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University of Texas, El Paso April 8, 2005 Nutrition, Endocrinology & Diabetes

University of Texas, El Paso April 8, 2005 Nutrition, Endocrinology & Diabetes Kenneth L. Campbell Professor of Biology University of Massachusetts at Boston.

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University of Texas, El Paso April 8, 2005 Nutrition, Endocrinology & Diabetes

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  1. University of Texas, El Paso April 8, 2005 Nutrition, Endocrinology & Diabetes Kenneth L. Campbell Professor of Biology University of Massachusetts at Boston

  2. This presentation is made possible by a grant entitled“Shortcourses in Endocrinology at Minority Undergraduate Institutions”from the National Institute of General Medical Sciences (NIGMS) to The Minority Affairs Committee of the Endocrine Society

  3. The Medical Problems of Diabetes & Obesity Over 16 million in the US have clinically diagnosed diabetes mellitus; about 8% of the population. Of these, 91% have type 2 diabetes (strongly linked to obesity) & 9% have type 1 diabetes (autoimmune & genetic origin). Up to 16% of US whites have diabetes by age 70. Prevalences are often higher in other ethnic groups. > 65% of the US population is > 20% over the healthy body weight for their height, age, & gender & at risk for diabetes, cardiovascular disease (heart attack, stroke), & high blood pressure

  4. www.michiganeye.com/images / retinopathy/pic2.gif www.telemedicine.org/ dm/dg.jpg www.mds.qmw.ac.uk/biomed/kb/metabolism/Pancreas%20lecture/sld019.htm www.telemedicine.org / dm/dd.jpg

  5. www.mds.qmw.ac.uk/biomed/kb/metabolism/Pancreas%20lecture/sld020.htmwww.mds.qmw.ac.uk/biomed/kb/metabolism/Pancreas%20lecture/sld020.htm

  6. Obtaining & Processing Nutrients

  7. What are nutrients? Why are they being extracted?Nutrients are those parts of food that provide sources of energy, molecular building blocks, or ions and small molecules needed to support biochemical functions. • Amino acids • Fats • Sugars • Nucleic Acid Components • Minerals • Vitamins

  8. Teeth: break food into smaller particles & mix in salivaSaliva: adds water, buffer salts & often enzymes that begin sugar digestion Stomach: adds HCl & pepsin, a proteolytic enzymeExocrine pancreas & bile: add enzymes & detergents for degrading protein, fats, sugars, & nucleic acidsSmall intestine: absorbs simple sugars, amino acids, fats, nucleosides, vitamins, & ions Cecum: often acts as a fermenter allowing bacteria to break down complex sugarsLarge intestine: absorbs water, ions, & small moleculesColon: absorbs water, stores feces Where does this occur?

  9. Evolutionary Adaptations for Digestion Shape & arrangement of teeth: From Wessells & Hopson, Biology, (Random House:1988), 817, 822, 819. Carnivore Omnivore Herbivore Contents of saliva: Contains amylases in cloven hoofed animals, rodents, rabbits, dogs, & primates. High content of HCO3 -2& PO4 -3 in herbivores. Venoms & proteases in some reptiles & invertebrates. Form & function of the gut.

  10. Small Intestine Histology Mucosa: HCl & pepsin www.iun.edu/~biologyn/ P262%20Web%20Pages/ EX-14%20Digestive% 20Histology/aa.GIF Smooth muscle layers www.le.ac.uk/pathology/teach / va/anatomy/case6/gi4.gif Stomach Histology www.uoguelph.ca/zoology/devobio/ miller/013634fig8-24.gif

  11. Digestive Tracts of Carnivores: Simple stomach, short small intestine, simple, short large intestine for extraction of high quality foods.

  12. Digestive Tracts of Herbivores: Ruminants, efficiently extract nutrients from low quality foods by symbiosis with bacteria in complex stomach. On similar feed, equids extract easily digested materials in foregut, & get more calories by fermentation in complex hindgut.

