Biol 300-M5 Applied Biochemistry, Barry University April 1,

Biol 300-M5 Applied Biochemistry, Barry University April 1,

Biol 300-M5 Applied Biochemistry, Barry University April 1, 2005 Diabetes: Basics & Drugs Kenneth L. Campbell Professor of Biology University of Massachusetts at Boston

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 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 www.michiganeye.com/images / retinopathy/pic2.gif

www.telemedicine.org/ dm/dg.jpg www.telemedicine.org www.mds.qmw.ac.uk/biomed/kb/metabolism/Pancreas%20lecture/sld019.htm / dm/dd.jpg www.mds.qmw.ac.uk/biomed/kb/metabolism/Pancreas%20lecture/sld020.htm

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 acids Fats Sugars Nucleic Acid Components Minerals Vitamins Where does this occur? Teeth: break food into smaller particles & mix in saliva

Saliva: adds water, buffer salts & often enzymes that begin sugar digestion Stomach: adds HCl & pepsin, a proteolytic enzyme Apocrine pancreas & bile: add enzymes & detergents for degrading protein, fats, sugars, & nucleic acids Small intestine: absorbs simple sugars, amino acids, fats, nucleosides, vitamins, & ions Cecum: often acts as a fermenter allowing bacteria to break down complex sugars

Large intestine: absorbs water, ions, & small molecules Colon: absorbs water, stores feces Mucosa: HCl & pepsin Small Intestine Histology

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 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 The Liver is 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 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) Hormones Play Key Roles in Controlling Blood Glucose

But what are hormones? Hormones are distinct molecules that act as intercellular chemical messages. Hormone Functions Maintain Internal Homeostasis

Support Cell Growth Coordinate Development Coordinate Reproduction Facilitate Responses to External Stimuli

What kinds of hormone are there? Known Hormonal Classes Proteins & peptides chemcases.com/olestra/ images/insulin.jpg Lipids (steroids, eicosanoids) Amino acid derived

(thyronines, neurotransmitters) chem.pdx.edu/~wamserc/ ChemWorkshops/ gifs/W25_1.gif Gases (NO, CO) website.lineone.net/~dave.cushman/ epinephrine.gif

Hormones Control the Islets of Langerhans Glucose Balance http://medlib.med.utah.edu/WebPath/jpeg4/ENDO039.jpg Pancreas Insulin acts on body cells to allow them to take in circulating glucose.

Insulin levels rise when glucose rises. Glucagon Insulin Adrenaline, cortisol, & growth hormone also

make blood glucose Glucagon acts on liver to stimulate glucose production rise. But insulin-like& release, & on fat to cause growth factor I acts fat breakdown. Glucagon like insulin. rises when glucose falls. www.labvision.com/images

/ IHCimage/1422.jpg lpha cells, 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. lpha cells, lpha cell www.biols.susx.ac.uk/home / Julian_Thorpe/tem20.jpg

.../ Julian_Thorpe/tem26r.jpg cell www.umanitoba.ca/dnalab/ graduate/pancreas13.gif Mechanism of Action of Insulin www.umanitoba.ca/dnalab/ graduate/pancreas19.gif

www.mds.qmw.ac.uk/biomed/kb/metabolism/Pancreas%20lecture/sld014.htm 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 www.mds.qmw.ac.uk/biomed/kb/metabolism/Pancreas%20lecture/sld016.htm www.umanitoba.ca/dnalab/graduate/pancreas28.gif

Drugs for Diabetes Type 1 Multiple preparations available Differ in multimerization of insulin, up to hexamers, & resulting speed of absorption, action, & clearance chemcases.com/olestra/ images/insulin.jpg

Insulin Idea in Rx is to provide basal insulin + peaks after meals Ultra-short acting, 5-15 = lispro Short acting, 15-30 = regular

Intermediate acting, 2-4 h = NPH, Lente Long acting, 4-5 h = Ultralente How fast is the insulin response to glucose? Antidiabetic (Hypoglycemic) Drugs Intestinal brush border lpha cells, 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

Sulfonylureas Stimulate insulin release from 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 Sulfonylurea Actions on 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

Meglitinide Analogs Bind to cells via SU receptor Rapid absorption, metabolism & clearance, T1/2 < 1 h After 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 h After www.bentham.org/sample-issues/cmc9-1/kecskemeti/fig9.gif

Thiazolindinediones Partial mimics of insulin actions, may bind insulin receptor or act through the peroxisomal proliferator activated receptor Metabolized with a long half life

After www.bentham.org/sample-issues /cmc9-1/kecskemeti/fig10.gif www.diabetes-mellitus.org/slidesho/ Traditional Treatments in the Southwest 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 hyperglycemic. Then, for maintenance therapy, trumpet flowerherb 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] Prospects for Long-Term Cures pumps implants gene therapies

Body Mass Homeostasis: Our New Understanding www.garvan.org.au/library / images/jpg/adipocytes.jpg 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 Use Compromised liver function Renal impairment Cardiovascular problems

Advanced age Concurrent use of contraceptive steroids or other medications After www.diabetes-mellitus.org/slidesho/slide22.gif 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 www.umanitoba.ca/dnalab/graduate/pancreas30.gif www.umanitoba.ca/dnalab/graduate/pancreas30.gif

users.cybercity.dk/.../diabetes/ billeder/glut2.JPG Modified from www.pharmacology2000.com/Endocrine/ Diabetes/Alpha.gif Definition of Diabetes Review: What do each of

these organs do? Teeth Saliva Pancreas & Bile

Large Intestine Cecum Stomach Small Intestine Colon

Relation of Animal Body Evolution to Digestion 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. Digestive Tracts of Carnivores: Simple stomach, short small intestine,

simple, short large intestine for extraction of high quality foods. 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: These are hybrid, systems: simple

stomachs, moderately long small intestines, & welldeveloped, but simple, large intestines.

Summary: 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.

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