Overweight, Obesity and
Diabetes
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Blood
sugar values, normal and diabetic
The current norms for blood glucose are shown in the
following table. The upper limit for normal levels of blood glucose is
currently set at less than 5.6 mmol/l while the
reference level 2 hours after a glucose load is less than 7.8 mmol/l.
Note that interpretation of the data is "temporary". Glucose
levels swing somewhat from day to day and from 
individual to individual. Therefore, if high
glucose levels are found, it is advised that measurement should be repeated on
the following three days. Only then should hyperglycemia be noted
as an enduring symptom and treatment started.
Fasting glucose levels between 5.6
mmol/l and 7.0 mmol/l indicate impaired glucose tolerance (IGT) while
higher levels signify diabetes. IGT can be viewed as
"pre-diabetes" as most individuals in this group develop diabetes
type 2 with time.
In 2003 an expert group suggested reducing the cut
point for impaired glucose tolerance from 6.1
mmoles/l to 5.6 mmoles/l. This is expected to increase the number of
individuals diagnosed as prediabetics by about 20%. Many of these people
have a large risk for development of diabetes type 2 later in life.
Therefore, they should be advised to revise their lifestyle and work for
reduction of their hyperglycemia.
Fasting blood glucose levels are proposed as the
leading indication of the metabolic state. This is a rapid, inexpensive
and accurate measure of the individual's metabolic situation. The
committee suggested that fasting blood sugar be determined every 3rd year after
reaching 45 years of age. A glucose tolerance test is deemed unnecessary
as long as fasting glucose does not exceed 5.6 mmoles/liter.
What's wrong with having a little
extra blood sugar?
Glucose intolerance and the development of disease.
The suggested blood glucose standards are based upon
statistical analysis of the correlation between of blood glucose levels and the
development of pathological states. Among these is retinopathy, which can
lead to blindness. One might have expected a linear relationship between
the level of blood sugar and the development of glucose-related diseases.
However, this is not the case, as shown in the next figure. Data from
three independent studies are shown in which elderly Americans, Pima Indians
and Egyptians were observed. These groups are known to be especially
prone to development of diabetes type 2. In all cases, an abrupt increase
in the frequency of retinopathy was noted when 
blood sugar levels exceeded 6.0-6.1 mmol/l. This
toxic effect of glucose may result from sorbitol formation or follow glycation
of proteins, a non-enzymatic coupling of glucose to proteins.
Classification of diabetes mellitus
Most diabetic patients fall into one of two classifications, diabetes type 1 and diabetes type 2. In the
Patients with diabetes type 1 must receive insulin to
survive. Patients with type 2 diabetes and glucose
intolerance are best treated by learning to control their own metabolism
through proper diet and motion. In addition, many use metformin to reduce
the liver's glucose production.
Specific treatment of the detailed cause of diabetes
type 2 is seldom possible. It would be of great advantage to have exact
knowledge of the origin of glucose intolerance and diabetes type 2 in each
patient. More than 40 differing causes have been found in some very few
cases. These mainly involve enzyme mutations. This is an active
research area and may, with time, lead to advances in
treatment.
Gestational diabetes is a passing hyperglycemia
in pregnancy. This is a genetically determined condition and is handled
without insulin treatment. Women who acquire gestational diabetes often
develop diabetes type 2 later in life.
Diabetes type 1
Insulin was first identified in pancreatic extracts by
Banting and Best in 1922. The first patient who received insulin was 14
year old Leonard Thompson, also in 1922. Diabetes type 1 was a fatal disease
prior to Banting and Best's work. Treatment of diabetes type 1 with
insulin is still not economically possible for many patients in underdeveloped
countries.
Diabetes type 1 results from an autoimmune destruction
of the ß-cells of the pancreas. It has been most commonly accepted that
this is a genetically controlled process associated with HLA alleles.
However there is a age-dependent spreading of the
disease and this has changed with time. Increasing evidence points to a
combination of factors leading to beta cell destruction. 
