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ScienceWeek
SCIENCEWEEK
ScienceWeek
June 6, 2003
Vol. 7 Number 23A
An Online Digest of Research in the Sciences
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Man may be the captain of his fate,
but he is also the victim of his blood sugar
-- Wilfrid Oakley
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Section 1
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Symposium: Diabetes
1. Introduction
2. Etiology
3. Pathophysiology
4. Clinical Aspects
Notices and Subscription Information
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Section 2
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1. INTRODUCTION
NOTES AND TERMINOLOGY
The term "hormone" was first used in 1902 by William Bayliss
(1860-1924) and Ernest Starling (1866-1927) to describe the
action of secretin, a hormone produced by the mammalian duodenum
and which stimulates the secretion of pancreatic juice. Based
more on physiological effects than on chemical structure,
subsequent use of the term "hormone" led to the definition of
hormones as signal molecules, products of glandular cells, with
the signal molecules secreted into the internal milieu, most
frequently into the blood. Acting on target cells, these chemical
messengers coordinate activities of different parts of the body.
Target cells, in turn, respond according to their degree of
differentiation, age, and functional and nutritional status, the
target cells integrating many hormonal and neuronal regulatory
stimuli. The target cell "receptor" is a specific chemical
structure required for target cells to receive and recognize a
hormone messenger. In general, hormone receptors transduce the
external chemical signals provided by hormones and are
responsible for the initiation of the first cellular responses to
hormones, this first response usually involving a cascade of
specific biochemical reactions inside the cell.
The disease diabetes mellitus has a long history, but it was only
in 1869 that Paul Langerhans (1847-1888) identified a new type of
cell in the pancreas, cells apparently glandular in character,
and histological groups of these cells came to be called "islets
of Langerhans". In 1889, von Mering and Minkowski demonstrated
that diabetes mellitus, characterized in its most evident form by
permanent high blood sugar (hyperglycemia) and glucose in the
urine (glycosuria; glucosuria) could be induced experimentally in
the dog by total removal of the pancreas. This demonstrated the
essential role of the pancreas in the regulation of glucose
balance (glucose homeostasis). The hormone responsible for this
action was called "insulin", and was finally isolated from the
pancreas in 1922 by Frederick Banting (1891-1941) and Charles
Best (1899-1978). This discovery had an enormous impact in
physiology, biochemistry, and medicine. The discovery had an
extremely beneficial effect on the prognosis and therapy of
insulin-dependent diabetes, allowing a specific replacement
treatment for endogenous insulin deficiency, which if untreated
is potentially fatal. The arrival of the insulin era was also of
major importance in protein chemistry. Insulin was one of the
first proteins to be crystallized (Abel 1926), and its primary
structure was the first to be elucidated (Sanger 1953). Partial
synthesis was accomplished between 1964 and 1966, and total
synthesis was completed in 1974. Human insulin, available
commercially, is currently prepared by a modification of pork
insulin or by a biosynthetic process involving genetic
engineering.
The insulin molecule consists of two polypeptide chains connected
by two disulfide bridges, with a third disulfide bridge linking
parts of one chain. This two-chain structure has evidently been
present throughout evolution, but major variations in the amino
acid sequences are observed between species. Various mammalian
insulins usually have similar potencies in all mammals, including
humans; fish insulin has considerable potency in mammals. It is
evidently the 3-dimensional structure of insulin, and not the
primary sequence of amino acid residues, which is responsible for
its potency across different species: variations in amino acid
sequence are still potent, provided the specific 3-dimensional
structure is maintained.
Insulin apparently exerts its glucose-lowering effects by
stimulating glucose uptake in tissues such as skeletal muscle,
suppressing fatty acid release from fat (adipose) tissue, and
inhibiting production of glucose by the liver. Muscle, liver, and
fat, therefore, are widely viewed as the principal insulin-
sensitive tissues in the body. The brain, in contrast, has
historically been considered insulin-insensitive because its
ability to use glucose does not require insulin. Because of this,
the idea that insulin participates in the central nervous system
control of food intake and body weight was received with
skepticism when it was first proposed more than 20 years ago.
Since then, however, support for this hypothesis has steadily
accumulated, including the demonstration that insulin is
transported across the blood-brain barrier, that it is effective
in suppressing food intake when given directly into the brain,
and that insulin receptors are concentrated in brain areas
involved in energy homeostasis.
For their isolation of insulin, Banting and MacLeod received the
Nobel Prize for Physiology and Medicine in 1923. The human story
has been told many times in books and in film. Briefly, Banting
was a scientifically-minded physician without a laboratory who
came to the established physiologist MacLeod in the early part of
1921 to beg laboratory space to work on the isolation of insulin.
MacLeod tried to discourage Banting, saying he would not succeed,
but finally MacLeod agreed to give Banting some laboratory space
and an assistant, Charles Best. MacLeod then went off to Europe
and did not return until September 1921, only to find Banting and
Best had indeed isolated insulin. Banting and Best wanted to
present their work to the December 1921 meeting of the American
Physiological Society, but they were unable to do this because
neither of them were members of the Society. MacLeod, who was a
member, attached his name to the paper, and the paper was
published under the three names in 1922. When the Nobel Prize was
awarded to Banting and MacLeod, Banting was furious at the
omission of Best and at first refused to accept the prize. He
finally did accept, but he immediately transferred half the prize
money to Charles Best. MacLeod then gave half _his_ prize money
to James Collip, an assistant who had helped in the later
purification of insulin.
"Arteriosclerosis" is a generic term for several diseases in
which the arterial wall becomes thickened and loses elasticity,
and "atherosclerosis" is a form of arteriosclerosis characterized
by patchy thickening (atheroma) in the subintimal layer (i.e.,
immediately below the innermost layer [intima]) of medium and
large arteries, the thickening capable of reducing or obstructing
blood flow.
The term "type 2 diabetes" refers to adult-onset diabetes
mellitus; Juvenile-onset diabetes mellitus is type 1 diabetes
mellitus. There are two major forms of diabetes: diabetes
mellitus and diabetes insipidus. When the term "diabetes" is used
alone, the usual referent is diabetes mellitus, which in turn has
two types: juvenile-onset (type 1) and adult-onset (type 2). The
various forms and types of diabetes differ in important ways in
both the physiology and biochemistry of the disease processes. In
general, diabetes mellitus is a metabolic disease in which
carbohydrate utilization is reduced and that of lipid and protein
enhanced, the disease caused by an absolute or relative
deficiency of the hormone insulin.
The term "impaired glucose tolerance" refers to excessive levels
of blood glucose developing after a carbohydrate-rich meal or
test dosage of glucose. The syndrome is not necessarily
diagnostic of diabetes mellitus.
The term "Insulin resistance" refers to a diminished
effectiveness of insulin in lowering plasma glucose levels.
The term "hyperinsulinemia" refers to abnormally large
concentrations of insulin in circulating blood.
"Adipocytes" are fat cells in connective tissue, each cell
containing one or more fat globules that compress the cytoplasm
of the cell into a thin envelope. The fat globules are
essentially energy storage bins, but adipocytes are involved in
more than mere storage of fat.
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2. ETIOLOGY
DIABETES MELLITUS AND GENETICALLY PROGRAMMED DEFECTS IN BETA-CELL
FUNCTION
Nature 2001 414:788
The following points are made by Graeme I. Bell and Kenneth S.
Polonsky:
1) Diabetes mellitus is a heterogeneous group of disorders
characterized by high blood glucose levels(1). The pancreatic
beta-cell and its secretory product insulin are central in the
pathophysiology of diabetes. Type 1 or insulin-dependent diabetes
mellitus results from an absolute deficiency of insulin due to
autoimmunological destruction of the insulin-producing pancreatic
beta-cells(2). In type 2 or non-insulin-dependent diabetes
mellitus, muscle and fat cells are "resistant" to the actions of
insulin and compensatory mechanisms that are activated in the
beta-cell to secrete more insulin are not sufficient to maintain
blood glucose levels within a normal physiological range(3,4).
2) Although the consequences of autoimmunological destruction of
pancreatic beta-cells are clear, the causes are not, and the
identification of the environmental factors that trigger this
destruction in genetically susceptible children, adolescents and
even adults still eludes us.
3) Type 2 diabetes is made up of different forms each of which is
characterized by variable degrees of insulin resistance and beta-
cell dysfunction, and which together lead to hyperglycemia(1). At
each end of this spectrum are single-gene disorders that affect
the ability of the pancreatic beta-cell to secrete insulin(5) or
the ability of muscle, fat and liver cells to respond to
insulin's actions.
