Endocrinology, lecture on Glucose Balance
USD Department of Biology
Endocrine Glands
2nd Messengers
Nuclear Receptors
Genetic Regulation
Hormone Synthesis
Receptor Regulation
Hypothalamo-Hypophysial Communication
Tropic Hormones
Neurohypophysial Nonapeptides
Thyroid Axis
Adrenal Axis
Adrenal Medulla
Osmotic-Pressure Balance
Reproductive Endocrinology
Somatic Axis
Growth Factors
Immune Factors
Ca++, PO4 Homeostasis
Pancreatic Hormones
GI Hormones
Guts 'n Brains
Brain Hormones
Endocrine Evolution
Figures for Endocrionology
text:Vertebrate Endocrinology5th Edition - David O. Norris:
Read pages 463-477 for this lecture
acronyms    end
XXVI. Pancreatic Hormones and Glucose Balance 		

	A. Endocrine pancreas primarily secretes 2 hormones: insulin and glucagon

		1. exocrine pancreas secretes digestive enzymes into
		   the lumen of the intestine

		2. insulin and glucagon are secreted from the
		    islets of Langerhans (1% of the organ)

			a. insulin from  b or B cells

				i. 2 polypeptide chains 21aa (A) & 30aa (B)
				    connected by disulfide bridges, MW = 6000

					(1) can aggregate as dimer ® hexamer (zinc)

					(2) from proinsulin (MW = 9000) = continuous chain
					   from N-terminal at B chain to C-terminus with A

				ii. even found in invertebrates, but there are major
				    variations in sequences between species of vertebrates

			b. glucagon from a2 cells (= A cells)

				i. 29 aa, very conservative
				   (homologies with secretin, VIP, GIP)

			c. F or PP cells secrete pancreatic polypeptide

				i. 36 aa

			d. D or  a1 or  d  secrete somatostatin

				i. inhibits both insulin and glucagon

			e. islets organised with a2 cortical (~15%),
			     then d (~10%), b medullary (~75%)

				i. a2, b and d work together as a
				   functional secretory unit

					(1) many gap junctions / tight junctions between cells

					(2) releases suitable proportions of glucagon and 
					    insulin to regulate minute-to-minute [glucose] 

						(a) modulate metabolism toward  
						    anabolism or catabolism in  
						    accordance with physiological needs

				ii. innervated by sympathetic (from VMH; NE)
				      & parasympathetic (VLH; ACh)

	B. Insulin

		1. Stimulated by Glucose, aa, fatty acids

			a. Glucose is transported into b cells via GLUT2 glucose transporters

				i. ATP induces closure of ATP-sensitive K+ channels
					(1) cell membrane depolarization.

			b. voltage-gated Ca++ channels open

			c.  intracellular Ca++ ® exocytosis of insulin

				i. incretins ®  cAMP  cytosolic Ca++

					1) incretins are peptide hormones 
					    released from the gut
				ii. glucose also  biosynthesis of insulin

			d. Amino acids, especially Arg (R), stimulate insulin release
		2.  Incretins, GI peptides (GLP1, GIP), stimulate insulin secretion and inhibit Glucagon (during hyperglycemia)
			a. GIP/GLP1cooperatively ¯blood sugar by reducing gastric emptying 
			b. GLP1 = glucagon-like peptide 1 and GIP (gastric inhibitory peptide) releasd after eating
 				i. dipeptidyl peptidase 4 (DPP4) inactivates incretins
					1)  DPP4 inhibitors used to treat diabetes 2
			c. also by glucagon
        3. Insulin is stimulated by the parasympathetic NS:
		    VLH ® Vagal N. ® vagus nerve  ACh

			a. inhibits glucagon

			b. hypothalamus integrates balance of sympathetic/parasympathetic regulation of islet

		4. Insulin is inhibited by NE, Epi, galanin, pancreostatin (Pst) & somatostatin (Sst)
			a. and insulin

		5. Insulin membrane receptor of 2 x 2 polypeptide chains
		     from a single chain precursor

			a. insulin (2) binds to two a subunits

				i. results phosphorylation of the b (2x): tyrosine PK

					1) substrate is IRS1  (insulin receptor substrate 1)

					    a) IRS1  activates
					       phosphatidylinositol 3 kinase (PI3-K)

					    b) and GRB2 (growth factor receptor bound protein-2)
					        which activates the Sos gene product
							+ SHP2 (Src homology protein tyrosine phosphatase-2)

							i) gene expression and cell growth

					   PI3-K ® PI-3,4,5-P æ
					    c) Sos ® Ras ® Raf1 ® MEK ® MAP K

					    d) MAP K ® Phosphatase 1 ® 
					       ® Glycogen synthase ® glucose storage
					     æ transcription factors	æ   glycogen

						e) PI3-K ® Akt ® mToR ® AS160 ® GLUT4 vesicle

				ii. receptor also binds G protein ®  PDE
					1) degrades cAMP, blocks glycogen conversion 
					    to glucose 

				iii. Tyr PK phosphorylates CAP-Cbl-Crk

					1) pCrk translocates GluT4 to the cell membrane

			b.  glucose uptake follows I-R ® PI3-K + TC10 (GTP binding protein) ®
			   ® translocating GLUT4 to membrane
			c. I-R desensitization results in type II diabetes
			d. insulin receptor family includes the receptor of IGF1

	C. Glucagon

		1. inverse relationship between extracellular [glucose]
		    and glucagon secretion

			a. inhibited by fatty acids and somatostatin

			b.  stimulated by aa, 

			c.   by NE, Epi from sympathetic NS,
			    via VMH ® N.Solitary Tract ® splanchnic nerve ®
				® celiac ganglion ® mixed pancreatic nerve

			d. paracrine insulin inhibits, endocrine insulin stimulates

		2. membrane receptor: Gs/AC/cAMP/PKA

	D. Function: Insulin and Glucagon have opposing actions

		1. insulin stimulates anabolism, energy storage; 

		    glucagon ® catabolism and energy mobilization

			a. insulin ®  glycogen, protein, & lipid synthesis

				i. blood sugar ¯

			b. glucagon ®  glycogenolysis, gluconeogenesis,
				 ketogenesis, proteolysis

				i. blood sugar 

			c. in the liver, but also in muscle and adipose tissue

		2. Diabetes mellitus (running through honey)

			a. Type 1 = Insulin-dependent (juvenile-onset)

				i. islet b-cells destroyed ® insulin deficiency

					(1) primarily via autoimmune reaction

			b. Type 2 = insulin-independent (maturity-onset)

				i. b-cells still functional ® elevated insulin secretion

				ii. decreased sensitivity to insulin = insulin resistance

					(1) ¯ I-R

			c. Other types = secondary 

			d. gestational

XXVII. Gastrointestinal Hormones