The disease most commonly develops before
20 years of age as is shown in the figure to the left. However, incidence
(cases/100,000) of the disease has changed in the latter half of the 20th
century. Patients develop diabetes at an earlier age and the frequency
has increased. This implies that there are other factors than the genetic
which lead to development of diabetes type 1. The data is from
A further indication that
factors other than the genetic are involved in development of diabetes type 1
is shown in the next figure. The data are also from 
Autoimmune attack on the
Langerhans Islets
It has been commonly assumed that antibodies and T
cells specifically attacked beta cells, leading to insulin deficiency and
destruction. 
However, in a recent publication, Shawn Winer et al
have shown that Schwann cells which surround the Langerhans islet are
autoimmune targeted and destroyed before the autoimmune attack on beta cells
and loss of beta cell activity. It appears that antigen-presenting cells
move from islets to the pancreatic lymph mode where cell-specific antigens are
produced. These attack Schwann cells surrounding the islets, destroying
the Schwann cell capsule which surrounds islets. Beta cell destruction
follows. (Nature Medicine 9, 198-205, 2003).
Diabetes type 1 patients are today completely
dependent upon injections of insulin to sustain life. Current research is
aimed at developing oral agents capable of activating the insulin-signal
pathway downstream of the insulin receptor. In this way the need for
injected insulin may perhaps be eliminated in the future.
Why don't we replace lost
ß-cells?
One might think that we could replace destroyed ß-cells
and restore insulin secretion and control of metabolism. After all, blood
cells, skin and intestine do not disappear after loss of tissue. This was
the question a group of researchers at Harvard put forward in a recent
study. They investigated generation of ß-cells in mice and looked for
formation of new pancreatic islets in adult animals. Surprisingly, they
found that no new islets could be identified. In adult mice, ß-cells are
formed only by self-duplication and appeared not to arise from stem
cells. The permanent loss of ß-cells seen in diabetes type 1 may,
therefore, occur because only preexisting ß-cells
give rise to new insulin-producing cells in the adult. The loss of
insulin producing ß-cells seen with time in diabetes type 2 may also develop
through this mechanism. Go to the original article for more information. Click here
to call up "Adult pancreatic ß-cells are formed by self-duplication rather
than stem-cell differentiation", Dor et al,
Nature 429, 41 (2004).
Is replacement therapy possible?
A fascinating approach to diabetes type 1 therapy would be to replace pancreatic
beta-cells with new cells produced in the laboratory. Is this possible? Can we produce human beta cells in
vitro? In a very recent publication in
Science Express
Diabetes type 2
Diabetes mellitus type 2 arises from a reduced
response of target tissues to insulin (so-called insulin resistance).
Insulin levels are often quite high in early type 2 diabetes. The etiology of insulin resistance remains unclear, although
many hypotheses have been set forth. I will go into these later, but
there is a very clear association between overweight (BMI 25-30) or obesity
(BMI>30), the metabolic syndrome and development of diabetes type 2. A
genetic factor is also clearly involved. Many ethnic groups are
predisposed for the disease. More detailed information about the causes
of and classification of diabetes mellitus can be found here.
Diabetes type 2, earlier called "maturity -onset
diabetes", typically develops over a period of many years. It
usually begins with overweight, goes through a period of glucose intolerance,
and ends with the full-blown diabetic state. In contrast to diabetes type
1, the disease develops slowly and goes through several stages as shown in the
following figure.
Obesity seems to be the most common factor
initiating development of diabetes type 2. The patient goes through a
period of increasing insulin resistance during which the body compensates by
producing higher levels of insulin after meals. Usually, the patient is
unaware of his or her situation. Following a period of many years, the
pancreatic ß-cells no longer manage to continue their enhanced insulin
secretion. Insulin levels fall in the face of continuing insulin resistance,
resulting in increased fasting blood glucose levels and markedly increased
post-meals levels of plasma glucose. It has been suggested that the
insulin-producing ß-cells are subject to attack even before this stage.
It should be noted that the global wave of obesity we
now experience applies to young children too. Social factors (fear of
kidnapping, parents who drive kids to school and after-school activities,
passive TV and PC use, etc.) contribute to reduced physical activity and
obesity in children. Simultaneously, energy intake is often increased
through an ever-increasing consumption of fast foods, soda pop, sugar coated
breakfast food, snacks and confection. The decreased physical activity
coupled to increased food intake must lead to pronounced weight gain.