4) Insulin concentrations are normally determined by a feedback
control system that is responsive to the prevailing level of
plasma glucose. The overall sensitivity of the pancreatic beta-
cell to glucose is determined by the sensitivity of peripheral
tissues to the action of insulin with insulin-resistant subjects
having higher insulin levels and insulin secretion rates than
insulin-sensitive subjects. Insulin is also secreted in response
to amino acids and fatty acids and the magnitude of this response
being modulated by a variety of neural (for example, sympathetic
and parasympathetic autonomic tone) and hormonal factors (for
example, glucagon, glucagon-like peptide, gastric inhibitory
polypeptide and somatostatin). Glucose, however, is the
overriding influence. Normal insulin secretion shows a rapid
response to glucose and a complex pulsatile profile. The increase
in insulin secretion that occurs after the intravenous
administration of glucose is virtually instantaneous; even after
oral glucose ingestion, increases in insulin secretion occur
within minutes. The temporal profile of insulin secretion
consists of small-amplitude pulses of insulin occurring every
5–10 minutes, superimposed on slower, larger-amplitude
oscillations that occur every 1–2 hours.
5) In summary: The pathways that control insulin secretion and
regulate pancreatic beta-cell mass are crucial in the development
of diabetes mellitus. Maturity-onset diabetes of the young
comprises a number of single-gene disorders affecting pancreatic
beta-cell function, and the consequences of mutations in these
genes are so serious that diabetes develops in childhood or
adolescence. A genetic basis for the more common form of type 2
diabetes, which affects 10–20% of adults in many developed
countries, is less clear cut. It is also characterized by
abnormal beta-cell function, but other tissues are involved as
well. However, in both forms identification of causative and
susceptibility genes are providing new insight into the control
of insulin action and secretion, as well as suggesting new
treatments for diabetes.
References (abridged):
1. American Diabetes Association. Report of the expert committee
on the diagnosis and classification of diabetes mellitus.
Diabetes Care 24 (Suppl. 1), S5-S20 (2001)
2. Atkinson, M. A. & Eisenbarth, G. S. Type 1 diabetes: new
perspective on disease pathogenesis and treatment. Lancet 358,
221-229 (2001)
3. Cavaghan, M. K., Ehrmann, D. A. & Polonsky, K. S. Interactions
between insulin resistance and insulin secretion in the
development of glucose intolerance. J. Clin. Invest. 106, 329-333
(2000)
4. Kahn, S. E. The importance of -cell failure in the development
and progression of type 2 diabetes. J. Clin. Endocrinol. Metab.
86, 4047-4058 (2001)
5. Fajans, S. S., Bell, G. I. & Polonsky, K. S. Molecular
mechanisms and clinical pathophysiology of maturity-onset
diabetes of the young. N. Engl. J. Med. 345, 971-980 (2001)
Related Background:
MITOCHONDRIAL FUNCTION IN NORMAL AND DIABETIC BETA-CELLS
Nature 2001 414:807
The following points are made by P. Maechler and C. Wollheim:
1) Mitochondria are present in most eukaryotic cells, varying in
number from hundreds to thousands(1), and have also been
visualized as a continuous network(2). Their origin is generally
thought to lie in the endosymbiotic association of oxidative
bacteria and glycolytic proto-eukaryotic cells(3). The phenotype
resulting from the absence of mitochondria is illustrated by
mammalian peripheral red blood cells, which depend entirely on
glycolysis for their energy supply. The endosymbiotic hypothesis
of mitochondrial origin is supported, for example, by the double
membrane surrounding the organelle and a unique genome in the
form of circular mitochondrial DNA (mtDNA) with bacterial
characteristics(3). Human mtDNA comprises only 37 genes (16,569
base pairs (bp)), the most notable of which are those encoding 13
polypeptides that are part of the multisubunit enzyme complexes
of the respiratory chain(1).
2) The mtDNA is transcribed and translated within the
mitochondrion. The nuclear genome specifies the remainder (the
majority) of the enzyme subunits and the other mitochondrial
proteins; these are synthesized in the cytosol and imported into
the mitochondrion(4). The nucleus also controls the
transcriptional activity of mtDNA through regulatory proteins
such as mitochondrial transcription factor A (TFAM), which are
encoded by nuclear genes(5). The mtDNA is maternally inherited
because of the non-persistence of sperm mtDNA in the zygote after
fertilization. The mitochondrial genome exists in multiple copies
in every cell. It is highly susceptible to mutation as, in
contrast to nuclear DNA, mtDNA consists only of coding sequences
and its repair mechanisms are poor. Consequently, it is
particularly sensitive to oxidative stress. Moreover, it is
juxtaposed to the respiratory chain, which generates mutagenic
oxygen derivatives.
3) The mitochondria are the main source of energy, essentially
ATP, which is required for such vital cellular functions as the
maintenance of transmembrane ion gradients, protein synthesis and
vesicular transport. Additionally, in the pancreatic beta-cell,
ATP and other mitochondrial factors accomplish the coupling of
glucose metabolism to insulin secretion. The mitochondria can be
activated by the three classes of fuel: amino acids, fatty acids
and carbohydrates, the latter being of most relevance in beta-
cells under physiological conditions. The principal mitochondrial
substrate is pyruvate, formed essentially by glycolysis. Pyruvate
carbons enter the tricarboxylic acid cycle (TCA cycle) in the
mitochondrial matrix, in which substrates are oxidized with the
formation of CO2 and the reduction of NAD+ and FADH to NADH and
FADH2, respectively. These provide electrons to the respiratory
chain upon their reoxidation.
4) In summary: The etiology of type 2, or non-insulin-dependent,
diabetes mellitus has been characterized in only a limited number
of cases. Among these, mitochondrial diabetes, a rare subform of
the disease, is the consequence of pancreatic beta-cell
dysfunction caused by mutations in mitochondrial DNA, which is
distinct from the nuclear genome. The impact of such mutations on
beta-cell function reflects the importance of mitochondria in the
control of insulin secretion. The beta-cell mitochondria serve as
fuel sensors, generating factors that couple nutrient metabolism
to the exocytosis of insulin-containing vesicles. The latter
process requires an increase in cytosolic Ca2+, which depends on
ATP synthesized by the mitochondria. This organelle also
generates other factors, of which glutamate has been proposed as
a potential intracellular messenger.
References (abridged):
1. Wallace, D. C. Mitochondrial diseases in man and mouse.
Science 283, 1482-1488 (1999)
2. Rizzuto, R. et al. Close contacts with the endoplasmic
reticulum as determinants of mitochondrial Ca2+ responses.
Science 280, 1763-1766 (1998)
3. Gray, M. W., Burger, G. & Lang, B. F. Mitochondrial evolution.
Science 283, 1476-1481 (1999)
4. Neupert, W. Protein import into mitochondria. Annu. Rev.
Biochem. 66, 863-917 (1997)
5. Larsson, N. G. et al. Mitochondrial transcription factor A is
necessary for mtDNA maintenance and embryogenesis in mice. Nature
Genet. 18, 231-236 (1998)
Related Background:
ON DIABETES, OBESITY, AND ADIPOCYTES
New Engl. J. Med. 2001 345:1345
The following points are made by A.R. Shuldiner et al:
1) Although 100 years ago type 2 diabetes mellitus was considered
a rare disease, there has recently been an explosive increase in
its incidence: currently, approximately 16 million Americans have
type 2 diabetes, and at least an equal number have impaired
glucose tolerance. Insulin resistance and hyperinsulinemia are
characteristic of both type 2 diabetes and impaired glucose
tolerance. These metabolic derangements, combined with the
hypertension and abnormal blood lipids that are common in type 2
diabetes and impaired glucose tolerance, markedly increase the
risk of cardiovascular, peripheral vascular, and cerebrovascular
disease.
2) Why has the incidence of type 2 diabetes increased so rapidly?
Considerable epidemiologic evidence points to excess caloric
intake and physical inactivity as the major reasons. A chronic
imbalance between energy expenditure and energy intake causes
obesity, which is one of the most potent risk factors for insulin
resistance and type 2 diabetes. These epidemiologic observations
underscore the importance of the relation of adipose tissue to
insulin resistance and glucose intolerance.
3) Recent studies have transformed our thinking about the
adipocyte. This cell type is no longer regarded as a passive
depot for storing excess energy in the form of triglycerides, but
as a cell that actively regulates the pathways responsible for
energy balance and whose activity is controlled by a complex
network of hormonal and neuronal signals. Indeed, the adipocyte
secretes chemical messengers that include leptin, tumor necrosis
factor alpha, angiotensinogen, and adiponectin. The most recently
discovered adipocyte-secreted hormone is resistin, which may be
an important link between increased fat mass and insulin
resistance.
