This presentation is made possible by a grant entitled

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This presentation is made possible by a grant
entitledShortcourses in Endocrinology at
Minority Undergraduate Institutionsfrom the
National Institute of General Medical Sciences
(NIGMS) to The Minority Affairs Committee of
the Endocrine Society
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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. gt 65 of
the US population is gt 20 over the healthy body
weight for their height, age, gender at risk
for diabetes, cardiovascular disease (heart
attack, stroke), high blood pressure
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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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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)
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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.
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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.
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Hormones Control the Glucose Balance
Insulin acts on body cells to allow them to take
in circulating glucose. Insulin levels rise when
glucose rises.
Adrenaline, cortisol, growth hormone also make
blood glucose rise. But insulin-like-growth
factor I acts like insulin.
Glucagon acts on liver to stimulate glucose
production release, on fat to cause fat
breakdown. Glucagon rises when glucose falls.
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Blood flow is away from ß cells toward the outer
cells. Insulin may block glucagon release.
alpha cells, red, lie at the outer edges of
islets along with D F cells.
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Mechanism of Action of Insulin
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Diagnosis Monitoring of Diabetes
Thirst, polyuria, unexplained weight
loss Hyperglycemia, random test gt 200
mg/dL Elevated fasting glucose gt 126
mg/dL Elevated glucose tolerance
curve Glycosuria Ketonuria Tests for capillary
blood glucose Tests for ketonuria Tests for
glycosylated hemoglobin, HbA1c
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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 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/H
ispanicHealth/Courses/ mod7/mod7.html
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Drugs for Diabetes Type 1
Multiple preparations available Differ in
multimerization of insulin, up to hexamers,
resulting speed of absorption, action,
clearance Ultra-short acting, 5-15
lispro Short acting, 15-30 regular Intermedia
te acting, 2-4 h NPH,
Lente Long acting, 4-5 h Ultralente
Insulin
Idea in Rx is to provide basal insulin peaks
after meals
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How fast is the insulin response to glucose?
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• Antidiabetic (Hypoglycemic) Drugs
• Intestinal brush border a 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

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Sulfonylureas
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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 lt 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 ? 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
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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/kecsk
emeti/Kecskemeti-ms.htm
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Prospects for Long-Term Curespumpsimplantsge
ne therapies
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Body Mass Homeostasis Our New Understanding
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A Little About the Central Players
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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.
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users.cybercity.dk/.../diabetes/
billeder/glut2.JPG
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Modified from www.pharmacology2000.com/Endocrine/
Diabetes/Alpha.gif
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Definition of Diabetes
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What kinds of hormone are there?

• Known Hormonal Classes
• Proteins peptides
• Lipids (steroids, eicosanoids)
• Amino acid derived
  (thyronines, neurotransmitters)
• Gases (NO, CO)