Pathophysiology of Adipose Tissues: Obesity and Insulin Resistance

Lipid storage in adipose tissue represents excess energy consumption relative to
energy expenditure, which in its pathological form has been coined ‘obesity’. In recent
years, overnutrition has reached epidemic proportions in developed as well as developing countries. This reflects recent lifestyle changes, however there is also a strong genetic component as well. While the biochemical mechanism(s) for this genetic predisposition are still under investigation, the genes that control appetite and regulate energy homeostasis are now better known. For example, adipocytes produce leptin (see above) that suppresses appetite and was initially considered a promising target for drug therapy. However, most overweight individuals overproduce leptin, and no more than 2–4% of the overweight population has defects in the leptin appetite

suppression pathway [14]. In contrast, genetic predisposition to obesity and/or T2D
when excess calories are consumed is common in the population: for instance, polymorphisms in the peroxisome proliferator-activated receptor-2 (PPAR-2) gene may have a broad impact on the risk of obesity and insulin resistance. A minority of people is heterozygous for the Pro12Ala variant of PPAR- and is less likely to become overweight and less likely to develop DM when overweight than the majority of Pro homozygotes in the population [15].

One striking clinical feature of overweight individuals is a marked elevation of
serum NEFAs, cholesterol, and triacylglycerols irrespective of the dietary intake of
fat. Obesity is obviously associated with an increased number and/or size of adipose
tissue cells. These cells overproduce hormones, such as leptin, and cytokines, such as TNF-, some of which appear to cause cellular resistance to insulin [16]. At the same time, the lipid-laden adipocytes decrease synthesis of hormones, such as adiponectin,which appear to enhance insulin responsiveness. The insulin resistance in adipose tissue results in increased activity of the hormone-sensitive lipase, which is probably sufficient to explain the increase in circulating NEFAs [17]. The high circulating levels of NEFAs may also contribute to insulin resistance in the muscle and liver (see below). Initially, the pancreas maintains glycemic control by overproducing insulin. Thus, many obese individuals with apparently normal blood glucose control have a syndrome characterized by insulin resistance of the peripheral tissue and high concentrations of insulin in the circulation. This hyperinsulinemia appears to stimulate the sympathetic nervous system, leading to sodium and water retention and vasoconstriction, which increase blood pressure [18]. The excess NEFAs are carried to the liver and converted to triacylglycerol and cholesterol. Excess triacylglycerol and cholesterol are released as very-low-density lipoprotein particles, leading to higher circulating levels of both triacylglycerol and cholesterol. Eventually, the capacity of the pancreas to overproduce insulin declines which leads to higher fasting blood sugar levels and decreased glucose tolerance (see below).

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The Insulin Receptor: Transduction through Tyrosine Kinase

An understanding of insulin resistance requires knowledge of the mechanisms of
insulin action in target tissues, such as liver, muscle and adipose tissue. The net
responses to this hormone include short-term metabolic effects, such as a rapid
increase in the uptake of glucose, and longer-term effects on cellular differentiation and growth [12]. The -subunits of the insulin receptor are located extracellularly and are the insulin-binding sites. Ligand binding promotes autophosphorylation of multiple tyrosine residues located in the cytoplasmic portions of -subunits. This autophosphorylation facilitates binding of cytosolic substrate proteins, such as IRS-1. When phosphorylated, this substrate acts as a docking protein for proteins mediating insulin action. Although the insulin receptor becomes autophosphorylated on tyrosines and phosphorylates tyrosines of IRS-1, other mediators are phosphorylated predominantly on serine and threonine residues. An insulin second messenger, possibly a glycoinositol derivative that stimulates phosphoprotein phosphatases, may be released at the cell membrane to account for the short-term metabolic effects of insulin. The activated -subunit also catalyzes the phosphorylation of other members of the IRS family, such as Shc and Cbl. Upon tyrosine phosphorylation, these proteins interact with other signaling molecules (such as p85, and Grb2-Sos and SHP-2) through their SH2 (Src-homolog-2) domains, which bind to a distinct sequence of amino acids surrounding a phosphotyrosine residue. Several diverse pathways are activated, and those include activation of phosphatidylinositol 3-OH kinase (PI3K), the small GTP-binding protein Ras, the mitogen-activated protein (MAP) kinase cascade, and the small GTP-binding protein TC10. Formation of the IRS-1/p85 complex activates PI3 kinase (class 1A), which transmits the major metabolic actions of insulin via downstream effectors such as phosphoinositide-dependent kinase 1 (PDK1), Akt and mTOR. The IRS-l/Grb2-Sos complex and SHP-2 transmit mitogenic signals through the activation of Ras to activate MAP kinase. Once activated via an exchange of GTP for GDP, TC10 promotes translocation of GLUT4 vesicles to the plasma membrane of muscle and fat cells, perhaps by stabilizing cortical actin filaments.