Related Background:
TELEVISION WATCHING AND OTHER SEDENTARY BEHAVIORS IN RELATION TO
RISK OF OBESITY AND TYPE 2 DIABETES MELLITUS IN WOMEN
J. Am. Med. Assoc. 2003 289:1785
The following points are made by F.B. Hu et al:
1) Current public health campaigns to reduce obesity and type 2
diabetes have largely focused on increasing exercise levels, but
have paid little attention to the reduction of sedentary
behaviors. Television (TV) watching is a major sedentary behavior
in the US. In a survey conducted in 1997, an adult male spent
approximately 29 hours per week watching TV, and an adult female
spent 34 hours per week.(1) In recent decades, in parallel with
increasing obesity, there has been a steady increase in the
number of homes with multiple TV sets, videocassette recorders
(VCRs), cable TV, and remote controls, as well as the number of
hours spent watching TV.(1)
2) Compared with other sedentary activities such as sewing,
playing board games, reading, writing, and driving a car, TV
watching results in a lower metabolic rate.(2) Constant exposure
to food advertising leads to increased food and calorie intake
and unhealthy eating patterns.(3-5) It is well established that
prolonged TV watching is associated with obesity in children.
However, the role of TV watching compared with other sedentary
behaviors, such as sitting at work or reading, in the development
of obesity and type 2 diabetes among adults has not been well
studied, especially among women.
3) The authors examined prospectively the relationship between
several common sedentary behaviors and incidence of obesity and
type 2 diabetes in a large cohort of women. A prospective cohort
study was conducted from 1992 to 1998 among women from 11 states
in the Nurses' Health Study. The obesity analysis included 50,277
women who had a body mass index (BMI) of less than 30 and were
free from diagnosed cardiovascular disease, diabetes, or cancer
and completed questions on physical activity and sedentary
behaviors at baseline. The diabetes analysis included 68,497
women who at baseline were free from diagnosed diabetes mellitus,
cardiovascular disease, or cancer.
4) The authors conclude: Independent of exercise levels,
sedentary behaviors, especially TV watching, were associated with
significantly elevated risk of obesity and type 2 diabetes,
whereas even light to moderate activity was associated with
substantially lower risk. The authors suggest this study
emphasizes the importance of reducing prolonged TV watching and
other sedentary behaviors for preventing obesity and diabetes.
References (abridged):
1. Nielsen Report on Television. New York, NY: Nielsen Media
Research; 1998
2. Ainsworth BE, Haksell WL, Leon AS, et al. Compendium of
physical activities. Med Sci Sports Exerc. 1993;25:71-80
3. Lank NH, Vickery CE, Cotugna N, Shade DD. Food commercials
during television soap operas. J Community Health. 1992;17:377-
384
4. Dietz WH, Gortmaker SL Jr. Do we fatten our children at the
television set? Pediatrics. 1985;75:807-812
5. Hu FB, Leitzmann MF, Stampfer MJ, Colditz GA, Willett WC, Rimm
EB. Physical activity and television watching in relation to risk
for type 2 diabetes mellitus in men. Arch Intern Med.
2001;161:1542-1548
Related Background:
THE GLYCEMIC INDEX: PHYSIOLOGICAL MECHANISMS RELATING TO OBESITY,
DIABETES, AND CARDIOVASCULAR DISEASE
J. Am. Med. Assoc. 2002 287:2414
The following points are made by David S. Ludwig:
1) All dietary carbohydrates, from starch to table sugar, share a
basic biological property: they can be digested or converted into
glucose. Digestion rate, and therefore blood glucose response, is
commonly thought to be determined by saccharide chain length,
giving rise to the terms complex carbohydrate and simple sugar.
This view, which has its origins in the beginning of the
century,(1) receives at least tacit support from nutritional
recommendations that advocate increased consumption of starchy
foods and decreased consumption of sugar.(2)
2) Throughout the past 25 years, however, the relevance of chain
length in carbohydrate digestion rate has been questioned.
Wahlqvist et al(3) demonstrated similar changes in blood glucose,
insulin, and fatty acid concentrations after glucose as a
monosaccharide, disaccharide, oligosaccharide, or polysaccharide
(starch) had been consumed. Bantle et al(4) found no differences
in blood glucose responses to meals with 25% sucrose compared
with meals containing a similar amount of energy from either
potato or wheat starch. Nevertheless, the physiological effects
of carbohydrates may vary substantially, as demonstrated by
marked differences in glycemic and insulinemic responses to
ingestion of isoenergetic amounts of white bread vs pasta.(5) For
this reason, the glycemic index has been proposed as a system for
classifying carbohydrate-containing foods according to glycemic
response.
3) Glycemic index is defined as the incremental area under the
glucose response curve after a standard amount of carbohydrate
from a test food relative to that of a control food (either white
bread or glucose) is consumed. The glycemic index of a specific
food or meal is determined primarily by the nature of the
carbohydrate consumed and by other dietary factors that affect
nutrient digestibility or insulin secretion. Glycemic index
values for common foods differ by more than 5-fold. In general,
most refined starchy foods eaten in the United States have a high
glycemic index, whereas nonstarchy vegetables, fruit, and legumes
tend to have a low glycemic index. Coingestion of fat or protein
lowers the glycemic index of individual foods somewhat, but does
not change their hierarchical relationship with regard to
glycemic index. Despite initial concerns, the glycemic response
to mixed meals can be predicted with reasonable accuracy from the
glycemic index of constituent foods when standard methods are
used. Regular consumption of high–glycemic index meals, compared
with isoenergetic and nutrient-controlled low–glycemic index
meals, results in higher average 24-hour blood glucose and
insulin levels, higher C-peptide excretion, and higher
glycosylated hemoglobin concentrations in nondiabetic and
diabetic individuals. The term glycemic load, defined as the
weighted average glycemic index of individual foods multiplied by
the percentage of dietary energy as carbohydrate, has been
proposed to characterize the impact of foods or dietary patterns
with different macronutrient composition on glycemic response:
thus, a carrot has a high glycemic index but a low glycemic load,
in contrast to a potato, in which both are high.
4) In summary: The glycemic index was proposed in 1981 as an
alternative system for classifying carbohydrate-containing food.
Since then, several hundred scientific articles and numerous
popular diet books have been published on the topic. However, the
clinical significance of the glycemic index remains the subject
of debate.
References (abridged):
1. Allen FM. Experimental studies on diabetes: production and
control of diabetes in the dog: effects of carbohydrate diets. J
Exp Med. 1920;31:381-402
2. Public Health Service. The Surgeon General's Report on
Nutrition and Health. Washington, DC: Dept of Health and Human
Services; 1988
3. Wahlqvist ML, Wilmshurst EG, Richardson EN. The effect of
chain length on glucose absorption and the related metabolic
response. Am J Clin Nutr. 1978;31:1998-2001
4. Bantle JP, Laine DC, Castle GW, Thomas JW, Hoogwerf BJ, Goetz
FC. Postprandial glucose and insulin responses to meals
containing different carbohydrates in normal and diabetic
subjects. N Engl J Med. 1983;309:7-12
5. Granfeldt Y, Bjorck I, Hagander B. On the importance of
processing conditions, product thickness and egg addition for the
glycaemic and hormonal responses to pasta: a comparison with
bread made from "pasta ingredients." Eur J Clin Nutr.
1991;45:489-499
Related Background:
GLOBAL AND SOCIETAL IMPLICATIONS OF THE DIABETES EPIDEMIC
Nature 2001 414:782
The following points are made by Paul Zimmet et al:
1) Diabetes mellitus, long considered a disease of minor
significance to world health, is now taking its place as one of
the main threats to human health in the 21st century(1). The past
two decades have seen an explosive increase in the number of
people diagnosed with diabetes worldwide(2,3). Pronounced changes
in the human environment, and in human behavior and lifestyle,
have accompanied globalization, and these have resulted in
escalating rates of both obesity and diabetes. Hence the recent
adoption of the term "diabesity"(4), first suggested by Shafrir
several decades ago(5).
2) There are two main forms of diabetes6. Type 1 diabetes is due
primarily to autoimmune-mediated destruction of pancreatic beta-
cell islets, resulting in absolute insulin deficiency. People
with type 1 diabetes must take exogenous insulin for survival to
prevent the development of ketoacidosis. Its frequency is low
relative to type 2 diabetes, which accounts for over 90% of cases
globally. Type 2 diabetes is characterized by insulin resistance
and/or abnormal insulin secretion, either of which may
predominate. People with type 2 diabetes are not dependent on
exogenous insulin, but may require it for control of blood
glucose levels if this is not achieved with diet alone or with
oral hypoglycemic agents.
