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The Pathophysiology of Type 2 Diabetes             


Pathophysiology and Pathogenesis of Type 2 Diabetes

Type 2 diabetes is the most common form of diabetes, with more than 90% of diabetics being Type 2, and 5%-10% being Type 1.

Type 2 diabetes mellitus is a heterogeneous disorder with varying prevalence among different ethnic groups. In the United States the populations most affected are Native Americans, particularly in the desert Southwest, Hispanic-Americans, African-Americans, and Asian-Americans. However, Caucasian-Americans are also affected, but not at the same disproportionate percentage levels.Understanding Type 2 Diabetes = Reversing Type 2 Diabetes

The pathophysiology of Type 2 diabetes mellitus is characterized by peripheral insulin resistance (insulin insensitivity), cell damage, impaired regulation of hepatic glucose production, and later on: declining beta (ß) cell function, eventually leading to  possible ß-cell failure.
 
The primary events are believed to be an initial insensitivity of insulin resulting in peripheral insulin resistance; and, later on, relative insulin deficiency.

The key message here is that the key cellular dysfunction that occurs in Type 2 diabetes is not due to the ß cells (as in Type 1 diabetes) -- it's the muscle, liver, and fat cells, and also the damage to the red blood cells (due to glycation)!

Author's Note: During my medical workshops with doctors, nurses, and other healthcare professionals, they were shocked to discover that ß cell dysfunction is NOT the primary issue with Type 2 diabetics -- especially when I show them the data from thousands of Type 2 diabetics. In fact, I was one of those Type 2 diabetics who was put on a drug protocol of 4 insulin shots a day because the doctors believed I was either a Type 1 diabetic, or a Type 2 diabetic with ß cell dysfunction.

But, because of my biochemistry background I knew enough to ask for specific blood/urine/hormone tests that verified that I wasn't Type 1 and didn't have beta cell dysfunction, i.e. insulin serum test, c-peptide, urine ketone test, hemoglobin A1C, glutamic acid decarboxylase (GAD) antibody tests, islet cell antibody (ICA) tests, insulin antibody tests, GTT. Unfortunately, most Type 2 diabetics don't know this, and are led to take diabetic drugs that don't really help in the long run. If I had not recognized this discrepancy I would still be diabetic today and I would be taking even more insulin.

Overview: Diabetes at the Cellular Level
The key cells that are affected when Type 2 diabetes initially develops (due to hyperinsulinemia) include the glycated red blood cells, and the muscle, fat, and liver cells, which are designed to take glucose (sugar) out of the blood, pull it into the cells and change it into energy.

These cells require insulin to absorb glucose. When these cells fail to respond adequately to circulating insulin, these cells lose their sensitivity to insulin (a condition known as insulin resistance) and blood glucose levels rise.

The body responds to this situation by signaling the pancreas to produce more insulin, causing insulin levels in the blood to become too high. This condition is known as hyperinsulinemia. The cells in the liver also become insulin resistant and respond by making too much blood sugar. Because blood sugar is not absorbed by the cells, it stays in the blood, causing blood sugar levels to rise — a condition known as hyperglycemia.

Red blood cells are damaged due to the high glucose levels, as sugar molecules are appended to the exterior part of the red blood cells, forming a crystalline (coarse) crust -- this is known as glycation (which creates AGEs). These coarse red blood cells cause damage throughout the circulatory system, damaging arteries and capillaries. This damage is repaired by the cholesterol produced by the liver, leading to arterial plaque formation -- all triggered by an inflammatory response. These coarse red blood cells cause greater damage in dense capillary areas such as the hands and feet, and fragile capillaries such as those that feed the kidneys and eyes.

All of this leads to diabetic complications that can lead to blindness, kidney failure, amputation, heart attack and stroke. Other health issues include high blood pressure, high cholesterol, high inflammation markers, periodontal disease, and erectile dysfunction.

Key Point!: Given the cellular dysfunction of the muscle cells, fat cells, and the liver cells, once can see that diabetic drugs are not going to help defeat or reverse your diabetes! Why? Because the majority of diabetic drugs are designed either to make the pancreas secrete more insulin or prevent the liver from releasing stored glycogen. The drugs do nothing to address the insulin resistance of the muscle and fat cells, or the inflammatory damage caused by the coarse (glycated) red blood cells.

