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

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

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  • This presentation is made possible by a grant entitledShortcourses in Endocrinology at Minority Undergraduate Institutionsfrom the National Institute of General Medical Sciences (NIGMS) to The Minority Affairs Committee of the Endocrine Society

  • The Medical Problems of Diabetes & ObesityOver 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

  • Obtaining & Processing Nutrients

  • 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 acidsFatsSugarsNucleic Acid ComponentsMineralsVitamins

  • 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 fecesWhere does this occur?

  • Evolutionary Adaptations for DigestionForm & function of the gut.

  • Digestive Tracts of Carnivores:

  • 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.

  • Digestive Tracts of Omnivores:

  • Digestion is an extraction & breakdown process optimized to provide metabolic building blocks & energy source molecules. Evolutionary adaptations match each animals anatomy & physiology to its food sources & quality.Summary:

  • Cholesterol and Other Fats 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.

  • 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.

  • 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.

  • Glucose HomeostasisThe 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:

    LiverFatMuscleBrainPancreas (endocrine cells)

  • Glucagon acts on liver to stimulate glucose production & release, & on fat to cause fat breakdown. Glucagon rises when glucose falls.Adrenaline, cortisol, & growth hormone also make blood glucose rise. But insulin-like-growth factor I acts like insulin. Hormones Control theGlucose BalanceInsulin acts on body cells to allow them to take in circulating glucose. Insulin levels rise when glucose rises.

  • lpha cells, red, lie at the outer edges of islets along with D & F cells.Blood flow is away from cells toward the outer cells.Insulin may block glucagon release.

  • Mechanism of Action of Insulin

  • Diagnosis & Monitoring of DiabetesThirst, polyuria, unexplained weight lossHyperglycemia, random test > 200 mg/dLElevated fasting glucose > 126 mg/dLElevated glucose tolerance curveGlycosuriaKetonuria

    Tests for capillary blood glucoseTests for ketonuriaTests for glycosylated hemoglobin, HbA1c

  • Drugs for Diabetes Type 1InsulinMultiple preparations availableDiffer 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 = UltralenteIdea in Rx is to provide basal insulin + peaks after meals

  • How fast is the insulin response to glucose?

  • Antidiabetic (Hypoglycemic) Drugs

    Intestinal brush border glucosidase inhibitors Stimulants of insulin release: sulfonylureas, meglitinide analogs Blockers of gluoneogenesis: Biguanides Insulin mimics or PPAR activators: thiazolidinediones

    Possibilities

    Endogenous insulin secretagogues: glucagon-like peptide 1 Glucagon antagonists

  • SulfonylureasAfter www.bentham.org/sample-issues/cmc9-1/kecskemeti/fig-1.gif

  • Sulfonylurea Actions on CellsAfter www.bentham.org/sample-issues/cmc9-1/kecskemeti/fig3.gifSU closes KATP channels causing membrane depolarization & opening of voltage - dependent, L - type Ca+2 channels.

  • Meglitinide AnalogsBind to cells via SU receptorRapid absorption, metabolism & clearance, T1/2 < 1 hAfter www.bentham.org/sample-issues/cmc9-1/kecskemeti/fig8.gif

  • Biguanides Act by inhibiting liver gluconeogenesis & increasing insulin sensitivity in other tissues

    Metformin is not metabolized, but excreted intact in 2-5 hAfter www.bentham.org/sample-issues/cmc9-1/kecskemeti/fig9.gif

  • ThiazolindinedionesPartial mimics of insulin actions, may bind insulin receptor or act through the peroxisomal proliferator activated receptor Metabolized with a long half lifeAfter www.bentham.org/sample-issues/cmc9-1/kecskemeti/fig10.gif

  • Diabetes is a hot 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]Traditional Treatments in the Southwest

  • Prospects for Long-Term Cures

    pumps

    implants

    gene therapies

  • Body Mass Homeostasis: Our New Understanding

  • A Little About the Central Players

  • Summary: Diabetes is a group of pathologies. Type 1 is due to autoimmunity to pancreatic cells & demonstrates genetic predispositions. Type 2 seems due to chronic overwork of cells & often appears during old age, especially in the chronically overweight. Monitoring tools are available as are drugs and therapies. 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.

  • Counterindications for Drug UseCompromised liver function

    Renal impairment

    Cardiovascular problems

    Advanced age

    Concurrent use of contraceptive steroids or other medications

  • Troglitazone MetabolitesKecskemeti1*, 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

  • users.cybercity.dk/.../diabetes/ billeder/glut2.JPG

  • Modified from www.pharmacology2000.com/Endocrine/ Diabetes/Alpha.gif

  • Definition of Diabetes

  • Review:What do each ofthese organs do?

  • Retrieve images of diurnal, menstrual, and life cycle of insulin, estradiol, DHEAS

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