These energy-rich foods appear not to function normally in the
appetite-controlling mechanism. The reason for this is not yet clear but
is the subject of much research. Diabetes type 2 in young children
(formerly limited to adults) is now a serious and growing problem.
Control of the long-term symptoms of diabetes type 2 will be a difficult and
very expensive problem in the coming decades.
A Simplistic Approach to Weight
Regulation
There are very many factors involved in normal weight
regulation. However, the end result is the consequence of the balance
between the amount of energy in the ingested food and the amount of energy
used. Hormone levels, altered hormone receptors, mutated metabolic
enzymes; all of these do influence appetite and
energy use. However, the bottom line is, you are what you eat (and do
not burn). Look at the next figure (modified after Marks, Marks and
Smith, Basic Medical Biochemistry). 
The activity levels shown here correspond to those
that are normal in a modern society. A young male student uses most of
the energy in his food to support normal body functions (basal metabolism or
BMR). Only about 20% of the consumed energy go to
support physical activity.
If one leads a more active life (cycling to work,
using stairs instead of the elevator, some sports after studying), the total
daily energy use increases to about that level that the average person used for
100-150 years ago. It is estimated that, at that time, both men and women
used about 3000 kcal/day for the usual daily chores. Note
that at this activity level physical activity still accounts for not more than
25-30% of the total energy used daily.
A heavy activity level, as judged by our modern
standards, will increase energy use to around 3500 kcalories/ day.
By the way, lumberjacks using axes and hand saws are said to have used about
5000 kcalories per day!
The drawings on the right show the result of balancing
(or not balancing) food intake with energy expenditure. Clearly, eating
more than one uses is "expansive", a balanced food and energy use
results in a stable body mass while under nutrition leads to weight
loss.
"The
Easy way and the hard way..."
Most experts believe that a sedentary or passive life
style is the best explanation for the trend to overweight. That is,
weight gain is more closely related to energy use than energy intake.
What has changed in the past decade?
A recent editorial in Mayo
Clinical Proceedings 
listed some examples of sedentary and active ways of
doing things. Many of the recent advances (read labor-saving)
in our daily environment reduce energy utilization. If you make some
assumptions you can calculate the approximate difference in total energy use
between the "easy and hard" ways of doing common tasks. This
lies somewhere around 10,000-15,000 kcal every
month or two. That is just about the equivalent of
1-1,5 kilograms of body fat. Few of us take this into account when
we plan our meals! Doing things the active way, a partial switch to a
plant-based diet with no more than 30-35 calorie-% fat and moderate daily
motion for between 30-60 minutes should help keep the fat away for many people.
We all have heard that "our western way of
life" leads to the physical downfall that we have experienced during the
past 10-20 years. The fact is that obesity is a global
phenomena linked more to physical activity than race and culture.
WHO has stated "At the other end of the
malnutrition scale, obesity is one of today’s most blatantly visible – yet most
neglected – public health problems. Paradoxically
coexisting with malnutrition, an escalating global epidemic of overweight and
obesity – “globesity” – is taking over many parts of the world. If immediate
action is not taken, millions will suffer from an array of serious health
disorders".
Let us look at rates of obesity in a global
perspective. We have most data from 
prospects facing health officials and physicians are
grim.
The situation is well-described in the following
quotations from Paul Zimmet's article entitled:
"The global
scope of diabetes and obesity -- an epidemic in progress: paradise lost"
"…
Type 2
diabetes is poised to become one of the major challenges to public
health in the 21st Century and will result in a huge economic burden,
particularly in developing nations, through premature morbidity and mortality.
…there will be
more than 230 million people with diabetes by 2010. The majority of the new
cases will be those with type 2 diabetes.
... Type
2 diabetes is the tip of the iceberg of a cluster of cardiovascular disease
(CVD) risk factors, including obesity, hypertension, and
dyslipidemia, otherwise known as the "Metabolic Syndrome," "New
World Syndrome," or "Deadly Quartet." The natural consequence will
be an epidemic of cardiovascular complications, such as coronary heart disease
and stroke as well as microvascular complications.
… Over 60% of the
adult population of the United States Australia Samoa and Nauru
… An important
and alarming feature of the diabetes epidemic is that type 2 diabetes is
increasing in these younger age groups. In
… Obesity and lack of
exercise have been implicated in this trend, that has
been labeled as "Nintendonization". Children
are often driven to and from school and then come home and race to the computer
or computer-game station instead of playing games or sports outdoors".
