Endocrinology, lecture on Glucose Balance
USD Department of Biology
Endocrinology
Summers
Hormones
Endocrine Glands
Receptors
Homeostasis
2nd Messengers
Nuclear Receptors
Genetic Regulation
Hormone Synthesis
Receptor Regulation
Hypothalamo-Hypophysial Communication
Tropic Hormones
Neurohypophysial Nonapeptides
Thyroid Axis
Steroids
Adrenal Axis
Adrenal Medulla
Osmo-Pressure Balance
Reproductive Endocrinology
Prolactin
Somatic Axis
Growth Factors
Immune System
Ca++, PO4 Homeostasis
Pancreatic Hormones
GI Hormones
Guts 'n Brains
Brain Hormones
Neurosteroids
Neuropeptides
Evolution
Figures for Endocrionology
text:Vertebrate Endocrinology4th Edition - David O. Norris:
Read pages 453-461, 475-484 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. Ý intracellular Ca++ ® exocytosis of insulin


				i. incretins ® Ý cAMP Ý cytosolic Ca++

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


		2.  Insulin is stimulated by the parasympathetic NS:
		    VLH ® Vagal N. ® vagus nerve Ý ACh

			a. inhibits glucagon


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

		3. Insulin is passively Ý by GIP (during hyperglycemia)

			a. also by glucagon 
			
			
		4. Insulin is inhibited by NE, Epi, galanin, pancreostatin (Pst) & somatostatin
		
			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


					   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 Ý  glycogen


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

			b. Ý 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. Ý  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 ® Ý glycogen, protein, & lipid synthesis

				i. blood sugar ¯


			b. glucagon ® Ý glycogenolysis, gluconeogenesis,
				 ketogenesis, proteolysis


				i. blood sugar Ý


			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