LSC 432 Basic Pharmacology April 1, 2003 Diabetes:

LSC 432 Basic Pharmacology April 1, 2003 Diabetes:

LSC 432 Basic Pharmacology April 1, 2003 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 Acute Problems in Diabetes Hyperglycemia: leads to hyperosmolality of serum, polyuria, dehydration, Na+ & K+ imbalances, weakness/fatigue, polyphagia with weight loss, glycosylation of proteins Ketoacidosis: decreases blood pH, HCO3-2,

Hb avidity for O2; leads to hypoxic coma &/ or tachycardia Hypoglycemia (especially in treated diabetics): lack of brain glucose leads to neuropathy & coma, autonomic hyperactivity 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 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)

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. After meals glucose from liver is mainly stored as glycogen in liver & muscle & as fat in fat cells. When

more energy is needed between meals, glycogen, fat & protein (last) are broken down & liver uses the parts to make glucose. Hormones (insulin,

glucagon, adrenalin, cortisol) signal the change from storage to synthesis. 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 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] 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 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 isulin 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 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.diabetes-mellitus.org/slidesho/

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. www.umanitoba.ca/dnalab/graduate/pancreas30.gif www.umanitoba.ca/dnalab/graduate/pancreas30.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 users.cybercity.dk/.../diabetes/ billeder/glut2.JPG Modified from www.pharmacology2000.com/Endocrine/ Diabetes/Alpha.gif Definition of Diabetes

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

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