Paul Zimmet MD, PhD
60th Scientific Sessions of the American
Diabetes Association
Why don't we eat less?
...and a somewhat subjective answer.
The amount of food we consume each day is regulated by
what we call appetite; the desire to eat. The hypothalamus is the central
coordinator of signals relating to hunger and satiety. The genetic basis
for this very complicated process has developed over a period of millions of
years. The following figure shows actual valves for energy expenditure
for modern man (to the right) and estimated values for many of our prehistoric
ancestors. 
Rates of both basal and total metabolism are
given. Both BMR and total metabolism seem to have been more or less
constant from earliest prehistoric times to those seen in now-living
"primitive" people (groups who base their existence on hunting and
gathering). An energy expenditure of around 200 kJ/kg
per day calculates out to about 3200 kcal/day for a 70 kg person.
The only exception shown in the figure is the modern city dweller, whose energy
use lies around 2000-2200 kcal/day.
About 150 years ago most people used around 3000 kcal
per day to come through a day's chores. Work was done manually. She
washed, cleaned and raised children without a car, a washing machine, vacuum
cleaner, or a dish washer. Food was prepared from raw products on a wood
stove. He built and worked on the farm without tractors,
harvesters and chain saws or in a factory or mine with heavy manual
tasks. Modern life goes back no further than to the beginning of the 20th
century. Modern or "post-modern" styles of life have existed
for no more than 100 years for people in industrial societies and far less for
those in developing countries. The current imbalance between intake of
food and expenditure of energy may well have followed the introduction of
powered labor-saving devices during this short
period. Genetic adaptation to changes in environment
occur slowly through many generations. Stable genetic adaptation to new environments in whole populations do not
occur "overnight".
Now, the fact is that the
frequency of obesity has not increased linearly during the past century but
quite rapidly during the past decade. This is clearly shown in 
the next figure from the
Overweight is probably as large a threat to health as
hunger in today's strange world. One of my colleagues was recently in
If we go back to the actual figures from the 
these cases are type 2 diabetes.
Overweight also increases the risks for
hypertension, dyslipidemia and coronary disease, renal failure, retinopathy
etc.
Sugar and Health
According to most sources, the yearly intake of sugar
has risen from 4-5 kilogram in the 1850s to about 40-50 kilos in the
1990's. Forty kilos equal about 400 kcal/day or
around 15-20% of the energy needed to maintain normal activity. Much of
this sugar comes from soft drinks. These contain approximately 30-40
sugar bits per liter! Sugar is used as a
"spice", giving a proper taste without a thought about its energy
content.
Now, the fact is that many individuals consume much
more sugar than 
the alleged 40 kilograms yearly. That figure
often includes only "table sugar" or
sucrose. In reality, soft drinks and cakes contain a lot of monomeric
sugar (fructose and glucose) made from corn syrup. While the officially
recognized sugar consumption in the
In the
Metabolic Syndrome or
Syndrome X
The relationship between diet, metabolism and poor
health expressed by the term "metabolic syndrome" was noted
simultaneously by cardiologists and endocrinologists about 10-15 years
ago. While the numbers of CVD patients was decreasing, an increasing
percent of new cardiac patients were found to be overweight, have increased
blood sugar, dyslipidemia and hypertension. These symptoms were also
noted in the ever-increasing number of patients with diabetes type 2.
This condition was called "Syndrome X" or metabolic syndrome.
There are several definitions of this syndrome. The
ATP III (Adult Treatment Panel III; a NIH expert committee) has defined
metabolic syndrome shown in the next figure (reference values in
italics). Those filling 3 of the 5 criteria have metabolic
syndrome. These 
criteria are objective, being based solely on
observations seen in many thousand patients. Overweight is characteristic
of most of these, especially those with an accumulation of fat surrounding the
intestines (central obesity). It has been suggested that this is because
of the relatively large metabolic activity of this tissue. A more recent
suggestion is that abdominal fat produces cortisol that may influence
metabolism. A newly discovered peptide
hormone, omentin, which increases food consumption is also produced here.