These pathways coordinate the regulation of vesicle trafficking (incorporation
of GLUT4 into the plasma membrane), protein synthesis, enzyme activation and
inactivation, and gene expression [for further details, see 12, 13]. The net result of these diverse pathways is regulation of glucose, lipid, and protein metabolism as well as cell growth and differentiation.

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Pathophysiology of Diabetes Mellitus Type 2: Roles of Obesity, Insulin Resistance and -Cell Dysfunction

Physiology of Adipose Tissues

Adipose tissues are located throughout the body. Some of these depots are structural,
providing mechanical support but contributing little to energy homeostasis. Other
adipocytes exist in the skin as subcutaneous fat. Finally, several distinct depots are found within the body cavity, surrounding the heart and other organs, associated
with the intestinal mesentery, and in the retroperitoneum. This visceral fat drains
directly into the portal circulation and has been linked to morbidities, such as cardiovascular disease and T2D. Adipose tissues modulate energy balance by regulating
both food intake and energy expenditure. They a lso have a considerable effect on
glucose balance, which is mediated by endocrine (mainly through the synthesis
and release of peptide hormones, the so-called ‘adipokines’) and non-endocrine
mechanisms.

Among the endocrine factors, adipocyte-derived proteins with antidiabetic action
include leptin, adiponectin, omentin and visfatin. For instance, in addition to its wellcharacterized role in energy balance, leptin reverses hyperglycemia by improving
insulin sensitivity in muscles and the liver. According to the current view that intracellular lipids may contribute to insulin resistance, this occurs most likely by reducing intracellular lipid levels through a combination of direct activation of AMP-activated protein kinase (AMPK) and indirect actions mediated through central neural pathways [2]. Other factors tend to raise blood glucose, including resistin, tumor necrosis factor- (TNF-), interleukin-6 (IL-6) and retinol-binding protein 4 (RBP4). TNF- is produced in macrophages and reduces insulin action [3]. IL-6 is produced by adipocytes, and has insulin-resistance-promoting effects as well [4]. Such ‘adipocytokines’ can induce insulin resistance through several mechanisms, including c-Jun N-terminal kinase 1 (JNK1)-mediated serine phosphorylation of insulin receptor substrate-1 (IRS-1) (see below), IB kinase- (IKK-)-mediated nuclear factor-B (NF-B) activation, induction of suppressor of cytokine signaling 3 (SOCS3) and production of ROS [for review, see 5]. RBP4, a secreted member of the lipocalin superfamily, is regulated by the changes in adipocyte glucose transporter 4 (GLUT4) levels. Studies have shown that overexpression of RBP4 impairs hepatic and muscle insulin action, and Rbp4/mice show enhanced insulin sensitivity [6]. Furthermore,
high serum RBP4 levels are associated with insulin resistance in obese humans and
patients with T2D [7]. The exact mechanisms how RBP4 impairs insulin action are,
however, not clear. Adipocytes also release non-esterified fatty acids (NEFAs) into the circulation, which may therefore be viewed as an adipocyte-derived secreted non-endocrine product. They are primarily released during fasting, i.e. when glucose is limiting, as a nutrient source for most organs. Circulating NEFAs reduce adipocyte and muscle glucose uptake, and also promote hepatic glucose output, consistent with insulin resistance. The net effect of these actions is to promote lipid burning as a fuel source in most tissues, while sparing carbohydrate for neurons and red blood cells, which depend on glucose as an energy source. Several mechanisms have been proposed to account for the effects of NEFAs on muscle, liver and adipose tissue, including protein kinase C (PKC) activation, oxidative stress, ceramide formation, and activation of Toll-like receptor 4 [for review, see 5, 8]. Because lipolysis in adipocytes is repressed by insulin, insulin resistance from any cause can lead to NEFA elevation, which, in turn, induces additional insulin resistance as part of a vicious cycle.
-Cells are also affected by NEFAs, depending in part on the duration of exposure; acutely, NEFAs induce insulin secretion (as after a meal), whereas chronic exposure to NEFAs causes a decrease in insulin secretion [9] (see below), which may involve lipotoxicityinduced apoptosis of islet cells [10] and/or induction of uncoupling protein-2 (UCP- 2), which decreases mitochondrial membrane potential, ATP synthesis and insulin secretion [10, 11]. The ability to store large amounts of esterified lipid in a manner
that is not toxic to the cell or the organism as a whole may therefore be one of the
most critical physiological functions of adipocytes.

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Handling the Physical and Emotional

Consequences of Type 1 Diabetes

What makes diabetes a difficult disease are the physical complications associated with poor control of the blood glucose. These complications are generallydivided into short-term complications and long-term complications.

