Insulin and the brain. Mary ET Boyle, Ph. D. Department of Cognitive Science UCSD
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1 Insulin and the brain Mary ET Boyle, Ph. D. Department of Cognitive Science UCSD
2 1921 Banting & Macleod Nobel Prize 1923 White, M. F. (2003) Science
3 Berg, J. M., Tymoczko, J. L. and Stryer, L. (2007) Biochemistry 6 Ed.; WH Freeman, NY
4 Berg, J. M., Tymoczko, J. L. and Stryer, L. (2007) Biochemistry 6 Ed.; WH Freeman, NY
5
6 Pancreas basics α cells glucagon β cells insulin & amylin δ cells somatostatin pancreatic duct exocrine acinus F cells pancreatic polypeptide ε cells ghrelin Images adapted from: Kapit. W. et al., (1987) The Physiology Coloring Book, Harper Collins, NY; splenic vein
7 Cell types in the islets of Langerhans: Cell Hormone Function α cells (15%) glucagon stimulate gluconeogenesis and release of glucose into blood stream β cells (75%) δ cells (5%) ε cells (<1%) F cells (<5%) insulin & amylin somatostatin ghrelin pancreatic polypeptide responsible for decreasing blood glucose levels and satiety (insulin 100:amylin 1) inhibition of insulin and glucagon secretion stimulating appetite hormone self regulate exocrine and endocrine pancreatic secretions Berg, J. M., Tymoczko, J. L. and Stryer, L. (2007) Biochemistry 6 Ed.; WH Freeman, NY
8 Insulin and glucagon are complementary Images adapted from: Kapit. W. et al., (1987) The Physiology Coloring Book, Harper Collins, NY
9 Insulin reduces blood glucose levels by activating glucose transporters (GLUT) enabling the uptake of glucose in: Glucose transporter (GLUT4) Cell metabolism Triglycerides High levels of glucose In blood Glucose sensor (GLUT2) Glycerol β cells insulin Insulin receptor Fatty Acid synthesis Protein synthesis Glycogen synthesis Glycogen synthesis Images adapted from: Kapit. W. et al., (1987) The Physiology Coloring Book, Harper Collins, NY
10 Tissue Distribution of glucose transporters Berg, J. M., Tymoczko, J. L. and Stryer, L. (2007) Biochemistry 6 Ed.; WH Freeman, NY
11 Actions of glucagon: Low levels of glucose in blood Detect glucose levels Glucagon receptors After glucagon binds to its receptors on the liver cells, There is an increase in cyclic AMP within hepatocytes. camp activates a cascade of enzymes degrading glycogen into glucose. glycogen phosphorylase Glycogen tree Glycogenolysis = breakdown of glycogen Gluconeogenesis = synthesis of glucose from amino acids in the liver Images adapted from: Kapit. W. et al., (1987) The Physiology Coloring Book, Harper Collins, NY
12 Glucose Tolerance Test: Images adapted from: Kapit. W. et al., (1987) The Physiology Coloring Book, Harper Collins, NY
13 Insulin deficiency Glucose entry is blocked fat Cells utilize their own stores of glycogen Fat Protein protein glycogen Excessive fatty acid utilization leads to formation of ketone bodies by liver Ketone bodies Hyperphagia Images adapted from: Kapit. W. et al., (1987) The Physiology Coloring Book, Harper Collins, NY
14 Kidney tubules cannot reabsorb the excess filtered glucose. The extra glucose spills over in urine (glycosuria) Ketonuria Polyuria Glycosuria The excess glucose causes osmotic diuresis (polyuria). Polyuria reduces plasma water, leading to excessive thirst (polydipsia). Images adapted from: Kapit. W. et al., (1987) The Physiology Coloring Book, Harper Collins, NY
15 Historically, there was little interest in insulin and the brain because: unlike [skeletal muscle], the brain does not require insulin to take up glucose brain was considered to be insulin independent insulin was considered too large to cross the blood brain barrier Begg, D. P and Woods, S. C. (2013) Adv Physiol. Educ 37: 53 60
16 Innervation of islet of Langerhans From the large nerve trunk at one pole of the islet emerges the peri insular plexus, the peri insular ganglia (p.i.g.), and the neural terminal net in and around the islet. The neural terminal is said to be composed of nerve fibers and interstitial Cajal s cells (in black). Part of the islet has been excised to show the interior structure of the islet. c capillary, 800. Image adapted from Honjin, 1956; courtesy of John Wiley & Sons, Inc) Durant, s. et al (2003) LABORATORY INVESTIGATION, Vol. 83, No.