You don't have to be a scientist to figure out that you need to reduce the insulin resistance (by increasing the insulin sensitivity of the cells) and reduce the cellular inflammation -- by reducing blood glucose levels and insulin levels.
 
Insulin Resistance
The presence of hyperinsulinism in type 2 diabetes, insulin resistance has been considered to play an integral role in the pathogenesis of the disease.

As chronic hyperinsulinemia inhibits both insulin secretion and action, and hyperglycemia can impair both the insulin secretory response to glucose as well as cellular insulin sensitivity, the precise relation between glucose and insulin level as a surrogate measure of insulin resistance has been questioned.

Lean type 2 diabetic patients over 65 years of age have been found to be as insulin sensitive as their age-matched non-diabetic controls. Moreover, in the majority of type 2 diabetic patients who are insulin resistant, obesity is almost invariably present. As obesity or an increase in intra-abdominal adiposetissue is associated with insulin resistance in the absence of diabetes, it is believed by some that insulin resistance in type 2 diabetes is entirely due to the coexistence of increased adiposity.

Additionally, insulin resistance is found in hypertension, hyperlipidemia, and ischemic heart disease, entities commonly found in association with diabetes, again raising the question as to whether insulin resistance results from different pathogenetic disease processes or is unique to the presence of type 2 diabetes.

Prospective studies have demonstrated the presence of either insulin deficiency or insulin resistance before the onset of type 2 diabetes.

Two studies have reported the presence of insulin resistance in non-diabetic relatives of diabetic patients at a time when their glucose tolerance was still normal.

In addition, first degree relatives of patients with type 2 diabetes have been found to have impaired insulin action upon skeletal muscle glycogen synthesis due to both decreased stimulation of tyrosine kinase activity of the insulin receptor and reduced glycogen synthase activity.

Other studies in this high risk group have failed to demonstrate insulin resistance, and in the same group, impaired early phase insulin release and loss of normal oscillatory pattern of insulin release have been described.

Based upon these divergent studies, it is still impossible to dissociate insulin resistance from insulin deficiency in the pathogenesis of type 2 diabetes. However,both entities unequivocally contribute to the fully established disease.

Cortisol
Insulin resistance creates high levels of insulin which then signal the release of cortisol (from the adrenal glands).  Cortisol is responsible for releasing fatty acids into the blood stream.  These fatty acids are very high energy fats or lipids. 
 
These systematic responses are normal in situations of high stress, such as running from a bear in the woods or fighting a tiger.  What would naturally follow is the lowering of these hormones back down to a stable state.   But, because we are leading stressful lives through worries and fears with very little physical activity and very poor eating habits, this leads to sustained high levels of cortisol, blood sugar and insulin. 
 
Excessive levels of cortisol leads to excessive levels of fatty acids in our blood stream.  Oxidation of fatty acids is a natural part of the bodies immune response, but when we have excessive amounts, we cause an over reaction of our immune response, and attack our own tissues.  This causes an inflammatory state in our bodies. 
 
These excessive fatty acids oxidize and lead to a build up of fatty tissue. This build up leads to plaque and “fatty streaks” as well as calcification. This is why cardiovascular disease and hardening of the arteries is a major result of this metabolic syndrome.  Consequently, when the cell isn’t converting blood sugar for energy, it’s converted to fat for storage.  Fat cells are responsible for hormone synthesis and storage of toxins.  Our environment is full of toxins from chemicals, detergents, pollution, drugs, food additives, pesticides, etc.  When our fat cells get too big, they leak these toxins back into the blood stream.  These toxins also inhibit the insulin function of the cells and stimulate inflammation.
 
Belly fat is also a predictor of insulin resistance.  Belly fat, also known as visceral fat, has the highest amount of cortisol receptors.  Visceral fat is found around the organs.  This fat is a power house for immune function.  This high immune type of tissue is critical for keeping viruses, bacteria and other foreign bodies out of our vital organs. High levels of cortisol from insulin resistance creates a high level of fatty acid release around these organs.  Subsequently, more oxidation occurs and this causes a large immune response, sending out white blood cells to destroy the invaders.  This causes the body to be in a constant state of inflammation which can lead to the attack of all types of tissues in the body. 

The Liver 
The ability of insulin to suppress hepatic glucose production both in the fasting state and postprandially is normal in first degree relatives of type 2 diabetic patients . It is the increase in the rate of postprandial glucose production that heralds the evolution of IGT. Eventually, both fasting and postprandial glucose production increase as type 2 diabetes progresses.
 
Hepatic insulin resistance is characterized by a marked decrease in glucokinase activity and a catalytic increased conversion of substrates to glucose despite the presence of insulin. Thus, the liver in type 2 diabetes is programmed to both overproduce and under-use glucose. The elevated free fatty acid levels found in type 2 diabetes may also play a role in increased hepatic glucose production. In addition, recent evidence suggests an important role for the kidney in glucose production via gluconeogenesis, which is unrestrained in the presence of type 2 diabetes.

Inflammation
Blood sugar control is important because the body is normally destroyed by increased levels of sugar in the blood which results in inflammation. The following text explains why inflammation is caused by increased levels of sugar in the body.

An increase in levels of sugar in the blood results in the creation of a bond between the sugar and the red blood cells. Normally this sugar appends itself to the hemoglobin molecule contained in the red blood cells. The amount of sugar appended to the hemoglobin molecule decreases if the levels of sugar in your blood are controlled; otherwise the amount of sugar appended to the hemoglobin molecule increases [Ref: Hemoglobin A1C test].

Sugar appended to the exterior part of the red blood can be compared to the way sand attaches itself to a moist object. A crystalline crust which is very coarse is created. Try to envision that there are millions of very coarse red blood cells in your body and the harm that would happen to your circulatory system. Arteries that are destroyed are sealed off by cholesterol and this can result in strokes and heart attacks in people suffering from Type 2 diabetes.

Fragile capillary beds can also be damaged by these coarse red blood cells. Capillaries are the minute blood vessels in our bodies. that feed our kidneys, eyes, and feet Patients with poor blood sugar control can experience greater damage in dense capillary areas such as the hands and feet. Poor flow of blood caused by damaged capillary beds can result in infections and more serious problems such as amputations in people with Type 2 diabetes.

These coarse red blood cells can also cause damage to the delicate capillaries that feed the retina and the kidneys. This damage can lead to  cataracts, blindness, and kidney failure (kidney dialysis).

If you imagine what your body will go through due to the inflammation and damage caused by these coarse red blood cells, you will be able to understand why diabetic patients experience so many terminal problems.

Good blood sugar control is very important since our bodies cannot stand that kind of mistreatment for a long time without severe consequences.Unfortunately, during a recent survey, more than 80% of diabetics did not believe that they will face blindness, amputation, heart attack, stroke, or kidney failure! The primary reasons for this is due to the denial by the patient and a lack of understanding of the science of diabetes by the patient and some doctors.

Advanced Glycation End Products (AGEs)

Hyperglycemia is still considered the principal cause of diabetes complications. Its deleterious effects are attributable, among other things, to the formation of sugar-derived substances called advanced glycation end products (AGEs). AGEs form at a constant but slow rate in the normal body, starting in early embryonic development, and accumulate with time. However, their formation is markedly accelerated in diabetes because of the increased availability of glucose.

AGEs are a heterogeneous group of molecules formed from the nonenzymatic reaction of reducing sugars with free amino groups of proteins, lipids, and nucleic acids. The initial product of this reaction is called a Schiff base, which spontaneously rearranges itself into an Amadori product, as is the case of the well-known hemoglobin A1c (A1C). These initial reactions are reversible depending on the concentration of the reactants. A lowered glucose concentration will unhook the sugars from the amino groups to which they are attached; conversely, high glucose concentrations will have the opposite effect, if persistent. 

A key characteristic of certain reactive or precursor AGEs is their ability for covalent crosslink formation between proteins, which alters their structure and function, as in cellular matrix, basement membranes, and vessel-wall components. Other major features of AGEs relate to their interaction with a variety of cell-surface AGE-binding receptors, leading either to their endocytosis and degradation or to cellular activation and pro-oxidant, pro-inflammatory events.

A large body of evidence suggests that AGEs are important pathogenetic mediators of almost all diabetes complications, conventionally grouped into micro- or macroangiopathies. For instance, AGEs are found in retinal vessels of diabetic patients, and their levels correlate with those in serum as well as with severity of retinopathy.

Aminoguanidine, an inhibitor of AGE formation, is shown to prevent retinopathy in diabetic animals. Also, it is known that AGEs accumulate in peripheral nerves of diabetic patients and that the use of anti-AGE agents improves nerve conduction velocities and neuronal blood flow abnormalities.

The characteristic structural changes of diabetic nephropathy, thickened glomerular basement membrane and mesangial expansion, are accompanied by accumulation of AGEs, leading to glomerulosclerosis and interstitial fibrosis. Prolonged infusion of nondiabetic rats with AGEs has led to the development of similar morphological changes and significant proteinuria. Here again, AGE inhibitors such as aminoguanidine prevented diabetic nephropathy in diabetic animal models and were recently shown to do the same in one clinical trial on diabetic patients.

Atherosclerosis is significantly accelerated in diabetic patients and is associated with greater risk of cardiovascular and cerebrovascular mortality. Animal and human studies have shown that AGEs play a significant role in the formation and progression of atherosclerotic lesions. Increased AGE accumulation in the diabetic vascular tissues has been associated with changes in endothelial cell, macrophage, and smooth muscle cell function. In addition, AGEs can modify LDL cholesterol in such a way that it tends to become easily oxidized and deposited within vessel walls, causing streak formation and, in time, atheroma. AGE-crosslink formation results in arterial stiffening with loss of elasticity of large vessels. This arterial stiffness has recently been shown to be reversed by the administration of another anti-AGE class of compounds called AGE-breakers.

In addition to those endogenously formed, AGEs can also be introduced in the body from exogenous sources. Tobacco smoke, for example, is a well-known exogenous source of AGEs. The combustion of various pre-AGEs in tobacco during smoking gives rise to reactive and toxic AGEs. Serum AGEs or LDL-linked AGEs are significantly elevated in cigarette smokers. Diabetic smokers, as a result, are reported to exhibit greater AGE deposition in their arteries and ocular lenses.

More importantly, recent studies have provided evidence that diet is a significant exogenous source of highly reactive AGEs. Food processing, heating in particular, has a significant accelerating effect in the generation of glyco- and lipoxidation products. Heat helps create tasteful flavors that humans have learned to enjoy. In recent decades, food manufacturers have been using this knowledge to boost the flavor of natural foods by incorporating synthetic AGEs into foods. Consequently, the AGEs content of the Western diet has increased vastly in the past 50 years, as has the quantity of food consumed.

A significant proportion (∼10%) of ingested AGEs is absorbed with food. There is apparently a direct correlation between circulating AGE levels and those consumed. Studies in animals have demonstrated an important relationship between high dietary AGE intake and development or progression of diabetes-related tissue damage, e.g., vascular and renal. In all instances, this was prevented by dietary AGE restriction.

A similarly significant contribution to the human body AGE pool by diet was demonstrated recently. More importantly, its effective reduction by a restriction of dietary AGEs was associated with a significant suppression of circulating levels of vascular disease markers (e.g., adhesion molecules) as well as of inflammatory mediators.

This new evidence suggests that modulation of food-AGE content could become an important ingredient of the therapeutic armamentarium in the management of diabetic patients. Until effective and safe drugs become available, physicians and dietitians can, for instance, advise increased reliance on fresh foods, cooked by brief applications of heat, in the presence of ample water or humidity.

A diet designed to be low in AGEs is apparently not lacking in taste, while not requiring compromises in important nutrients. Such a regimen can decrease AGE intake by more than 50%; this in turn was shown to reduce circulating AGEs by ∼30% within a month without a change in A1C. On the contrary, short-term euglycemia or temporary normalization of A1C are not sufficient means for reducing serum AGEs; instead this requires extended periods of time, e.g., months or years.

In conclusion, current evidence points to glucose not only as the body’s main short-term energy source, but also as the long-term fuel of diabetes complications, mainly in the form of oxidative, pro-inflammatory AGEs. Food commonly consumed after exposure to heat contains a significant amount of pre-formed AGEs, a fact that offers a new perspective on food as a major environmental risk factor. It may be necessary, for instance, to restructure our guidelines to include methods of food preparation along with or in addition to routine recommendations about food quantity and composition.

It is reasonable to consider that good glycemic control, in combination with a careful diet in terms of reduced AGE consumption, should be among the new goals for optimal management of diabetic patients. Addressing dietary habits from a new perspective, while difficult, could achieve the best long-term effects as novel drug interventions become available for clinical use in the future.

The ß-cell Dysfunction
After many years of the pancreas secreting high levels of insulin to keep up with the high levels of blood glucose, the pancreas begins to wear out, leading to ß-Cell dysfunction.  This dysfunction is initially characterized by an impairment in the first phase of insulin secretion during glucose stimulation and may precede the onset of glucose intolerance in type 2 diabetes.
 
Initiation of the insulin response depends upon the transmembranous transport of glucose and coupling of glucose to the glucose sensor. The glucose/glucose sensor complex then induces an increase in glucokinase by stabilizing the protein and impairing its degradation. The induction of glucokinase serves as the first step in linking intermediary metabolism with the insulin secretory apparatus. Glucose transport in ß-cells of type 2 diabetes patients appears to be greatly reduced, thus shifting the control point for insulin secretion from glucokinase to the glucose transport system.
 
Later in the course of the disease, the second phase release of newly synthesized insulin is impaired, an effect that can be reversed, in part at least in some patients, by restoring strict control of glycemia. This secondary phenomenon, termed desensitization or ß-cell glucotoxicity, is the result of a paradoxical inhibitory effect of glucose upon insulin release and may be attributable to the accumulation of glycogen within the ß-cell as a result of sustained hyperglycemia. Other candidates that have been proposed are sorbitol accumulation in the ß-cell or the non-enzymatic glycation of ß-cell proteins.

Other defects in ß-cell function in type 2 diabetes mellitus include defective glucose potentiation in response to non-glucose insulin secretagogues, asynchronous insulin release, and a decreased conversion of proinsulin to insulin.

An impairment in first phase insulin secretion may serve as a marker of risk for type 2 diabetes mellitus in family members of individuals with type 2 diabetes mellitus and may be seen in patients with prior gestational diabetes. However, impaired first phase insulin secretion alone will not cause impaired glucose tolerance.

Autoimmune destruction of pancreatic ß-cells may be a factor in a small subset of type 2 diabetic patients and has been termed the syndrome of latent autoimmune diabetes in adults.This group may represent as many as 10% of Scandinavian patients with type 2 diabetes and has been identified in the recent United Kingdom study, but has not been well characterized in other populations.

Glucokinase is absent within the ß-cell in some families with maturity-onset diabetes of young . However, deficiencies of glucokinase have not been found in other forms of type 2diabetes.

In summary, the delay in the first phase of insulin secretion, although of some diagnostic import, does not appear to act independently in the pathogenesis of type 2 diabetes. In some early-onset patients with type 2 diabetes (perhaps as many as 10%), there may be a deficiency in insulin secretion that may or may not be due to autoimmune destruction of the ß-cell and is not due to a deficiency in the glucokinase gene. In the great majority of patients with type 2 diabetes (±90%), the delay in immediate insulin response is accompanied by a secondary hypersecretory phase of insulin release as a result of a compensatory response to peripheral insulin resistance.
 
Over a prolonged period of time, perhaps years, insulin secretion gradually declines, possibly as a result of intra-islet accumulation of glucose intermediary metabolites. In view of the decline in ß-cell mass, sulfonylureas and other  diabetic drugs appear to serve a diminishing role in the long term management of type 2 diabetes. Unanswered is whether amelioration of insulin resistance with earlier detection or newer insulin-sensitizing drugs will retard the progression of ß-cell failure, obviating or delaying the need for insulin therapy.

Mitochondria Dysfunction
Given their essential function in aerobic metabolism, mitochondria are intuitively of interest in regard to the pathophysiology of diabetes. Qualitative, quantitative, and functional perturbations in mitochondria have been identified and affect the cause and complications of diabetes. Moreover, as a consequence of fuel oxidation, mitochondria generate considerable reactive oxygen species (ROS). Evidence is accumulating that these radicals per se are important in the pathophysiology of diabetes and its complications.

Insulin resistance in skeletal muscle is a major hallmark of type 2 diabetes mellitus (T2D) and obesity that is characterized by impaired insulin-mediated glucose transport and glycogen synthesis and by increased intramyocellular content of lipid metabolites. Several studies have provided evidence for mitochondrial dysfunction in skeletal muscle of type 2 diabetic and pre-diabetic subjects, primarily due to a lower content of mitochondria (mitochondrial biogenesis) and possibly to a reduced functional capacity per mitochondrion -- but, more research and studies need to be performed.

