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Biol 300-M5 Applied Biochemistry, Barry University
April 1, 2005
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
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
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
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
Where does this occur?
www.iun.edu/~biologyn/P262%20Web%20Pages/EX-14%20Digestive%20Histology/aa.GIF
www.le.ac.uk/pathology/teach/ va/anatomy/case6/gi4.gif
Smoothmusclelayers
Mucosa:HCl & pepsin
StomachHistology
Small IntestineHistology
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:
LiverFatMuscleBrainPancreas (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
• 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
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
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
SU closes KATP channels causing membrane depolarization & opening of voltage - dependent, L - type Ca+2 channels.
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 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
www.diabetes-mellitus.org/slidesho/slide5.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
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.
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.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 ofthese organs do?
Stomach
SmallIntestine
ColonCecum
LargeIntestine
Pancreas& Bile
Saliva
Teeth
Relation of Animal Body Evolution to Digestion
Evolutionary Adaptations for Digestion
Form & function of the gut.
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.
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, & well-developed, but simple, large intestines.
Digestion is an extraction & breakdown process optimized to provide metabolic building blocks & energy source molecules.
Evolutionary adaptations match each animal’s anatomy & physiology to it’s food sources & quality.
Summary: