extracted from Adiposity 101
INSULIN has been called "the fattening hormone". Insulin promotes
differentiation of white fat cells, fat deposition, lipoprotein lipase (LPL),
inhibits growth hormone release, and inhibits the fat-releasing action of
catecholamines. Insulin inhibits the hormone-sensitive lipase that
releases stored fat from adipose tissue [fat]. In normal individuals, insulin
primarily increases glucose uptake by muscle tissue and lowers glucose
production by the liver.
In
Syndrome X, the liver and muscles are resistant to insulin,
forcing the production of more insulin to control blood glucose. This causes
hyperinsulinaemia (too much insulin), shunting dietary energy to fat stores. A
high level of insulin precedes obesity and hypertension in
Syndrome X. Tight control in Type I diabetics increases average insulin
concentration and causes weight gain. Since obesity is associated with
resistance to insulin action, a vicious cycle of insulin->weight gain->more
insulin is possible. High insulin levels appear to be a factor in
development of high blood pressure, abnormal lipid levels and
atherosclerosis. It is known that insulin induces the growth of
human vascular smooth muscle [thickening of the arteries and blood vessels]
and stimulates the proto-oncogene c-myc through the IGF-I receptor. Low
levels of insulin caused by untreated type I diabetes [childhood onset] can lead
to lipoatrophy (loss of fat tissue). Dietary carbohydrate, but not fat or
protein, increases plasma insulin levels.
Syndrome X" or "insulin resistance syndrome" is defined as: Resistance to
insulin-mediated glucose uptake.
1. glucose intolerance
2. hyperinsulinemia
[too much insulin in the blood]
3. increased very low
density triglycerides (VLDL) [BAD cholesterol]
4. decreased
high-density lipoprotein cholesterol (HDL) [good cholesterol]
5. hypertension [high
blood pressure]
6. Elevated systolic BP
during submaximal exercise [high blood pressure during mild exercise]
7. increased fat mass
[obesity]
The inherited defect is insulin resistance in skeletal muscles, the other abnormalities are consequences. (American J of Obstet Gynecol July 1990 292-5) Since the differences in insulin resistance between Pima Indians and Caucasians remains even after matching for obesity, the increased insulin resistance could not be blamed on their obesity. (Progress in Obesity Research 1990: 361) In genetically prone individuals, insulin resistance is the earliest detectable defect. This defect may occur 15-25 years before the clinical onset of the disease.
A study by teams in
Australia and the United States confirms a genetic defect in certain populations
with a high risk of developing obesity-linked disease such as diabetes. The
research defined the defect in a critical metabolic step in the body's
capacity to metabolise sugar. "...this discovery is classed as a major
breakthrough in that it has identified a genetic tendency which causes the
disorder." Professor Paul Zimmet, director of the International Diabetes
Institute (Reuters, July 2 1992).
Some types of Type II
diabetes in human were linked to gene locations in 1992.
A connection between a
gene and one type of diabetes with implications for hundreds of thousands of
Americans was reported in February, 1993. "This is the first clear definition of
a genetic cause of Type II diabetes," said Dr. Simon Pilkis, chairman of the
Department of Physiology and Biophysics at the Stony Brook Health Sciences
Center in New York. "Moreover, it may be one of the largest single-gene
disorders described to date." "Tools are now available to screen for gene
mutations, and it is only a matter of time before other genes implicated in Type
II diabetes are identified," Pilkis said. "We will be able to screen different
diabetic populations or the general population for these mutations, which will
tell us whether someone has a predisposition to diabetes and what category they
fall into." (UPI 02/28/1993)
Miller and
Colagiuri have pointed out that humans were primarily flesh-eating hunters
consuming a low carbohydrate high protein diet until recently.
Insulin resistance offered a survival and reproductive advantage during the
Ice Ages which dominated the last two million years of human evolution. The
introduction of agriculture and subsequent food processing have raised the
quantity and quality of dietary carbohydrates, reversing the dietary evolution
of the last two million years, causing the recent epidemic of NIDDM [Non Insulin
Dependent Diabetes]. This is the only theory that explains why the prevalence of
NIDDM is lower in European and Middle Eastern populations, which developed
agriculture thousands of years ahead of the rest of the world. [Actually,
it's because they still eat more animal fats than Americans-LP] (Diabetologia
(1994) 37;1280-6)
Research has been
accumulating on the fattening effect of high levels of
insulin during gestation and
infancy. High insulin levels are sometimes caused by excessive serum glucose in
the mother's blood and leakage of insulin-antibody pairs across the placenta.
Obese individuals almost always exhibit high insulin levels.
Hyperinsulinaemia
itself could be one of the driving forces responsible for producing increased
glucose utilization by white adipose tissue [insulin is consumed by the fat
cells. Each molecule of insulin, with its load of triglyeride, is consumed,
which is why the pancreas has to continually secrete more and more],
increased total lipid synthesis with fat accumulation in adipose tissue and the
liver, together with an insulin-resistant state in the muscles. (Biochemical
Journal 1990 267:99-103)
A decrease in
glucose induced thermogenesis [body heat and warming] already exists at the
onset of obesity. (Am J Clin Nutr 1993;57:851-6)
One or two
decades before type II diabetes is diagnosed, reduced glucose clearance (insulin
resistance) is already present. This reduced clearance is accompanied by
compensatory hyperinsulinemia, suggesting that the
primary defect is in
peripheral tissue response to
insulin
and glucose, not defective pancreatic beta cells.
(Annals of Internal Medicine 1990 113:909-915)
Slow glucose
removal rate and hyperinsulinemia precede the development of Type II diabetes in
the offspring of diabetic parents. (Annals of
Internal Medicine 1990:113;909-15)
Insulin-mediated glucose
disposal is reduced in otherwise healthy, lean normotensive subjects.
Insulin resistance is present in these hypertension-prone individuals
before the development of hypertension. (Hypertension 1993:21; 273-9)
"...impairment of
insulin sensitivity precedes both the development of overt hypertension
and gain or redistribution of body fat.
Therefore the concept that insulin sensitivity is low as a result of altered fat
distribution has to be reconsidered" (Lancet 1993; 341: 327-31)
"...our data
strongly support suggestion that hyperinsulinemia [too much insulin in
the blood] could be a common link between cardiological
Syndrome X and recently
postulated metabolic Syndrome X with the same characteristic finding -
insulin resistance."
(Kendereski et al, U of
Beograd, Beograd, Yugoslavia, Abstracts, IJO 1993)
Increased lipid oxidation
is one of the earlier dysfunctions observed in recent-onset obesity;
lipid
oxidation may induce a decrease of glucose oxidation, insulin resistance, and
increased fasting
insulin
secretion. (DIABETES 1993:42 1010-16)
This increased lipid oxidation
may explain the higher percentage of energy from dietary fat sometimes reported
in fatter children.
Muscle fiber composition
changed with hyperinsulinemia, with more fast-twitch fibers and fewer
slow-twitch fibers. (DIABETES 1993:42 1073-81)
Hyperinsulinemia imposed
on normal rats increased in vivo glucose utilization, lipogenesis and the fat
accumulation in white adipose tissue, while producing an insulin resistant
glucose transport in muscles. (Endocrinology 1990:127;6 3246-8)
A large portion of middle
aged and elderly people in Western countries suffer from a combination of
metabolic disorders and cardiovascular risk factors. This combination includes
hyperinsulinemia (elevated insulin levels), insulin resistance
(reduced sensitivity to insulin), hyperlipidemia (elevated lipid levels),
obesity, and hypertension. This combination is sometimes termed "Syndrome
X" or "insulin resistance syndrome." Amlyin Pharmaceuticals scientists
and others have observed that most subjects with hyperinsulinemia also have
elevated amylin levels, or hyperamylinemia. The finding that amylin can
stimulate renin [enzyme associated with hypertension] secretion is consistent
with the idea that amylin may be a missing link between hypertension and the
other metabolic disorders. (Amlyin Pharmaceuticals press release)
Insulin resistance and
NIDDM are accompanied by a progressive deterioration of the microcirculation
in many tissues, including the skeletal muscles that provide most of the body's
insulin mediated glucose disposal. Vascular and circulatory changes causing
a decline in muscle blood flow may be the cause of the metabolic disorder [as
well as loss of warmth in extremities and skin].
(Diabetologia 1993;36:876-9)
PROINSULIN is one of many metabolically defective insulin-like substances produced by the pancreas in addition to insulin. The ability to distinguish insulin from the other substances is new and not widespread. Some now think most Type II diabetics are in fact insulin deficient because much of their "insulin" is actually proinsulin. (The Lancet, Feb 11 1989, 293--5) Several lines of evidence suggest proinsulin is not merely a weak insulin, but a unique hormone of its own with specific target receptors, functions, and diseases. Proinsulin preferentially binds at proliferative target cells (lymphocytes, arterial smooth muscle cells, small gut crypt cells). It is thought to be an important cardiovascular risk factor. Predominately released already in small-for-date babies, aging, obesity, and type II diabetes, it may be an early marker if not pathogenic principle of Syndrome X (q.v.). Proinsulin is a potent risk factor in obesity. (5th European Congress on Obesity 10-12 June 1992)