Many of these individuals show high levels of serum total triglycerides and
this is often observed in overweight. High density lipoprotein levels
(HDL) are often lower than normal. Interestingly, LDL levels do not
correlate well with the pathological changes seen in metabolic syndrome.
However, a shift to large lipid-rich LDL particles is often seem.
Hypertension is common in metabolic syndrome as is hyperglycemia.
Dependent upon the level of blood glucose, these patients can be classified as
having impaired glucose tolerance (IGT) or diabetes type 2.
The scope of the metabolic syndrome problem is
enormous. Weight gain is common among older persons with a gradually
increasing BMI from 30-40 years of age. This correlates well with
development of metabolic syndrome as shown in the next figure 
from the
Weight reduction and
diabetes type 2
The importance of overweight in the development of
metabolic syndrome and 
diabetes type 2 cannot be overrated. Simply
dieting and reducing weight can be sufficient to improve a patient's
situation. This figure from Medscape/Diabetes Care shows the effect of
weight loss on the response to a 75g glucose load. After 12 weeks of
dieting, fasting glucose levels were reduced as were the plateau levels
following a glucose load. We know from this and many other studies that
the difference noted is dependent upon increased sensitivity to insulin.
In other words, weight loss often leads to decreased glucose resistance and a
normalized metabolism.
Global
perspectives of the incidence of diabetes
Predictions of the global frequency of
metabolic syndrome, insulin resistance and diabetes are frightening. The consequences
of urbanization and overweight are much more threatening that the AIDS/HIV
epidemic. One of many estimates of the spreading of this global epidemic are shown in the following figure. Most of the
increase in diabetes will be that of type 2. Overweight with associated
insulin resistance and metabolic syndrome will lead to an almost 50% increase 
in the number of individuals suffering from diabetes
within the current decade. Over 200 million persons will be
involved. Most of this expansion will occur in developing countries where
health services will be unable to cope with the coming situation. Without
indispensable guidance and treatment, these people will develop coronary
and vascular disease, chronic kidney disorders, hypertension and the many other
complications of diabetes. Predictions for the middle of the century
indicate that at least 300 million persons will develop diabetes type 2.
Genetic background is a strong component in the
development of type 2 diabetes. People of western European origin
are less sensitive to the effects of overweight than non-Europeans. In
the
This "puzzle" of sensitivity to diet and
development of type 2 diabetes was taken up in a recent article by Jared
Diamond in Nature.
A figure from this article is presented below.
Prevalence of diabetes is relatively low in Europeans and native people living
in their accustomed environment. However, native people who convert to a
western diet or urban life present a markedly
increased incidence type 2 diabetes. Genetic variation can explain
differing frequencies of diabetes development in diverse racial groups.
However, development of type 2 diabetes among urbanized groups must be a
response to the environment. Genes do not change so quickly!
One explanation for this has been the
development of a set of "thrifty genes", a genetic adaptation to a
poor milieu with a meager diet. A switch to an urban diet and
activity level is suggested to rapidly lead to obesity and associated illnesses
in such people. Please go to the original article for discussion of
this data.
An excellent review article concerning the development
and possible causes of the global diabetes epidemic can be
found here. Medscape
(May 2003) offers a CME entitled "The Obesity Epidemic: Prevention
and Treatment of the Metabolic Syndrome".
Insulin
resistance, the key to diabetes type 2
The next figure comes from a study of glucose levels
in obese and control individuals after meals. The overweight persons
depicted here were on the way towards developing glucose intolerance, but still
had control over their blood sugar levels. We can clearly see that
obesity is accompanied by insulin resistance. The obese persons produced more
insulin after meals than controls to counteract this. In this way they
can counteract their insulin resistance and regulate glucose uptake and hepatic
glucose production.
I have previously explained that diabetes type 2
develops in response to a loss of reactivity to insulin at
target organs. To counter
this, the pancreatic ß-cells produce more insulin to counter the decreased
target organ sensitivity. Initially, metabolic control will be normalized
through this mechanism. However, with time, the individual will develop
impaired glucose tolerance and diabetes type 2.
