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
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/ retinopathy/pic2.gif
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/ dm/dd.jpg
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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
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.
αlpha cell
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/ Julian_Thorpe/tem20.jpg
.../ Julian_Thorpe/tem26r.jpg
ß cell
www.umanitoba.ca/dnalab/ graduate/pancreas13.gif
Mechanism of Action of Insulin
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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
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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 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
Sulfonylureas
Stimulate
insulin
release from
ß cells via
binding to
the SU
receptor =
K+ATP
channel
Mostly long
metabolic
T1/2
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Sulfonylurea Actions on ß Cells
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Meglitinide Analogs
Bind to ß cells via SU receptor
Rapid absorption, metabolism & clearance, T1/2 < 1
h
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Biguanides
Act by inhibiting liver
gluconeogenesis &
increasing insulin
sensitivity in other
tissues
Metformin is not
metabolized, but
excreted intact in 2-5 h
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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
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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/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.
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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)
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• Gases (NO, CO)
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epinephrine.gif