17 Nervous system Central Nervous System Nervous system divisions: Peripheral Nervous System Autonomic Nervous system Parasympathetic nervous system Sympathetic nervous system Enteric nervous system Slowly activated dampening system
18 Autonomic Nervous System Control of insulin release: Para sympathetic Lateral hypothalamus Ventromedial hypothalamus Sympathetic parasympathetic celiac ganglion superior mesenteric ganglion Kiba, T (2004) Pancreas, Vol 29
19 parasympathetic sensory B F A Insulin/ Amylin Pancreatic Polypeptide Glucagon islets sympathetic D Somatostatin Kiba, T (2004) Pancreas, Vol 29 ; Ahren, B. (2000) Diabetologia 43:
20 Parasympathetic nerve input: B F A D ACh: acetylcholine GRP: gastrin releasing polypeptide VIP: vasoactive intestinal polypeptide PACAP: pituitary adenylate cyclase activating polypeptide ACh GRP PACAP VIP Kiba, T (2004) Pancreas, Vol 29 ; Ahren, B. (2000) Diabetologia 43:
21 Parasympathetic nerve input: B F A D GLUT2 β ACh insulin release α,δ ACh releases: glucagon somatostatin VIP & PACAP glucose dependent insulin release GRP may be involved in neuro regulation F PP is released by parasympathetic activity Vagus Nerve stimulation ACh: acetylcholine GRP: gastrin releasing polypeptide VIP: vasoactive intestinal polypeptide PACAP: pituitary adenylate cyclase activating polypeptide Kiba, T (2004) Pancreas, Vol 29 ; Ahren, B. (2000) Diabetologia 43:
22 Sympathetic nerve input: B F A D NA NPY Galanin NPY: Neuropeptide Y NA: Noradrenalin Kiba, T (2004) Pancreas, Vol 29 ; Ahren, B. (2000) Diabetologia 43:
23 Sympathetic nerve input: B F A D splanchnic nerve stimulation β NA inhibits glucose dependent insulin release α,f NA releases glucagon and PP NPY & Galanin inhibit insulin release δ NA inhibits somatostatin release NA: Noradrenaline NPY: Neuropeptide Y Kiba, T (2004) Pancreas, Vol 29 ; Ahren, B. (2000) Diabetologia 43:
24 Other & sensory nerve input: B F A D Other nerve CCK NO Sensory nerve CGRP SP CCK: cholecystokinin NO: nitric oxide SP: Substance P CGRP: Calcitonin gene related polypeptide Kiba, T (2004) Pancreas, Vol 29 ; Ahren, B. (2000) Diabetologia 43:
25 Sensory nerve input: B F A D β CGRP inhibits insulin release α CGRP stimulates glucagon release CGRP involved with Amylin Sensory nerve stimulation SP reported to increase and decrease insulin secretion CGRP: Calcitonin Gene related peptide SP: Substance P CGRP is thought to exert a tonic inhibition of insulin secretion. Kiba, T (2004) Pancreas, Vol 29 ; Ahren, B. (2000) Diabetologia 43:
26 Other nerve input: B F A D β CCK stimulates insulin release NO inhibition of NO synthase inhibits insulin release (mice) Other nerve stimulation Enteropancreatic neuro regulation from the duodenum CCK: Cholecystokinin NO: Nitric Oxide Kiba, T (2004) Pancreas, Vol 29 ; Ahren, B. (2000) Diabetologia 43:
27 Ahren, B. (2000) Diabetologia 43:
28 Kiba, T. Pancreas Volume 29, Number 2, August 2004
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