We can identify two processes in which insulin
resistance is involved in the next figure. The panel on the left shows
that glucose disposal (glucose taken up from the blood) is reduced in type 2
diabetes. This indicates that muscle and adipose tissue take up less
glucose in these patients than control persons, leading to hyperglycemia
after meal
Another central function of insulin is inhibition of
hepatic gluconeogenesis. Remember that it is the balance between glucagon
and catecholamines on one side, and insulin the other that directs hepatic
gluconeogenesis and release. Glucagon and the catecholamines stimulate glucose
production and glycogenolysis when blood glucose levels fall: insulin
inhibits gluconeogenesis when there are adequate levels of glucose in the
blood. In the right-hand panel we can see that hepatic glucose
production is less sensitive to insulin in diabetes type 2. In spite of
high blood sugar levels, the liver produces glucose and releases it to the
circulation. People suffering from diabetes synthesize glucose in spite
of the fact that blood glucose levels are elevated! Therefore, treatment with
a glucose synthesis inhibitor, metformin, is often started in addition to
adjusting to a new life style.
How does
insulin resistance develop?
The key to this problem seems to lie in the
interaction between adipose tissue and skeletal muscle. In
"the old days", we looked on fat as a relatively inactive, not
especially attractive part of our bodies. We now know that adipose tissue
is metabolically quite active and is one of the body's most important 
endocrine organs. No less than 14 peptide hormones
have been found in adipose tissue. In the past few years three of these,
leptin, adiponectin and resistin have received most attention.
Leptin seems to have many
actions; it is involved in thermoregulation, bone metabolism, fatigue and
especially appetite regulation together with insulin and blood sugar. Current opinion (spring 2004) seems to be that
leptin is a signal of reduced energy and stimulates hunger as a result of
reduced release from adipocytes. Release of leptin appears to be
triggered by the rise in insulin levels seen after a meal. Together,
insulin and leptin act centrally to reduce hunger.
Resistin has been implicated in regulation of insulin
sensitivity (and insulin resistance) in muscle and adipose tissue.
Adiponectin is also possibly involved in regulation of target-cell's
sensitivity to insulin.
One can conclude that adipose tissue is actively
involved in regulation of energy homeostasis through two major functions:
1. As a storage tissue for excess nutrients and as a
source of energy reserves to all of the body's organs
(remember ketogenesis and the brain).
2. As an endocrine organ
involved in regulation of appetite and insulin sensitivity.
The first world congress on insulin resistance was held in
Central Control of Appetite
Those of us who studied medical biochemistry a few
decades ago learned that appetite was controlled centrally through
glucose-sensitive cells in the brain or hypothalamus. Indeed, this is
still a "fact". However, we now know that many other factors
are involved. Initially, insulin and recently leptin were seem as the major elements controlling appetite. The
levels of these are affected by the food we eat, our activity level and our fat
stores. Central control of appetite is discussed in detail in a review
article in Nature 404, 661-671, 2000. Click here if you have a
subscription to this journal. The next figure, taken from this article, shows the roles of
insulin and leptin in this system. I have earlier emphasized
the balance between food consumption and physical
activity. These factors define "energy balance". While we
really are not aware of regulation of appetite, most people managed to hold
this balance and a more or less constant body weight before all of our "labor-saving" devices became common. This
implies that a very well regulated system must exist. The combined
effects of insulin and leptin in the central nervous system appear to fine-tune
our urge to eat, leading to a decreased food intake at weight gain and
increased appetite following physical activity or weight loss.
Please go to the original article if you wish follow this further.
More recently, several additional peptide hormones
that couple the digestive system to appetite regulation have been
identified. These are ghrelin, released from the stomach and the
intestinal hormone PYY3-36. These hormones interact with insulin
and leptin sensitive neural cells in the brain. These produce an effect
through interaction with hypothalamic neurons producing neuropeptide Y (NPY)
and the Agouti-related protein (AgRP) (the GO system) or by activating the
melanocortin system: (the STOP system). The balance between "stop
and go" signals effects neurons that regulate the sense of hunger and
appetite. Insulin and leptin are thought to regulate long-term effects
and body weight, while the 
hormones derived from the digestive system appear to
regulate meal-eating on a short-term basis.
Please go to the original publication for more
details: Nature 418, 595 - 597 (2002).
For a recent (2005) and very up-to date review article
see Plum, Schubert and Brüning’s paper in TRENDS in
Endocrinology and Metabolism. At the
present time this not yet published but can be called up by
clicking here.