• Short-term complications, which I cover in Chapter 4, are the result of a blood glucose that’s either very low or very high. Low blood glucose(called hypoglycemia) can occur in minutes as a result of too much insulin,too much exercise, or too little food, but high blood glucose often takes several hours to develop. Whereas low blood glucose often can be managed at home, severe high blood glucose (called diabetic ketoacidosis) is an emergency that’s managed by a doctor in the hospital. Nevertheless,it’s important that you understand how it develops in order to prevent it.Chapter 4 describes the signs and symptoms associated with both ofthese complications and the best ways of handling them.

• Long-term complications,which I cover in Chapter 5, can be devastating. It’s much better to prevent them with very careful diabetes management than to try to treat them after they develop. Fortunately, they take 15 or more years to fully develop, and there’s time to slow them down if not reverse them if you’re aware of them. All long-term complications can be detected in the very earliest stages.The long-term complications consist of eye disease known as retinopathy,kidney disease known as nephropathy, and nerve disease known as neuropathy. Diabetes is the leading cause of new cases of blindness; new cases of kidney failure requiring dialysis, which cleanses the blood of toxins when the kidneys can no longer do their job; and loss of sensation in the feet as well as other consequences of nerve damage

Not only does T1DM have short- and long-term physical consequences, but
as an autoimmune disease, T1DM also is associated with other autoimmune
diseases such as celiac disease, an inflammation of the gastrointestinal tract;
thyroid disease; and skin diseases. Chapter 5 explains the importance of
checking for those diseases and correcting them, if present.

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Understanding What Type

1 Diabetes Is (and Isn’t)
T1DM, simply stated, is an autoimmune disease. Immunity is what protects you from foreign invaders like bacteria and viruses. In autoimmunity, your body mistakenly acts against your own tissues. In T1DM, the immune cells and proteins react against the cells that make insulin, destroying them. (Insulin is the chemical or hormone that controls the blood glucose; glucose is sugar that provides instant energy.)

Although it often begins dramatically, T1DM doesn’t occur overnight. Many patients give a history of several months of increasing thirst and urination,among other symptoms. Also, T1DM usually begins in childhood, but some folks don’t develop it until they’re adults. In either case, to verify a diagnosis of T1DM, a sample of blood is taken and its glucose level is measured. If the patient is fasting, the level should be no more than 125 mg/dl; if there’s no fast, the level should be no more than 199 mg/dl. For further confirmation,tests should be done at two different times to check for inconsistencies.However, a person with a blood glucose of 300 to 500 mg/dl who has an acetone smell on his breath clearly has T1DM until proven otherwise.

So how is type 1 diabetes different from type 2 diabetes (T2DM)? The central problem in T2DM isn’t a lack of insulin but insulin resistance; in other words,the body resists the normal, healthy functioning of insulin. Before the development of T2DM, when a person’s blood glucose is still normal, the level of insulin is abnormally high because the person is resistant to the insulin and therefore more is needed to keep the glucose normal.To complicate matters, a type of diabetes called Latent Autoimmune Diabetes in Adults (LADA) is a cross between T1DM and T2DM; a person with LADAexhibits traits of both diseases. Chapter 2 details the basics of T1DM, including how insulin works, what goes wrong when blood glucose levels are too high, the specific symptoms to watch
for, and gathering a team of doctors and other specialists after a diagnosis.Chapter 3 fully explains how T2DM and LADA are different from T1DM.

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Dealing with Type 1 Diabetes

1. Discovering what type 1 diabetes is
2. Dealing with physical and emotional effects
3. Treating type 1 diabetes
4. Living life to the fullest with type 1 diabetes


In 2005, the most recent year for which there are statistics, there were 340,000 people in the United States with type 1 diabetes (T1DM) according to the Centers for Disease Control. About half were children up to age 20.There are 30,000 new cases every year, almost all in children.Whether you’re an older child or young adult able to take care of your owndiabetes, or a parent or other caregiver for a young child with this disease,
you should be aware that there’s a great deal that you can do to minimizeboth the short- and long-term complications that may develop and live a longand healthy life with T1DM.What! You don’t believe me! Consider the story of two brothers, Robert and
Gerald. Robert is 85 years old and developed T1DM at age 5. Gerald is 90 and developed T1DM at age 16. The physician who follows them, Dr. George L. King,research director of the Joslin Diabetes Center in Boston, studies patients withT1DM who have lived more than 50 years with the disease. He has more than400 such patients. Dr. King says that these patients have a lot in common.
They Keep extensive records of their blood sugars, their diet, their exercise,
their insulin dosage, and their daily food consumption
• Do a lot of exercise
• Eat very carefully
• Have a very positive outlook

These actions form the basis of effective T1DM treatment, which I introduce in this chapter. I also give you an overview of the potential consequences of T1DM and tips for living well with it.At the present time, there’s no way to prevent T1DM, but I believe a change isn’t far off and T1DM may be preventable in perhaps in the next five years.The breakthrough will come with the use of stem cells, transplantation, or the elimination of the cause of T1DM. You can read much more about this

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