Key Message: Despite all of the multiple root causes for the development, progression, and pathogenesis of Type 2 diabetes,  there is over-whelming evidence that a superior balanced nutritional therapy provides the best solution for effectively controlling and possibly reversing Type 2 diabetes.

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United States/International Scope
In 2007, the estimated prevalence of diabetes in the United States was 7.8% (23.6 million people); almost one third of cases were undiagnosed. More than 90% of cases of diabetes are type 2 diabetes mellitus. With increasing obesity in the population, an older population, and an increase in the population of higher-risk minority groups, prevalence is increasing.

Type 2 diabetes mellitus is less common in non-Western countries where the diet contains fewer calories and caloric expenditure on a daily basis is higher. However, as people in these countries adopt Western lifestyles, weight gain and type 2 diabetes mellitus are becoming virtually epidemic.

Mortality/Morbidity
Diabetes mellitus is one of the leading causes of morbidity and mortality in the United States because of its role in the development of optic, renal, neuropathic, and cardiovascular disease. These complications, particularly cardiovascular disease (~50-75% of medical expenditures), are the major sources of expenses for patients with diabetes mellitus. Approximately two thirds of people with diabetes die from heart disease or stroke. Men with diabetes face a 2-fold increased risk for coronary heart disease, and women have a 3- to 4-fold increased risk. In 1994, 1 of every 7 health care dollars in the United States was spent on patients with diabetes mellitus. The 2002 estimate for direct medical costs due to diabetes in the United States was $92 billion, with another $40 billion in indirect costs. Approximately 20% of Medicare funds are spent on these patients.
  • Diabetes mellitus is the leading cause of blindness in working-age adults in the United States; diabetic retinopathy accounts for 12,000-24,000 newly blind persons every year.The National Eye Institute estimates that laser surgery and appropriate follow-up care can reduce the risk of blindness from diabetic retinopathy by 90%.
  • Diabetes mellitus is the leading cause of end-stage renal disease (ESRD), accounting for 44% of new cases, according to the Centers for Disease Control and Prevention (CDC).In 2005, 46,739 people in the United States and Puerto Rico began renal replacement therapy, and 178,689 people with diabetes were on dialysis or had received a kidney transplant.
  • Diabetes mellitus is the leading cause of non-traumatic lower limb amputations in the United States, with a 15- to 40-fold increase in risk over that of the non-diabetic population. In 2004, about 71,000 non-traumatic lower limb amputations were performed related to neuropathy and vasculopathy.
Race
The prevalence of type 2 diabetes mellitus varies widely among various racial and ethnic groups. Type 2 diabetes mellitus is becoming virtually pandemic in some groups of Native Americans and Hispanic people. The risk of retinopathy and nephropathy appears to be greater in blacks, Native Americans, and Hispanics.

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The Biochemical Pathology of Insulin Resistance and the Metabolic Syndrome
Over the past decade the metabolic syndrome  has become prominent in the literature in addition to emerging as a major public health concern. The metabolic syndrome presents many diagnostic problems for clinicians and laboratorians alike. The metabolic syndrome is a constellation of symptoms and signs that include central obesity, insulin resistance, dysglycemia, dyslipidemia, and hypertension. The definition has many subtleties and clinically, there are a multitude of presentations. Included in the current understanding of the metabolic syndrome is a subtext of a pro-inflammatory and a pro-thrombotic state.
 
There is certainly no agreement on any single causative agent; however, it is clear that the modern calorie-rich Western diet in the setting of little or no regular exercise plays a central role. A recent concise review on metabolic syndrome was published in this journal. The current review addresses the biology of insulin resistance, viz., what is it and how does it present? The insulin resistance of the metabolic syndrome remains somewhat of an enigma, but a number of plausible models have come to light in recent years.
 
Here we review: (a) the many metabolic actions of insulin, (b) the pathogenesis of type 2 diabetes mellitus, (c) insulin resistance (in general), (d) the ectopic fat hypothesis of insulin resistance, (e) the possible role of the hormones leptin, resistin, and adiponectin, and (f) the connection between insulin resistance and islet amyloid.
 