  13. Digestive Tracts of Omnivores: These are hybrid, systems: simple stomachs, moderately long small intestines, & well-developed, but simple, large intestines.

  14. Digestion is an extraction & breakdown process optimized to provide metabolic building blocks & energy source molecules. Summary: Evolutionary adaptations match each animal’s anatomy & physiology to it’s food sources & quality.

  15. While nucleotides, amino acids, vitamins, & minerals are absorbed by the gut, transported in blood & lymph to the cells where they are used, fats & sugars often need other processing to generate the forms actually used by cells. Cholesterol and Other Fats

  16. Fats are often broken down after being absorbed by the small intestine. They are moved as complexes wrapped in specific proteins. The earliest complexes have the most fat relative to protein and are the least dense. hsc.usf.edu/2005/ lipoprotmet.jpg

  17. The Liver is Also Central to Processing of Sugars. Converts many simple sugars, several amino acids, acetate & glycerol to glucose ( =gluconeogenesis) then secretes it into blood. Stores glucose as a macromolecule, glycogen, & hydrolyzes glycogen to glucose. Makes fat from fatty acids & glycerol, & breaks fat down to acetate & glycerol. Stores amino acids as protein, & can break proteins down to amino acids.

  18. Glucose Homeostasis The body must control glucose levels because all cells use glucose to make ATP, the energy currency of cells. Some tissues like brain almost never burn any other fuel molecule. But too much glucose damages cells by getting attached to certain proteins and changing their function. Key tissues in this balancing act are: Liver Fat Muscle Brain Pancreas (endocrine cells)

  19. Islets of Langerhans http://medlib.med.utah.edu/WebPath/jpeg4/ENDO039.jpg Pancreas Glucagon Insulin Hormones Control the Glucose Balance Insulinacts on body cells to allow them to take in circulating glucose. Insulin levels rise when glucose rises. Adrenaline, cortisol, & growth hormone also make blood glucose rise. But insulin-like-growth factor I acts like insulin. Glucagonacts on liver to stimulate glucose production & release, & on fat to cause fat breakdown.Glucagon rises when glucose falls.

  20. www.labvision.com/images / IHCimage/1422.jpg αlpha cell www.biols.susx.ac.uk/home / Julian_Thorpe/tem20.jpg .../ Julian_Thorpe/tem26r.jpg ß cell Blood flow is away from ß cells toward the outer cells. Insulin may block glucagon release. αlpha cells, red, lie at the outer edges of islets along with D & F cells.

  21. www.umanitoba.ca/dnalab/ graduate/pancreas13.gif

  22. Mechanism of Action of Insulin www.umanitoba.ca/dnalab/ graduate/pancreas19.gif

  23. www.mds.qmw.ac.uk/biomed/kb/metabolism/Pancreas%20lecture/sld014.htmwww.mds.qmw.ac.uk/biomed/kb/metabolism/Pancreas%20lecture/sld014.htm

  24. Diagnosis & Monitoring of Diabetes Thirst, polyuria, unexplained weight loss Hyperglycemia, random test > 200 mg/dL Elevated fasting glucose > 126 mg/dL Elevated glucose tolerance curve Glycosuria Ketonuria Tests for capillary blood glucose Tests for ketonuria Tests for glycosylated hemoglobin, HbA1c

  25. www.mds.qmw.ac.uk/biomed/kb/metabolism/Pancreas%20lecture/sld016.htmwww.mds.qmw.ac.uk/biomed/kb/metabolism/Pancreas%20lecture/sld016.htm

  26. www.umanitoba.ca/dnalab/graduate/pancreas28.gif

  27. Drugs for Diabetes Type 1 chemcases.com/olestra/ images/insulin.jpg Multiple preparations available Differ in multimerization of insulin, up to hexamers, & resulting speed of absorption, action, & clearance Ultra-short acting, 5-15’ = lispro Short acting, 15-30’ = regular Intermediate acting, 2-4 h = NPH, Lente Long acting, 4-5 h = Ultralente Insulin Idea in Rx is to provide basal insulin + peaks after meals