3) The diabetes epidemic relates particularly to type 2 diabetes,
and is taking place both in developed and developing nations7.
Paradoxically, part of the problem relates to the achievements in
public health during the 20th century, with people living longer
owing to elimination of many of the communicable diseases. Non-
communicable diseases such as diabetes and cardiovascular disease
have now become the main public health challenge for the 21st
century, as a result of their impact on personal and national
health and the premature morbidity and mortality associated with
the non-communicable diseases.
4) In summary: Changes in human behavior and lifestyle over the
last century have resulted in a dramatic increase in the
incidence of diabetes worldwide. The epidemic is chiefly of type
2 diabetes and also the associated conditions known as
"diabesity" and "metabolic syndrome". In conjunction with genetic
susceptibility, particularly in certain ethnic groups, type 2
diabetes is brought on by environmental and behavioral factors
such as a sedentary lifestyle, overly rich nutrition and obesity.
The prevention of diabetes and control of its micro- and
macrovascular complications will require an integrated,
international approach if we are to see significant reduction in
the huge premature morbidity and mortality it causes.
References (abridged):
1. Zimmet, P. Globalization, coca-colonization and the chronic
disease epidemic: can the doomsday scenario be averted? J.
Intern. Med. 247, 301-310 (2000)
2. Amos, A., McCarty, D. & Zimmet, P. The rising global burden of
diabetes and its complications: estimates and projections to the
year 2010. Diabetic Med. 14, S1-S85 (1997)
3. King, H., Aubert, R. & Herman, W. Global burden of diabetes,
1995-2025. Prevalence, numerical estimates and projections.
Diabetes Care 21, 1414-1431 (1998)
4. Astrup, A. & Finer, N. Redefining type 2 diabetes: 'diabesity'
or 'obesity dependent diabetes mellitus'? Obesity Rev. 1, 57-59
(2000)
5. Shafrir, E. Development and consequences of insulin
resistance: lessons from animals with hyperinsulinemia. Diabetes
Metab. 22, 131-148 (1997)
Notes:
The term "metabolic syndrome" encompasses type 2 diabetes (or
prediabetes) and a common constellation of closely linked
clinical features. Characteristic factors include insulin
resistance per se, obesity (in particular abdominal adiposity),
hypertension, and a common form of dyslipidaemia (raised
triglycerides and low high-density lipoprotein (HDL)–cholesterol
with or without elevation of low-density lipoprotein
(LDL)–cholesterol). Metabolic syndrome is associated with a
markedly increased incidence of coronary, cerebral and peripheral
artery disease.
Related Background:
INSULIN RESISTANCE IS A POOR PREDICTOR OF TYPE 2 DIABETES IN
INDIVIDUALS WITH NO FAMILY HISTORY OF DISEASE
Proc. Nat. Acad. Sci. 2003 100:2724
The following points are made by A.B. Goldfine et al:
1) Both insulin resistance and insulin deficiency are components
of the pathogenesis of type 2 diabetes. However their temporal
relationships in the disease process remains unclear (1).
Hyperglycemia, per se, induces defects in both insulin secretion
and in insulin action (2). Thus, it is not possible to
distinguish the role of either in the development of diabetes in
persons already affected with disease. To elucidate the
predictive values of these parameters on the occurrence of type 2
diabetes, studies must be performed in normoglycemic individuals.
However there are few prospective studies evaluating
normoglycemic subjects to determine their contribution to the
pathogenesis of type 2 diabetes. Individuals with a family
history of type 2 diabetes are at greater risk of developing the
disease than people who have no family history of disease.
Insulin sensitivity (SI) and the acute insulin response to
glucose (AIRg) exhibit familial clustering, suggesting these are
inherited traits (3,4).
2) Several studies have shown that insulin resistance (or
hyperinsulinemia) predate glucose intolerance and type 2 diabetes
in normoglycemic individuals at high risk of developing diabetes,
including ethnic Mexican American (5) and Pima Indian groups and
Caucasians. In a longitudinal study of nondiabetic Caucasian
offspring of two type 2 diabetic parents, the authors found both
low SI and low glucose effectiveness (SG), but not low first-
phase insulin secretion, were associated with development of type
2 diabetes one to two decades later. Euglycemic insulin-clamp
studies have also shown early defects in glucose metabolism with
decreased total-body glucose metabolism and impaired nonoxidative
glucose metabolism (primarily glycogen storage) in persons at
risk for type 2 diabetes, including normoglycemic first-degree
relatives of patients with type 2 diabetes.
3) Other studies have focused on the role of insulin secretion in
the development of type 2 diabetes and demonstrated reduced cell
function. Although fasting insulin levels may appear normal or
elevated in patients with type 2 diabetes, other studies have
shown that islet function testing at matched glucose levels in
patients with type 2 diabetes is impaired in both basal and
stimulated states.
4) In summary: In normoglycemic offspring of two type 2 diabetic
parents, low insulin sensitivity (SI) and low insulin-independent
glucose effectiveness (SG) predict the development of diabetes
one to two decades later. The authors report that to determine
whether low SI, low SG, or low acute insulin response to glucose
are predictive of diabetes in a population at low genetic risk
for disease, 181 normoglycemic individuals with no family history
of diabetes (FH) and 150 normoglycemic offspring of two type 2
diabetic parents (FH+) underwent i.v. glucose tolerance testing
(IVGTT) between the years 1964-82. During 25 ± 6 years follow-up,
comprising 2,758 person years, the FH cohort (54 ± 9 years) had
an age-adjusted incidence rate of type 2 diabetes of 1.8 per
1,000 person years, similar to that in other population-based
studies, but significantly lower than 16.7 for the FH+ cohort.
Even when the two study populations were subdivided by initial
values of SI and SG derived from IVGTT's performed at study
entry, there was a 10- to 20-fold difference in age-adjusted
incidence rates for diabetes in the FH vs. FH+ individuals with
low SI and low SG. The acute insulin response to glucose was not
predictive of the development of diabetes when considered
independently or when assessed as a function of SI, i.e., the
glucose disposition index.
5) The authors suggest these data demonstrate that low glucose
disposal rates are robustly associated with the development of
diabetes in the FH+ individuals, but insulin resistance per se is
not sufficient for the development of diabetes in individuals
without family history of disease and strongly suggest a familial
factor, not detectable in our current measures of the dynamic
responses of glucose or insulin to an IVGTT is an important risk
factor for type 2 diabetes. Low SI and low SG , both measures of
glucose disposal, interact with this putative familial factor to
result in a high risk of type 2 diabetes in the FH+ individuals,
but not in the FH individuals.
References (abridged):
1. DeFronzo, R. A. (1988) Diabetes 37, 667-687
2. Rossetti, L., et al (1990) Diabetes Care 13, 610-630
3. Warram, J.H., et al (1988) Adv. Exp. Med. Biol. 246, 175-179
4. Watanabe, R.M., et al (1999) Hum. Hered. 49, 159-168
5. Haffner, S.M., et al (1986) N. Engl. J. Med. 315, 220-224
Related Background:
ON INSULIN SIGNALING IN THE BRAIN
Science 2000 289:2066,2122
The following points are made by J.C. Bruening et al:
1) Insulin receptors and insulin signaling proteins are widely
distributed throughout the central nervous system. To study the
physiological role of insulin signaling in the brain, the authors
created mice with a neuron-specific disruption of the insulin
receptor gene (no-insulin-receptor knockout mice = NIRKO mice).
Inactivation of the insulin receptor had no effect on brain
development or neuronal survival.
2) The authors report that female NIRKO mice showed increased
food intake, and both male and female mice developed diet-
sensitive obesity with increases in body fat and plasma *leptin
levels, mild insulin resistance, elevated plasma insulin levels,
and *hypertriglyceridemia. NIRKO mice also exhibited impaired
*spermatogenesis and *ovarian follicle maturation because of
*hypothalamic dysregulation of *luteinizing hormone. The authors
conclude: "Thus, insulin receptor signaling in the central
nervous system plays an important role in regulation of energy
disposal, fuel metabolism, and reproduction."
In a commentary on the this work, Michael W. Schwartz states:
"Bruening and colleagues provide important evidence to support
[the hypothesis that insulin participates in the central nervous
system control of food intake and body weight]... The stage is
now set for studies to determine if impaired central nervous
system signaling by insulin and leptin contribute to the
pathogenesis of two common metabolic diseases, obesity and *type
2 diabetes."
Notes:
*duodenum: The duodenum is the first segment of the intestine
attached to the stomach.
*blood-brain barrier: A selective mechanism opposing the passage
of most ions and large molecular-weight compounds from the blood
to brain tissue, the mechanism operating in a continuous layer of
endothelial cells connected by tight junctions between cells.
(Endothelial cells are flat cells forming a layer lining blood
vessels, lymphatic vessels, the heart, etc.)
*leptin: First isolated in 1994 by Y. Zhang et al, leptin is a
hormone secreted by fat cells (adipocytes), the hormone
circulating in blood at levels proportionate to fat stores and
acting in the brain to reduce food intake and body weight.
Insulin deficiency in type 1 diabetes does not cause weight gain,
but rather is associated with severe and progressive weight loss.
In contrast, leptin deficiency is associated with severe obesity
syndrome.
*hypertriglyceridemia: Abnormally high concentrations of
triglycerides in blood.
*spermatogenesis: In general, the entire process that results in
the production of sperm cells.
*ovarian follicle: One of the spherical cell aggregations in the
ovary, the aggregation containing an egg cell (ovum).
*hypothalamic: The hypothalamus is a deep brain structure with
various clusters of nerve cells controlling several important
homeostatic functions such as temperature regulation and food
intake, and in addition the sex drive, aggressive emotions,
psychosomatic effects, etc. The hypothalamus essentially
integrates the activity of the autonomic nervous system, and it
acts as an intermediary between the endocrine (hormone) system
and the nervous system, with various hypothalamic neuron types
secreting hormones themselves.
*luteinizing hormone: A hormone produced by the pituitary gland.
Luteinizing hormone has a complex interaction spectrum, but in
general, this hormone stimulates secretion of testosterone in
males, and stimulates secretion of estrogen in females. The
hormone is important both in the production of sperm and in the
production of egg cells.
Related Background:
OBESITY AND DIABETES IN THE US
J. Am. Med. Assoc. 2001 286:1185
A.H. Mokdad et al (NIH, US) discuss the continuing epidemics of
obesity and diabetes in the US. Obesity and diabetes are
currently major causes of morbidity and mortality in the US, and
evidence from several studies indicates that obesity and weight
gain are associated with an increased risk of diabetes. Each
year, an estimated 300,000 US adults die of causes related to
obesity. Obesity also substantially increases morbidity and
impairs quality of life, and overall, the direct costs of obesity
and physical inactivity account for approximately 9.4 percent of
US health care expenditures. The direct and indirect costs of
health care associated with diabetes in 1997 were an estimated
$98 billion. The authors report a study of the prevalence of
obesity, diabetes, and use of weight control strategies among US
adults in the year 2000. A random-digit telephone survey was
conducted in all states in the year 2000 with 184,000 adults aged
18 years or older. The body-mass index was calculated from self-
reported weight and height; also analyzed were self-reported
diabetes, prevalence of weight loss or weight maintenance
attempts, and weight control strategies used. In the year 2000,
the prevalence of obesity, defined as body-mass index equal to or
greater than 30 kilograms per mass-squared, was 19.8 percent. The
prevalence of diabetes was 7.3 percent, and the prevalence of
both combined in the same individual was 2.9 percent. The state
of Mississippi had the highest rates of obesity (24.3 percent)
and of diabetes (8.8 percent). Colorado had the lowest rate
obesity (13.8 percent), and Alaska had the lowest rate of
diabetes (4.4 percent). 27 percent of US adults did not engage in
any physical activity, and another 28.2 percent were not
regularly active. Only 24.4 percent of US adults consumed fruits
and vegetables 5 or more times daily. The authors conclude that
the prevalence of obesity and diabetes continues to increase
among US adults, and that interventions are needed to improve
physical activity and diet in communities nationwide.
Related Background:
OBESITY AND MORTALITY: SPINNING SCIENCE NEWS
New Engl. J. Med. 1998 1 Jan 98
Stevens et al (6 authors at 4 installations, US), in a study of
the mortality of 62,116 men and 262,019 women during a 12 year
period (1960-1972), report that excess body weight increases the
risk of death from any cause and from cardiovascular disease in
adults between 30 and 74 years of age, and that the relative risk
associated with greater body weight is higher among younger
subjects. The above words are essentially the exact conclusions
chosen to be published by the authors. Nevertheless, two variants
of contrary journalistic "spin" have appeared, an interesting
illustration of how public health news is formulated. In the
first variant, in an editorial in the same journal in which the
Stevens et al report appeared, two journal editors emphasize that
the mortality increase with body-mass is modest and age-
dependent, and they urge an end to people "suffering immeasurable
torment in fruitless weight-loss schemes and scams." In the
second variant, published by the New York Times and echoed by
many newspapers across the US, news items took note of the
journal editorial and went a step further in headlines suggesting
excess weight has now been shown to be harmless. The spin-logic
in the case of both the journal editors and the news media is
apparently that since the effect is small, the public can well
disregard it. The researchers and authors of the article,
however, apparently believe otherwise, and the last sentence of
their article is unequivocal: "In healthy white adults below the
age of 75 who have never smoked cigarettes, our results are
consistent with the healthy weight ranges proposed in the 1995
Dietary Guidelines for Americans."
Related Background:
EVIDENCE FOR RETROVIRUS INVOLVEMENT IN AUTOIMMUNE DIABETES
Cell 1997 90:303
1) Retroviruses store their genetic information in molecules of
RNA rather than in molecules of DNA. When they enter a cell, they
carry an enzyme called reverse transcriptase, which utilizes RNA
as a template for directing DNA synthesis. The end result of a
successful retroviral invasion of the cell is that the virally
produced DNA becomes integrated into the host DNA, where it can
be maintained for an indefinite period of time. In fact, there is
evidence that parts of the human genome are actually pieces of
endogenous ancient retroviral DNA now permanent genetic
residents, and that under specific conditions these endogenous
retroviruses can be activated to begin a pathogenic process. Now
2) B. Conrad et al report that the trigger for the autoimmune
disease insulin-dependent diabetes mellitus may be a retrovirus.
This idea has been suggested previously, but this new evidence is
apparently stronger, including isolation of the complete genome
of a heretofore unknown endogenous retrovirus in the supernatant
from pancreatic-islet cultures from a diabetic patient. Workers
in the field are calling this an exiting advance in the
understanding of this autoimmune disease.
ScienceWeek http://www.scienceweek.com
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3. PATHOPHYSIOLOGY
INSULIN SIGNALING AND THE REGULATION OF GLUCOSE AND LIPID
METABOLISM
Nature 2001 414:799
The following points are made by A. Saltiel and C. Kahn:
1) Despite periods of feeding and fasting, plasma glucose remains
in a narrow range between 4 and 7 mM in normal individuals. This
tight control is governed by the balance between glucose
absorption from the intestine, production by the liver, and
uptake and metabolism by peripheral tissues. Insulin increases
glucose uptake in muscle and fat, and inhibits hepatic glucose
production, thus serving as the primary regulator of blood
glucose concentration. Insulin also stimulates cell growth and
differentiation, and promotes the storage of substrates in fat,
liver and muscle by stimulating lipogenesis, glycogen and protein
synthesis, and inhibiting lipolysis, glycogenolysis and protein
breakdown. Insulin resistance or deficiency results in profound
dysregulation of these processes, and produces elevations in
fasting and postprandial glucose and lipid levels.
2) Insulin increases glucose uptake in cells by stimulating the
translocation of the glucose transporter GLUT4 from intracellular
sites to the cell surface. Up to 75% of insulin-dependent glucose
disposal occurs in skeletal muscle, whereas adipose tissue
accounts for only a small fraction(1). Despite this, mice with a
knockout of the insulin receptor in muscle have normal glucose
tolerance(2), whereas those with a knockout of the insulin-
sensitive glucose transporter in fat have impaired glucose
tolerance, apparently owing to insulin resistance being induced
in muscle and liver(3). Both obesity and lipoatrophy also cause
insulin resistance and predisposition to type 2 diabetes,
demonstrating that adipose tissue is crucial in regulating
metabolism beyond its ability to take up glucose(4). Although
insulin does not stimulate glucose uptake in liver, it blocks
glycogenolysis and gluconeogenesis, and stimulates glycogen
synthesis, thus regulating fasting glucose levels. Insulin action
in tissues not normally considered insulin sensitive, including
brain and pancreatic beta-cell, may also be important in glucose
homeostasis(2,5)
3) In summary: The epidemic of type 2 diabetes and impaired
glucose tolerance is one of the main causes of morbidity and
mortality worldwide. In both disorders, tissues such as muscle,
fat and liver become less responsive or resistant to insulin.
This state is also linked to other common health problems, such
as obesity, polycystic ovarian disease, hyperlipidemia,
hypertension and atherosclerosis. The pathophysiology of insulin
resistance involves a complex network of signaling pathways,
activated by the insulin receptor, which regulates intermediary
metabolism and its organization in cells. But recent studies have
shown that numerous other hormones and signaling events attenuate
insulin action, and are important in type 2 diabetes.
References (abridged):
1. Klip, A. & Paquet, M. R. Glucose transport and glucose
transporters in muscle and their metabolic regulation. Diabetes
Care 13, 228-243 (1990)
2. Bruning, J. C. et al. A muscle-specific insulin receptor
knockout exhibits features of the metabolic syndrome of NIDDM
without altering glucose tolerance. Mol. Cell 2, 559-569 (1998)
3. Abel, E. D. et al. Adipose-selective targeting of the GLUT4
gene impairs insulin action in muscle and liver. Nature 409, 729-
733 (2001)
4. Gavrilova, O. et al. Surgical implantation of adipose tissue
reverses diabetes in lipoatrophic mice. J. Clin. Invest. 105,
271-278 (2000)
5. Kulkarni, R. N. et al. Tissue-specific knockout of the insulin
receptor in pancreatic beta cells creates an insulin secretory
defect similar to that in type 2 diabetes. Cell 96, 329-339
(1999)
Related Background:
MOLECULAR ASPECTS: HYPERGLYCEMIA AND DIABETIC COMPLICATIONS
J. Am. Med. Assoc. 2002;288:2579-2588
The following points are made by M.J. Sheetz and G.L. King:
1) Complications of diabetes are the major cause of morbidity and
mortality in persons with type 1 and type 2 diabetes. Although
the pathogenesis of type 1 diabetes is different from that of
type 2 diabetes, the pathophysiology of microvascular
complications in the two conditions appears to be similar.
2) Chronic hyperglycemia is a major initiator of microvascular
complications of diabetes (eg, retinopathy, neuropathy,
nephropathy). Two landmark studies, the Diabetes Control and
Complications Trial (DCCT) and the United Kingdom Prospective
Diabetes Study (UKPDS), showed that intensive control of
hyperglycemia can reduce the occurrence or progression of
retinopathy, neuropathy, and nephropathy in persons with type 1
and type 2 diabetes, respectively.(1-2) These data strongly
suggested that hyperglycemia is responsible for diabetic
microvascular complications. Still, control of hyperglycemia to
the strict levels achieved in these studies is very difficult to
maintain and may lead to weight gain; therefore, the use of
therapies that specifically target diabetic microvascular
complications may be helpful in addition to a strict glucose-
monitoring regimen.
3) Diabetic retinopathy occurs in three fourths of all persons
with diabetes after more than 15 years of the disease.(3) It is
the most common cause of blindness in the industrialized world in
persons between the ages of 25 and 74 years.(4) Diabetic
retinopathy is diagnosed by the appearance of retinal vascular
lesions of increasing severity, culminating in the growth of new
vessels (proliferative diabetic retinopathy. A loss of vision can
result through either a nonclearing vitreous hemorrhage or
through fibrosis causing traction retinal detachment. In
addition, retinal vessels can leak at any stage of retinopathy
and produce macular edema with potentially irreversible loss of
central vision.
In summary: Diabetic complications are the major cause of
morbidity and mortality in persons with diabetes. Chronic
hyperglycemia is a major initiator of diabetic microvascular
complications (eg, retinopathy, neuropathy, nephropathy). Glucose
processing uses a variety of diverse metabolic pathways; hence,
chronic hyperglycemia can induce multiple cellular changes
leading to complications. Several predominant well-researched
theories have been proposed to explain how hyperglycemia can
produce the neural and vascular derangements that are hallmarks
of diabetes. These theories can be separated into those that
emphasize the toxic effects of hyperglycemia and its
pathophysiological derivatives (such as oxidants,
hyperosmolarity, or glycation products) on tissues directly and
those that ascribe pathophysiological importance to a sustained
alteration in cell signaling pathways (such as changes in
phospholipids or kinases) induced by the products of glucose
metabolism.(5)
References (abridged):
1. Diabetes Control and Complications Trial Research Group. The
effect of intensive treatment of diabetes on the development and
progression of long-term complications in insulin-dependent
diabetes mellitus. N Engl J Med. 1993;329:977-986
2. UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-
glucose control with sulphonylureas or insulin compared with
conventional treatment and risk of complications in patients with
type 2 diabetes (UKPDS 33). Lancet. 1998;352:837-853
3. Klein R, Klein BEK, Moss SE. The Wisconsin epidemiological
study of diabetic retinopathy: a review. Diabetes Metab Rev.
1989;5:559-570
4. Klein R, Klein BEK. Vision disorders in diabetes. In: Hamman
R, Harris MWH, eds. Diabetes in America. Bethesda, Md: National
Institutes of Health; 1982. US Public Health Service/NIH
Publication 85-1468, vol 13:1-36
5. Bursell SE, Clermont AC, Kinsley BT, et al. Retinal blood flow
changes in patients with insulin-dependent diabetes mellitus and
no diabetic retinopathy. Invest Ophthalmol Vis Sci. 1996;37:886-
897
Related Background:
DIABETES AND ATHEROSCLEROSIS
J. Am. Med. Assoc. 2002 287:2570
The following points are made by J.A. Beckman et al:
1) Diabetes mellitus magnifies the risk of cardiovascular
morbidity and mortality.(1) Besides the well-recognized
microvascular complications of diabetes, such as nephropathy and
retinopathy, there is a growing epidemic of macrovascular
complications, including diseases of coronary arteries,
peripheral arteries, and carotid vessels, particularly in the
burgeoning type 2 diabetic population. The traditional
therapeutic approaches emphasize glycemic control, which limits
microvascular disease but lacks an established benefit in
macrovascular disease. Understanding atherosclerosis in diabetes
and instituting therapy guided by emerging evidence should
improve outcomes in patients. The evidence supports aggressive
antiatherosclerotic management strategies upon diagnosis of type
2 diabetes to minimize the risk of cardiovascular morbidity and
mortality.
2) Clinical manifestations of atherosclerosis occur primarily in
three vascular beds: coronary arteries, lower extremities, and
extracranial carotid arteries. Diabetes increases the incidence
and accelerates the clinical course of each.
3) Coronary artery disease (CAD) causes much of the serious
morbidity and mortality in patients with diabetes, who have a 2-
to 4-fold increase in the risk of CAD.(2) In one population-based
study,(3) the 7-year incidence of first myocardial infarction
(MI) or death for patients with diabetes was 20% but was only
3.5% for nondiabetic patients. History of MI increased the rate
of recurrent MI or cardiovascular death events for both groups
(18.8% in nondiabetic persons and 45% in those with diabetes).
Thus, patients with diabetes but without previous MI carry the
same level of risk for subsequent acute coronary events as
nondiabetic patients with previous MI. Such results led the Adult
Treatment Panel III of the National Cholesterol Education Program
to establish diabetes as a CAD risk equivalent mandating
aggressive antiatherosclerotic therapy.(4)
4) Diabetes also worsens early and late outcomes in acute
coronary syndromes. In unstable angina pectoris or non–Q-wave MI
compared with control, the presence of diabetes increases the
risk of in-hospital MI, complications of MI, and mortality.(5) In
the OASIS registry, a 6-nation study of unstable angina and
non–Q-wave MI, diabetes independently increased the risk of death
by 57%. The age-adjusted relative risk of mortality for patients
with diabetes in the GISSI-2 trial of fibrinolytic therapy in MI
was 1.4 for men and 1.9 for women, regardless of intervention
assignment. In the SHOCK trial of revascularization for MI
complicated by cardiogenic shock, the relative risk of death for
patients with diabetes was 1.36 compared with that of nondiabetic
patients. Regardless of the severity of clinical presentation,
patients who have diabetes and coronary events experience
increased rates of MI and death.
References (abridged):
1. Resnick HE, Shorr RI, Kuller L, et al. Prevalence and clinical
implications of American Diabetes Association-defined diabetes
and other categories of glucose dysregulation in older adults. J
Clin Epidemiol. 2001;54:869-876
2. Feskens EJ, Kromhout D. Glucose tolerance and the risk of
cardiovascular disease: the Zutphen Study. J Clin Epidemiol.
1992;45:1327-1334
3. Haffner SM, Lehto S, Ronnemaa T, et al. Mortality from
coronary heart disease in subjects with type 2 diabetes and in
nondiabetic subjects with and without prior myocardial
infarction. N Engl J Med. 1998;339:229-234
4. Executive summary of the third report of the National
Cholesterol Education Program (NCEP) Expert Panel on Detection,
Evaluation, and Treatment of High Blood Cholesterol in Adults
(Adult Treatment Panel III). JAMA. 2001;285:2486-2497.
5. Kjaergaard SC, Hansen HH, Fog L, et al. In-hospital outcome
for diabetic patients with acute myocardial infarction in the
thrombolytic era. Scand Cardiovasc J. 1999;33:166-170
Notes: The sequence of waves of the electrocardiogram are
categorized as P, Q, R, S, and T, with the characteristics of
each wave of diagnostic significance for various cardiac
abnormalities. The QRS segment, consisting of 3 waves (Q, R, and
S) is associated with the normal physiological event of
ventricular depolarization, and an enlarged Q wave may indicate a
myocardial infarction (heart attack).
Related Background:
BETA-CELL DEATH DURING PROGRESSION TO DIABETES
Nature 2001 414:792
The following points are made by D. Mathis et al:
1) Type 1 diabetes is an autoimmune disease resulting from
specific destruction of the insulin-producing beta-cells of the
islets of Langerhans of the pancreas(1). It has two distinct
phases: insulitis, when a mixed population of leukocytes invades
the islets; and diabetes, when most beta-cells have been killed
off, and there is no longer sufficient insulin production to
regulate blood glucose levels, resulting in hyperglycemia.
Individuals can have covert insulitis for a long time (years in
humans, months in rodent models) before it finally progresses to
overt diabetes, and sometimes it never does.
2) Type 1 diabetes is an old disorder -- descriptions of it
appear in ancient Egyptian and Greek writings. It is also a
common disease, currently affecting approximately 0.5% of the
population in developed countries and increasing in incidence. In
addition, there is mounting evidence that a fraction (variously
estimated at 5–15%) of people originally diagnosed as type 2
diabetic may actually have a slowly progressing and less severe
form of type 1 termed "latent autoimmune diabetes of adults". It
is surprising, then, that we remain so ignorant about the
etiology and pathogenesis of autoimmune diabetes. We do not know
what triggers it, have little understanding of the genetic and
environmental factors regulating its progression, and have a
confused view of the final effector mechanism(s). Consequently,
we still do not know how to prevent or reverse type 1 diabetes in
a sufficiently innocuous manner to be therapeutically useful.
Faced with the difficulties of addressing these issues in humans,
many investigators have turned to small-animal models of
diabetes, in particular the non-obese diabetic mouse and
transgenic derivatives of it.
3) Type 1 diabetes is primarily a T-lymphocyte-mediated
disease(1,2). Immunohistological analyses show that most
leukocytes in the islet infiltrate are T cells. Disease does not
develop in non-obese diabetic (NOD) mice that are genetically
athymic or T lymphopenic, or were thymectomized at birth;
likewise, it is dampened or even abrogated by reagents that
interfere with T-cell function. Finally, diabetes can be
transferred by injecting T cells from diseased donors into
healthy NOD recipients -- the purest demonstration being
inoculation of a single T-cell clone into a lymphocyte-deficient
NOD mouse. Although most of these data derive from rodent
diabetes models, there is ample indication that the human disease
is also mediated by T lymphocytes, and has a similar islet
histology and positive response to treatment with T-cell
inhibitors.
4) In summary: The hallmark of type 1 diabetes is specific
destruction of pancreatic islet beta-cells. Apoptosis of beta-
cells may be crucial at several points during disease
progression, initiating leukocyte invasion of the islets and
terminating the production of insulin in islet cells. Beta-Cell
apoptosis may also be involved in the occasional evolution of
type 2 into type 1 diabetes.(3-5)
References (abridged):
1. Tisch, R. & McDevitt, H. Insulin-dependent diabetes mellitus.
Cell 85, 291-297 (1996)
2. Bach, J. F. & Mathis, D. 70th forum in immunology: the NOD
mouse. Res. Immunol. 148, 281-370 (1997)
3. Hoglund, P. et al. Initiation of autoimmune diabetes by
developmentally regulated presentation of islet cell antigens in
the pancreatic lymph nodes. J. Exp. Med. 189, 331-339 (1999)
4. Green, E. A., Eynon, E. E. & Flavell, R. A. Local expression
of TNF in neonatal NOD mice promotes diabetes by enhancing
presentation of islet antigens. Immunity 9, 733-743 (1998)
5. Katz, J. D., Benoist, C. & Mathis, D. T helper cell subsets in
insulin-dependent diabetes. Science 268, 1185-1188 (1995)
Related Background:
BIOCHEMISTRY AND MOLECULAR CELL BIOLOGY OF DIABETIC COMPLICATIONS
Nature 2001 414:813
The following points are made by Michael Brownlee:
1) All forms of diabetes are characterized by chronic
hyperglycemia and the development of diabetes-specific
microvascular pathology in the retina, renal glomerulus and
peripheral nerve. As a consequence of its microvascular
pathology, diabetes is a leading cause of blindness, end-stage
renal disease, and a variety of debilitating neuropathies.
Diabetes is also associated with accelerated atherosclerotic
macrovascular disease affecting arteries that supply the heart,
brain, and lower extremities. As a result, patients with diabetes
have a much higher risk of myocardial infarction, stroke and limb
amputation. Large prospective clinical studies show a strong
relationship between glycemia and diabetic microvascular
complications in both type 1 and type 2 diabetes(1,2).
Hyperglycemia and insulin resistance both seem to have important
roles in the pathogenesis of macrovascular complications(2-5).
2) Diabetes-specific microvascular disease in the retina,
glomerulus and vasa nervorum has similar pathophysiological
features. Early in the course of diabetes, intracellular
hyperglycemia causes abnormalities in blood flow and increased
vascular permeability. This reflects decreased activity of
vasodilators such as nitric oxide, increased activity of
vasoconstrictors such as angiotensin II and endothelin-1, and
elaboration of permeability factors such as vascular endothelial
growth factor (VEGF). Quantitative and qualitative abnormalities
of extracellular matrix contribute to an irreversible increase in
vascular permeability. With time, microvascular cell loss occurs,
in part as a result of programmed cell death, and there is
progressive capillary occlusion due both to extracellular matrix
overproduction induced by growth factors such as transforming
growth factor-beta (TGF-beta), and to deposition of extravasated
periodic acid–Schiff-positive plasma proteins. Hyperglycemia may
also decrease production of trophic factors for endothelial and
neuronal cells. Together, these changes lead to edema, ischaemia
and hypoxia-induced neovascularization in the retina,
proteinuria, mesangial matrix expansion and glomerulosclerosis in
the kidney, and multifocal axonal degeneration in peripheral
nerves.
3) In summary: Diabetes-specific microvascular disease is a
leading cause of blindness, renal failure and nerve damage, and
diabetes-accelerated atherosclerosis leads to increased risk of
myocardial infarction, stroke and limb amputation. Four main
molecular mechanisms have been implicated in glucose-mediated
vascular damage. All seem to reflect a single hyperglycemia-
induced process of overproduction of superoxide by the
mitochondrial electron-transport chain. This integrating paradigm
provides a new conceptual framework for future research and drug
discovery.
References (abridged):
1. The Diabetes Control and Complications Trial Research Group.
The effect of intensive treatment of diabetes on the development
and progression of long-term complications in insulin-dependent
diabetes mellitus. N. Engl. J. Med. 329, 977-986 (1993)
2. UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-
glucose control with sulphonylureas or insulin compared with
conventional treatment and risk of complications in patients with
type 2 diabetes (UKPDS 33). Lancet 352, 837-853 (1998)
3. Wei, M., Gaskill, S. P., Haffner, S. M. & Stern, M. P. Effects
of diabetes and level of glycemia on all-cause and cardiovascular
mortality. The San Antonio Heart Study. Diabetes Care 7, 1167-
1172 (1998)
4. Ebara, T. et al. Delayed catabolism of apoB-48 lipoproteins
due to decreased heparan sulfate proteoglycan production in
diabetic mice. J. Clin. Invest. 105, 1807-1818 (2000)
5. Ginsberg, H. N. Insulin resistance and cardiovascular disease.
J. Clin. Invest. 106, 453-458 (2000)
Related Background:
INSULIN SECRETION, BETA-CELL MITOCHONDRIA, AND DIABETES
New Engl. J. Med. 2001 345:1772
The following points are made by Dominique Langin:
1) Type 2 diabetes, the most common form of diabetes, affects
approximately 135 million people worldwide. Insulin resistance
and dysfunction of pancreatic beta cells are central
abnormalities of the disease. Insulin resistance is a disordered
state in which insulin inadequately stimulates glucose transport
in skeletal muscle and fat and inadequately suppresses hepatic
glucose production. Glucose intolerance and then diabetes develop
as the compensatory hypersecretion of insulin by beta cells
declines.
