Transcript Diabetes and Metabolic Disease

Diabetes and Metabolic
Disease
Paul R. Earl
Facultad de Ciencias Biológicas
Universidad Autónoma
de Nuevo León
San Nicolás,
NL 66450, Mexico
[email protected]
Nicolas Paulescu
Discovery
In the middle of the 19th century, evidence
from autopsies started to suggest a link
between the pancreas and Diabetes
Mellitus. Diabetics were sometimes seen to
have pancreas damage, and patients with
damaged pancreases almost always had
diabetes.
In 1869 at 22 years, Paul Langerhans
(1847-1888) discovered the existence of
two systems of cells in the pancreas: the
acinar cells, secreting the pancreatic juice,
mostly trypsin, into the digestive system,
and islets--the islets of Langerhans-floating among the acini with an unknown
function.
In 1889, Oskar Minkowski (1858-1931)
and Josef Von Mering (1849-1908)
depancreatized a dog, causing a state of
polyuria indistinguishable from diabetes.
This was the first direct evidence of the
link between diabetes and the pancreas.
They also showed that it was not the
absence of the pancreatic juice that
caused diabetes by studying the effect of
ligating the pancreatic ducts rather than
removing the whole pancreas. In most
cases this caused minor digestive
problems, but never diabetes.
Oskar Minkowski
All roads lead to
Minkowski & Von
Mering, yet various
discoveries had been
made through the long
centuries. William
Prout (1785-1859)
associated coma with
diabetes. Georg Ludwig
Zülzer's (1870-1949)
unsuccessful toxic
pancreatic extract
tested in Minkowski's
clinic in 1908 was
abandoned.
In 1916, Nicolas Paulescu (1869-1931)
succeeded in developing an aqueous
pancreatic extract that normalized a
diabetic dog. In 1921, he published 4
papers in the Society of Biology in
Paris centering on the successful
effects of the pancreatic extract in
diabetic dogs.
Research on the Role of the Pancreas
in Food Assimil-ation by Paulescu was
published in August, 1921 in the
Archives Internationales de
Physiologie, Liège, Belgium.
Eight months after Paulescu's works
were published, Sir Frederick Grant
Banting (1891-1941) and biochemist
John James Richard Macleod (18761935) of the University of Toronto
published their paper on the
successful use of a pancreatic extract
for normalizing blood sugar (glucose)
levels (hyperglycemia) in diabetic
dogs. Their 1922 paper confirms
Paulescu's article with direct
reference. Banting & Best (18991978) also published then.
Fredrick Sanger and his coworkers
sequenced bovine insulin in 1955, and he
thus won the Nobel prize in 1980. Read
The Discovery of Insulin by Michael Bliss
in 1982, University of Chicago Press.
Other parts of insulin's unfinished story
include the hormones leptin and
adiponectin. Helpful information sources
are the International Diabetes Federation
www.idf.org , the Disease Monitoring and
Telecommunication, WHO Collaborating
Centre at [email protected] and Diabesity
at www.eurodiabesity.org.
Acini and islets of Langerhans
The parenchyma of the exocrine
pancreasis composed of darkstaining serous cells arranged in
acini. "Dark" refers to H&E which of
course is hemotoxylin-eosin--purple
and rose-orange--basic vs acidic.
Interspersed among these many
acini is the endocrine component of
the pancreas, ovoid groups of islet
cells.
Islet of Langerhans
Islet with acinar cells
The central feature: Insulin
Insulin mobilizes glucose for
storage. When thousands upon
thousands of insulin receptors
along the linings of the arteries
are lost, even when the pancreas
pumps out more insulin, diabetes
type 2 or metabolic disease may
arise to strongly shorten our
lives.
Insulin Resistance occurs when the body can’t
absorb glucose
Abdominal fat–in men with over a 102 cm
waist (40 inches) and in women with 89 cm or
more (35 inches)
High blood sugar levels–at least 110
milligrams per deciliter (mg/dL) after fasting
as overnight
High triglycerides–at least 150 mg/dL in the
blood stream
Low high density lipidprotein (HDL, the “good”
cholesterol)–less than 40 mg/dL if male and 50
mg/dL if female.
Prothrombotic state (e.g., high fibrinogen or
plasminogen activator inhibitor in the blood)
Blood pressure of 130/85 mmHg or higher
The actions of insulin include:
membrane transport of glucose,
amino acids and certain ions;
increased storage of glycogen;
formation of triglycerides;
stimulation of DNA, RNA and
protein synthesis.
Three other peptide
hormones are produced in
the islets of Langerhans in
the pancreas:
-glucagon, consisting of 29
amino acids
-somatostatin, a cyclic 14 amino
acids
-pancreatic polypeptide, 36
amino acids with an amide C
terminus
Insulin controls glucose homeostasis by
stimulating the uptake of glucose into
skeletal muscle and, to a lesser extent, into
liver and adipose tissue. In muscle and
adipocytes, this uptake is mediated by
glucose transporter GLUT-4. Other processes
in the regulation of glucose balance are:
alterations in glycogen metabolism in muscle
and liver, and decreased gluconeogenesis in
the liver. Perhaps, YOU can improve this
understanding. What is glucokinin? What are
cytokinins?
TOO MUCH INSULIN can cause hypoglycemic
shock.
