LSC 432 Basic Pharmacology April 1, 2003 Diabetes: Basics & Drugs Kenneth L. Campbell Professor of...
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Transcript of LSC 432 Basic Pharmacology April 1, 2003 Diabetes: Basics & Drugs Kenneth L. Campbell Professor of...
LSC 432 Basic Pharmacology
April 1, 2003
Diabetes: Basics & Drugs
Kenneth L. CampbellProfessor 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 DiabetesHyperglycemia: 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 tachycardiaHypoglycemia (especially in treated diabetics): lack of brain glucose leads to neuropathy & coma, autonomic hyperactivity
www.mds.qmw.ac.uk/biomed/kb/metabolism/Pancreas%20lecture/sld019.htm
www.telemedicine.org/ dm/dg.jpg
www.telemedicine.org
/ dm/dd.jpg
www.michiganeye.com/images
/ retinopathy/pic2.gif
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:
LiverFatMuscleBrainPancreas (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.
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.
Pancreas
Hormones Control theGlucose Balance
Insulin acts on body cells to allow them to take in circulating glucose. Insulin levels rise when glucose rises.
InsulinGlucagon
Islets of Langerhanshttp://medlib.med.utah.edu/WebPath/jpeg4/ENDO039.jpg
αlpha cells, red, lie at the outer edges of islets along with D & F cells.
Blood flow is away from ß cells toward the outer cells.Insulin may block glucagon release.
www.labvision.com/images/ IHCimage/1422.jpg
.../ Julian_Thorpe/tem26r.jpg
ß cell
www.biols.susx.ac.uk/home/ Julian_Thorpe/tem20.jpg
αlpha 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 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
www.mds.qmw.ac.uk/biomed/kb/metabolism/Pancreas%20lecture/sld016.htm
www.umanitoba.ca/dnalab/graduate/pancreas28.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
Drugs for Diabetes Type 1
Insulin
Multiple 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 = Ultralente
Idea in Rx is to provide basal insulin + peaks after meals
chemcases.com/olestra/ images/insulin.jpg
How fast is the insulin response to glucose?
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
SulfonylureasStimulate insulin release from ß cells via binding to the SU receptor = K+
ATP channelMostly long metabolic T1/2
After www.bentham.org/sample-issues/cmc9-1/kecskemeti/fig-1.gif
Sulfonylurea Actions on ß Cells
After www.bentham.org/sample-issues/cmc9-1/kecskemeti/fig3.gif
Meglitinide AnalogsBind 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
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 γ
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 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
www.diabetes-mellitus.org/slidesho/slide5.gif
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 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.
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
• Lipids (steroids, eicosanoids)
• Amino acid derived (thyronines, neurotransmitters)
• Gases (NO, CO)
chemcases.com/olestra/ images/insulin.jpg
chem.pdx.edu/~wamserc/ChemWorkshops/ gifs/W25_1.gif
website.lineone.net/~dave.cushman/ epinephrine.gif