2) Knowledge of the molecular control of insulin secretion is
therefore important for understanding the beta-cell dysfunction
of type 2 diabetes. Zhang et al (Cell 2001 105:745) recently
provided compelling evidence that a mitochondrial anion carrier
called "uncoupling protein 2" is a critical modulator of insulin
secretion, and that an increase in this protein may cause beta-
cell dysfunction.
3) The steps that link changes in glucose levels to insulin
secretion are well characterized. Following its entry into the
beta cell, glucose is phosphorylated by glucokinase. This rate-
limiting enzymatic step constitutes a glucose sensor, since it
allows rapid and precise adjustments to be made in response to
changes in extracellular glucose levels. Further products of
glucose metabolism enter the mitochondrial respiratory chain,
which uses them to generate adenosine triphosphate (ATP). The
increase in ATP inhibits ATP-sensitive potassium channels, which
in turn stimulates insulin secretion. The hypoglycemic effect of
sulfonylureas, which are widely used in the treatment of type 2
diabetes, is due to the inhibition of these channels. In the
process of generating ATP, control of the coupling between oxygen
consumption and ATP synthesis is essential, since it modulates
ATP levels.
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4. CLINICAL ASPECTS
NEW DRUG TARGETS FOR TYPE 2 DIABETES AND THE METABOLIC SYNDROME
Nature 2001 414:821
The following points are made by David E. Moller:
1) Type 2 insulin-resistant diabetes mellitus accounts for 90–95%
of all diabetes. This heterogeneous disorder afflicts an
estimated 6% of the adult population in Western society; its
worldwide frequency is expected to continue to grow by 6% per
annum, potentially reaching a total of 200–300 million cases in
2010(1,2). The main force driving this increasing incidence is a
staggering increase in obesity, the single most important
contributor to the pathogenesis of diabetes.
2) It is now clear that aggressive control of hyperglycemia in
patients with type 2 diabetes can attenuate the development of
chronic complications such as retinopathy and nephropathy(3). At
present, therapy for type 2 diabetes relies mainly on several
approaches intended to reduce the hyperglycemia itself:
sulphonylureas (and related insulin secretagogues), which
increase insulin release from pancreatic islets; metformin, which
acts to reduce hepatic glucose production; peroxisome
proliferator-activated receptor-gamma (PPAR) agonists
(thiazolidinediones), which enhance insulin action; alpha-
glucosidase inhibitors, which interfere with gut glucose
absorption; and insulin itself, which suppresses glucose
production and augments glucose utilization.
3) These therapies have limited efficacy, limited tolerability
and significant mechanism-based side effects. Of particular
concern is the tendency for most treatments to enhance weight
gain. Several current approaches are also associated with
episodes of hypoglycemia, and few of the available therapies
adequately address underlying defects such as obesity and/or
insulin resistance. A problem particular to the sulphonylureas is
that many patients who respond initially become refractory to
treatment over time ("secondary failures"). Thus, newer
approaches are desperately needed. Particular emphasis should be
placed on finding and using mechanisms that are dependent on
physiological responses (for example, glucose-mediated insulin
secretagogues), and that result in weight loss (or lack of weight
gain).
4) In summary: An insidious increase in features of the
"metabolic syndrome" -- obesity, insulin resistance and
dyslipidaemia -- has conspired to produce a worldwide epidemic of
type 2 insulin-resistant diabetes mellitus. Most current
therapies for this disease were developed in the absence of
defined molecular targets or an understanding of disease
pathogenesis. Emerging knowledge of key pathogenic mechanisms,
such as the impairment of glucose-stimulated insulin secretion
and the role of "lipotoxicity" as a probable cause of hepatic and
muscle resistance to insulin's effects on glucose metabolism, has
led to a host of new molecular drug targets. Several have been
validated through genetic engineering in mice or the preliminary
use of lead compounds and therapeutic agents in animals and
humans.(3-5)
References (abridged):
1. Kopelman, P. G. & Hitman, G. A. Diabetes. Exploding Type II.
Lancet 352, SIV5 (1998)
2. Amos, A. F., McCarty, D. J. & Zimmet, P. The rising global
burden of diabetes and its complications: estimates and
projections by 2010. Diabet. Med. 14 (Suppl. 5), S5-S85 (1997)
3. UKPDS. UK prospective diabetes study 33: intensive blood
glucose control with sulphonylureas or insulin compared with
conventional treatment and risk of complications with type 2
diabetes. Lancet 352, 837-853 (1998)
4. Executive summary of the third report of the National
Cholesterol Education Program Expert Panel on Detection,
Evaluation, and Treatment of High Blood Cholesterol in Adults. J.
Am. Med. Assoc. 285, 2486-2496 (2001)
5. Haffner, S. M., Lehto, S., Ronnemaa, T., Pyorala, K. & Laakso,
M. Mortality from coronary heart disease in subjects with type 2
diabetes and in non-diabetic subjects with and without prior
myocardial infarction. N. Engl. J. Med. 339, 229-234 (1998)
Related Background:
A CENTRAL ROLE FOR JNK IN OBESITY AND INSULIN RESISTANCE
Nature 2002 420:333
The following points are made by J. Hirosumi et al:
1) Obesity and type 2 diabetes are the most prevalent and serious
metabolic diseases; they affect more than 50% of adults in the
USA5. These conditions are associated with a chronic inflammatory
response characterized by abnormal cytokine production, increased
acute-phase reactants and other stress-induced molecules. Many of
these alterations seem to be initiated and to reside within
adipose tissue, an unusual site for inflammation3. Elevated
production of tumor necrosis factor (TNF)-alpha by adipose tissue
decreases sensitivity to insulin and has been detected in several
experimental obesity models and obese humans. Free fatty acids
(FFAs) are also implicated in the etiology of obesity-induced
insulin resistance, although the molecular pathways involved in
their action remain unclear(4). Because both TNF-alpha and FFAs
are potent JNK activators, the authors investigated whether
obesity is associated with alterations in stress-activated and
inflammatory responses through this signalling pathway and
whether JNKs are causally linked to aberrant metabolic control in
this state.
2) The authors examined JNK activity in liver, muscle and adipose
tissues of various models of obesity compared with lean controls
to determine whether obesity activates the JNK pathway. In both
dietary and genetic (ob/ob) models of obesity, there was a
significant increase in total JNK activity in all tissues tested.
In these tissues there was no apparent difference in the
expression of either JNK1 or JNK2 polypeptides, suggesting that
the activity of one or both of these kinases is increased in
response to obesity.
3) In summary: Obesity is closely associated with insulin
resistance and establishes the leading risk factor for type 2
diabetes mellitus, yet the molecular mechanisms of this
association are poorly understood(1). The c-Jun amino-terminal
kinases (JNKs) can interfere with insulin action in cultured
cells(2) and are activated by inflammatory cytokines and free
fatty acids, molecules that have been implicated in the
development of type 2 diabetes(3,4). The authors demonstrate that
JNK activity is abnormally elevated in obesity. Furthermore, an
absence of JNK1 results in decreased adiposity, significantly
improved insulin sensitivity and enhanced insulin receptor
signaling capacity in two different models of mouse obesity.
Thus, JNK is a crucial mediator of obesity and insulin resistance
and a potential target for therapeutics.(5)
References (abridged):
1. Saltiel, A. R. & Kahn, C. R. Insulin signaling and the
regulation of glucose and lipid metabolism. Nature 414, 799-806
(2001)
2. Aguirre, V., Uchida, T., Yenush, L., Davis, R. & White, M. F.
The c-Jun NH2-terminal kinase promotes insulin resistance during
association with insulin receptor substrate-1 and phosphorylation
of Ser307. J. Biol. Chem. 275, 9047-9054 (2000)
3. Sethi, J. K. & Hotamisligil, G. S. The role of TNF alpha in
adipocyte metabolism. Semin. Cell. Dev. Biol. 10, 19-29 (1999)
4. Boden, G. Role of fatty acids in the pathogenesis of insulin
resistance and NIDDM. Diabetes 46, 3-10 (1997)
5. Must, A. et al. The disease burden associated with overweight
and obesity. J. Am. Med. Assoc. 282, 1523-1529 (1999)
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