gangrene (gangrene) in advanced stages.
3. The normal blood glucose level of 60-80 mg/100 ml is maintained by insulin and glucagon messages to liver, fat, and muscle tissues, i.e., the main tissues involved in glucose homeostasis.
II. ANATOMY OF THE ENDOCRINE PANCREAS (Fig. 11.2)
1. 1-2 million islets of Langerhans make up 1-2% of the pancreatic tissue.
2. Endocrine islet cells have paracrine effects on exocrine enzyme-secreting cells (amylase).
a. ß-cells (72% of islets) produce insulin (51 AAs)
b. a -cells (20% of islets) produce glucagon (29 AAs)
c. d -cells (7% of islets) in splenic lobe of pancreas produce somatostatin (14 AAs)
d. F-cells (i.e., PP cells—1%) in duodenal lobe produce pancreatic polypeptide (36 AAs)
4. Gap junctions, especially between ß-cells, form electrical coupling.
III.
INSULIN (the
"mealtime" hormone) (insulin
structure) (Figs.
11.6)
(NOTE: Connecting peptide had beneficial therapeutic effects for diabetics, and vascular muscle.)
A. SECRETION (ß-cells) (Fig. 11.15)
1. Insulin secretion is stimulated by:
a. an increase in blood glucose, and glucose transport into b-cells (see below for transporters).
b. b-cell glucokinase converts glucose to glucose 6-phosphate that enters the glycolytic pathway.
c. glycolysis produces more ATP, inhibiting K+ channels—causing depolarization of b-cell
d. depolarization opens Ca++ channels and causes insulin vesicles to fuse with plasma membrane.
2. Insulin half-life in blood is 5 min, due to hepatic glutathione insulin dehydrogenase.
B. ACTION
1. Most body cells (especially. hepatocytes, fat & muscle cells) have insulin receptors.
2. Characteristics of the insulin receptor: (Fig. 11.7)
a. the receptor is a dimer (a- & ß-subunits) that operate in pairs in membrane.
b. insulin binding to a-subunit causes autophorphorylation of ß-subunit, which undergoes a conformational change to become an active tyrosine kinase.
c. this tyrosine kinase phosphorylates many proteins, including IRS-1.
d. activated IRS-1 energizes PI 3-kinase at its SH2-domain.
(NOTE: SH stands for Src Homology, and Src is an oncoprotein.)
e. thus, it is the SH2 domains on effector proteins that bind phosphorylated tyrosine residues.
3. Insulin activation
of glucose
transporter (GLUT) system. (Fig.
11.10)
a. constitutive transporters are in most cells (e.g., erythroid GLUT, or GLUT1)
b. induced transporters are mainly in insulin target tissues, i.e., muscle and fat tissue (e.g., GLUT4).
(i) GLUT4 is sequestered in unique intracellular vesicles.
(ii) insulin activates phosphoinositide 3-kinase (PI 3-kinase) (see Fig. 11.7 for activation)
(iii) PI 3-kinase causes translocation of GLUT4s to the plasma membrane.
4. Summary of insulin-activated signaling pathways (Fig. 11.8). (Omit?)
C. RESPONSE (Fig. 11.3)
1. Of liver hepatocytes:
a. facilitates diffusion of glucose into hepatocytes by stimulating glucokinase to form glucose-6-PO4 (original action of insulin in liver may be to stimulate a glucose transporter)
b. stimulates glycogen synthase to form glycogen from excess glucose (i.e., glycogenesis).
c. insulin promotes some lipogenesis in hepatocytes (see “2.b., below, under adipocytes)
2. Of adipocytes:
a. insulin can stimulate >30-fold glucose uptake by fat cells (converts glucose to glycerol).
b. insulin promotes storage of free fatty acids (FFAs) in adipocytes
(i) mono-, di-, and tri-glycerides. are transported in lymph & blood as micelles (chylomicrons).
(ii) lipoprotein lipase in endothelial cells of fatty tissue capillaries releases FFAs.
(iii) the FFAs diffuse into adipocytes where they are re-esterified into triglycerides for storage.
3. Of myocytes:
a. insulin stimulates >30-fold uptake of glucose (and AAs) by glucose transporters.
IV. GLUCAGON (the "exercise" hormone) ( a 29 AA peptide)
A. SECRETION (a -cells)
1. It is secreted when there is a drop in plasma sugars & fatty acids, or a rise in AAs (arginine).
2. Its secretion by a-cells is apparently like insulin secretion.
B. ACTION
1. It acts on receptors in hepatocyte plasma membrane to produce cAMP (Figs.11.12).
2. Epinephrine has a similar effect of increasing cAMP in hepatocytes.
C. RESPONSE
1. Glucagon's principal target is hepatocytes:
a. it promotes glycogenolysis by activating glycogen phosphorylase (i.e., phosphorylase a) (Fig. 11.3)
b. also, it promotes gluconeogenesis by increasing transamination/deamination.
c. also, it promotes gluconeogenic conversion of lactate, pyruvate and alanine from muscles.
2. In adipose tissue it promotes lipases and ketogenesis (Fig. 11.3)
V. SOMATOSTATIN (the "starvation" hormone) (14 AAs)
A. SECRETION (d -cells)
1. It is produced mainly by the pancreas, hypothalamus and GI tract.
B. ACTION & RESPONSE
1. It promotes neither anabolic nor catabolic activity, but conserves energy.
2. It inhibits nutrient utilization, whether newly ingested or stored.
3. It inhibits growth hormone release, and dampens growth.
4. It inhibits gastric acid secretions and intestinal motility.
VI. PANCREATIC POLYPEPTIDE (the "hunger" hormone?) (36 AAs)
A. SECRETION (F-cells at the head of the pancreas near the duodenum)
1. Even slight hypoglycemia increases PP secretion markedly (via vagal activity)
2. Glucose infusions suppress PP secretion, but meals tend to increase PP.
3. Especially protein meals and AAs stimulate PP secretion.
B. ACTION & RESPONSE
1. It suppresses SS secretions from gut and pancreas. (omit?)
2. It inhibits gall bladder secretion and pancreatic enzyme secretion. (omit?)
3. It might stimulate the hunger center.
VII. PARACRINE SIGNALING OF THE PANCREATIC HORMONES
1. Insulin inhibits glucagon secretion from a-cells (in order to preserve stored nutrients).
2. Glucagon stimulates insulin and SS from b- and d-cells (facilitates utilization of new nutrients).
3. Somatostatin inhibits both insulin and glucagon from b- and a-cells (to minimize metabolism).
4. Pancreatic polypeptide has unknown paracrine action.
VIII. EFFECT OF A MEAL ON
INSULIN AND GLUCAGON LEVELS IN BLOOD (Fig.
11.14)