  28. How fast is the insulin response to glucose?

  29. Antidiabetic (Hypoglycemic) Drugs • Intestinal brush border α glucosidase inhibitors • Stimulants of insulin release: sulfonylureas, meglitinide analogs • Blockers of gluoneogenesis: Biguanides • Insulin mimics or PPARγ activators: thiazolidinediones • Possibilities • Endogenous insulin secretagogues: glucagon-like peptide 1 • Glucagon antagonists

  30. Sulfonylureas Stimulate insulin release from ß cells via binding to the SU receptor = K+ATP channel Mostly long metabolic T1/2 After www.bentham.org/sample-issues/cmc9-1/kecskemeti/fig-1.gif

  31. Sulfonylurea Actions on ß Cells SU closes KATP channels causing membrane depolarization & opening of voltage - dependent, L - type Ca+2 channels. After www.bentham.org/sample-issues/cmc9-1/kecskemeti/fig3.gif

  32. Meglitinide Analogs Bind to ß cells via SU receptor Rapid absorption, metabolism & clearance, T1/2 < 1 h After www.bentham.org/sample-issues/cmc9-1/kecskemeti/fig8.gif

  33. Biguanides Act by inhibiting liver gluconeogenesis & increasing insulin sensitivity in other tissues Metformin is not metabolized, but excreted intact in 2-5 h After www.bentham.org/sample-issues/cmc9-1/kecskemeti/fig9.gif

  34. Thiazolindinediones Partial mimics of insulin actions, may bind insulin receptor or act through the peroxisomal proliferator activated receptor γ Metabolized with a long half life After www.bentham.org/sample-issues /cmc9-1/kecskemeti/fig10.gif

  35. www.diabetes-mellitus.org/slidesho/slide5.gif

  36. Traditional Treatments in the Southwest Diabetesis ahot illness (characterized by vasodilation & a high metabolic rate). Various remedies are used: nopal (or cactus), aloe vera juice, bitter gourd. In some areas in Texas & Mexico treatment is started with maturique root infusion for about 1 week if the person is extremely hyper-glycemic. Then, for maintenance therapy, trumpet flower-herb or root infusion (tronadora), brickle bush (prodigiosa) tea, or sage tea (salvia) are used. Proven safety & efficacy of maturique, trumpet flower, or bricklebush are not known. Aloe vera juice is reasonably safe but aloe vera latex is a powerful purgative. Sage tea taken chronically can lower the seizure threshold & has been reported to cause mental & physical deterioration because it contains thujones & tannins. [Nancy Neff, Dept. of Community Medicine, Baylor College of Medicine Module VII, Folk Medicine in Hispanics in the Southwestern United States, ww.rice.edu/projects/HispanicHealth/Courses/ mod7/mod7.html]

  37. Prospects for Long-Term Curespumpsimplantsgene therapies

  38. Body Mass Homeostasis: Our New Understanding www.garvan.org.au/library / images/jpg/adipocytes.jpg

  39. A Little About the Central Players

  40. Summary: Diabetes is a group of pathologies. Type 1 is due to autoimmunity to pancreatic ß cells & demonstrates genetic predispositions. Type 2 seems due to chronic overwork of ß cells & often appears during old age, especially in the chronically overweight. Monitoring tools are available as are drugs and therapies. ß cell implants are being tested. Prevention of Type 2 is often accessible by control of life-style. Prevention of Type 1 will only be possible when causes are identified.

  41. Counterindications for Drug Use Compromised liver function Renal impairment Cardiovascular problems Advanced age Concurrent use of contraceptive steroids or other medications

  42. After www.diabetes-mellitus.org/slidesho/slide22.gif

  43. Troglitazone Metabolites Kecskemeti1*, V., Z. Bagi1, P. Pacher1, I. Posa2, E. Kocsis2 & M. Zs. Koltai2 (~2000) New Trends in the Development of Oral Antidiabetic Drugs, www.bentham.org/sample-issues /cmc9-1/kecskemeti/Kecskemeti-ms.htm

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