Leptin
Leptin is a 16 kiloDalton protein
hormone regulating energy input and
utilization. It decreases appetite and
increases metabolism. In 1994, leptin
was discovered in mice by Jeffrey M
Friedman and coworkers at
Rockefeller University, NYC.
The obesity Ob gene in mice is called
the Lep gene in humans. Leptin is
produced by adipose tissue, having 6
different types of receptos.
Adiponectin
Adiponectin is a protein hormone that
regulates glucose and fatty acid
catabolism. Produced by adipocytes, it can
be involed in vascular deteriorization.
It was discovered in 1997 by Yuji M
Matsuzawa and his coworkers. Its APM1
gene maps to chromosome 3q27. Among
other actions, adiponectin inhibits the
myelomonocytic lineage cells. Itis a
negative regulaton in the hemotopoiesis
and immune system, thus antiinflamatory.
Metabolic disease
In his book Syndrome X: Overcoming
the Silent Killer That Can Give you a
Heart Attack (2000, Simon & Schuster,
New York), Gerald Reaven gives the
history of his discovery of Metabolic
Syndrome.
"This deadly heart ailment begins in the
bloodstream, shortly after we eat. We know that
eating fatty or cholesterol-laden foods can be
bad for our hearts. However, the Metabolic
Syndrome culprit is carbohydrates. Yet these
are reluctant, inadvertent offenders.
The Metabolic Syndrome
Environmental
Genetic
Obesity
Overeating and then overweight often lead to
diabetes. Note that regular exercise maintains and
improves health. This worldwide social problem
began by the 1980s via sedentary life, fast foods
and other changes in life style.
Obese persons are more likely to suffer from one
or more of several disorders. These include:
-diabetes mellitus, type 2
-high blood pressure
-high levels of cholesterol and triglycerides
-gout
-gall bladder and urinary calculus
-osteoarthritis in the back, knees and feet
-coronary heart disease
-stroke
-cancer of the colon and prostate in men, and of the
breasts, uterus and polycystic ovaries in women
Averages using adult Mexicans of the
north (N) and the south (S) as
anthropometric examples are:
Height Weight Waist
m
kg
cm
N Men
N Women
S Men
S Women
1.69
1.56
1.62
1.50
77.2
69.2
69.5
62.0
95.8
94.7
91.6
92.3
Diabetes Type 1
Type I diabetes mellitus is insulin-dependent,
autoimmune disease. The disease is organspecific resulting in pancreatic islet cell
destruction. Evidence of cellular destruction
includes autoantibodies to 1) islet cells (ICA),
2) antibodies to insulin (IAA) and 3) glutamic
acid decarboxylase autoantibodies (GAD Ab).
ICA (as detected on thin frozen sections of
human pancreas by indirect
immunofluorescence) are present in about 80
% of newly diagnosed patients. ICA, GAD Ab
and IAA are each helpful in screening firstdegree relatives of patients with IDDM.
Diabetes Type 2
Type 2 is also caused by insulin
deficiency, even though the pancreas
is producting it. The cause of
morbidity is insulin resistance with
consequent hyperglycemia. While
diabetes cannot be cured, it can be
controlled by insulin, diet, weight
control and physical fitness by
running, walking and sports.
Overeating can sometimes result in
diabetes.
Glucose tolerance test
After an overnight fast, a sample of blood is
drawn. Then 75 g of glucose dissolved in about
200-300 ml of water is drunk. Two hours later
another blood sample is taken. Account is taken
of the fact that the concentration of glucose
measured in plasma is 10 % higher than in
whole blood.
Diabetes is present when the fasting blood
sample is over 6.7 mmol/L or the level in
plasma is over 7.8 mmol/L, or the second
sample has 10 mmol/L of blood.
In healthy persons, the glucose concentration
rises to about twice the normal level within the
first hour and returns to normal within 2 hours.
Cholesterol test
Cholesterols and triglycerols are types of
fats called lipids. Too much fat increases
your risk of a heart attack or vascular
diseases. Heart disease is the # 1 killer of
both men and women.
Low density lipoprotein (LDL) cholesterol at
abnormally high levels can cause fatty
deposits in the arteries which is defined as
atheroscelosis,
High density lipoprotein (HDL) cholesterol
can help carry away LDLs, keeping arteries
open. Some triglycerides may result from
extra calories.
The cholesterol test depends on fasting for 7-12
hours. Normal total cholesterol is < 200
mg/dL/. Borderline cases have 200-239, and
abnormal cases have > 240 mg/dL.
Levels of LDL are < 129, 130-149 and > 150
mg/dL.
Levels of HDL (the "good" cholesterol) are <
149, 150-199 and > 200 mg/dL.
Trigylcerides have < 149, 150-199 and > 200
mg/dL.
New tests based on nuclear resonance are
coming along.
Closing remarks
The definitions and additional information
supplied in this lecture give you the necessary
basic "Introduction to Diabetes." Your task now
can be to amplify this information and to follow
the lightning pace of diabetes research.
A major yet recent trend in life style in the
direction of fast high-energy foods can lead to
obesity and also diabetes, while chronic
malnutrition with stunting continues in very
many worldwide rural populations. Ecology
including the global warming trend has not
been even touched upon here. Of course, such
topics deserve their place in the diabetes
curriculum.