Insulin and insulin resistance
Insulin is an essential polypeptide hormone produced under conditions of feeding by the beta cells of the pancreatic islets of Langerhans. Insulin is critical for entry of glucose into multiple tissues, including skeletal muscle and adipose tissue (via activation of the glucose transporter molecule [GLUT4]), but is not necessary for glucose entry into erythrocytes, liver, or brain.  Insulin promotes the oxidation of glucose to carbon dioxide and water by tissues and also blocks "new" glucose biosynthesis (i.e., gluconeogenesis) by hepatic tissue.

Insulin is also very important in promoting the storage of glucose in the form of glycogen by liver and muscle. The drive of glucose into the cells with its subsequent oxidation is the basis for the glucose-lowering effect of insulin. Insulin also has major effects on lipid metabolism. It blocks the breakdown of triacylglycerols (triglycerides) by adipose tissue and promotes the biosynthesis of fatty acids and triacylglycerols by liver and adipose tissue. In short, insulin promotes fat storage.
 
This summary of insulin's many actions helps to clarify the effects of insulin deficiency. In the absence of sufficient insulin, glucose (now unable to enter cells) accumulates in excess within the extracellular fluid. This has two major effects: (a) the cells undergo a functional starvation and (b) the high plasma glucose has many untoward physiologic effects, including osmotic problems and tissue damage from protein glycation. Cell starvation manifests as increased synthesis of ketone bodies.

Furthermore, there is adipose tissue breakdown with production and release of fatty acids. The latter are delivered to the liver in such high quantities that hepatic lipoprotein synthesis is increased and the liver puts out abundant very low-density lipoproteins (VLDLs). Insulin is required for VLDL breakdown in the capillary beds via lipoprotein lipase and so, in cases of insulin deficiency, these large triglyceride-rich lipoproteins persist.
 
Diabetes is a disease that results from decreased insulin action. Insulin action is a product of insulin concentration and tissue insulin sensitivity. For many decades, researchers have been aware of the essential differences between type 1 and type 2 diabetes. In type 1 diabetes, there is a true deficiency of insulin due to pancreatic beta-cell damage by an autoimmune, cell-mediated response. Insulin concentrations are very low. In type 2 diabetes, insulin concentrations may be normal or even high. In type 2 diabetes, there is an insensitivity of the tissues to the effects of insulin--an effect termed insulin resistance. Insulin is present, but it cannot get its message through to the cells. What has happened? Before addressing this, let us review what normally happens when insulin interacts with a cell.
 
In order to initiate its many metabolic effects, insulin must interact with a specific cell-surface receptor that belongs to a family of receptor-enzymes known as tyrosine kinases. The binding of insulin to the insulin receptor  initiates a complex chain of events that ultimately generates a multitude of intracellular second messengers. The latter eventually produce the characteristic effects of insulin, for example, by promoting the movement of GLUT4 molecules to the cell surface.

Although cases of insulin resistance have been described due to specific mutations in the insulin cell-surface receptor tyrosine kinase, these are rather rare and constitute only a minority of cases. They have, however been extensively studied and have shed much light on the biology of insulin action. The insulin resistance of the common type 2 diabetes is not related to receptor mutations, but is somehow related to the amount of fat in the body.
 
The standard model of type 2 diabetes is that the body tissues progressively become more insulin resistant, so that ever-higher blood concentrations of the hormone are needed to produce the identical effect. In the early stages of the disease, plasma insulin concentrations tend, therefore, to be higher than normal.

The insulin resistance eventually achieves a level where the person is relatively insulinopenic. He has above-normal concentrations of insulin, but the circulating insulin nevertheless is still not sufficient to fully activate the insulin-resistant tissues, such as skeletal muscle and adipose tissue.  There is a price to pay for this profligate expenditure of insulin. The beta cells cannot keep up with the demand and begin to fail--an event that may also be promoted by body-fat content. Such individuals enter a stage where they are truly insulinopenic. Indeed, even when the beta cells are still able to secrete large amounts of insulin, the temporal pattern of insulin secretion is no longer normal.
 
Initially, the insulin resistance is most likely sub-clinical, since insulin is not routinely measured in the clinical laboratory as part of a standard clinical chemistry analysis. As the condition progresses, there will be evidence of pre-diabetes, either impaired fasting glucose and/or impaired glucose tolerance, the latter based upon a standard oral two-hour glucose-tolerance test.

Eventually, frank hyperglycemia sets in and the physician can make the diagnosis of diabetes. Interestingly, insulin resistance, besides producing diabetes, may produce other physical signs. One of these is a skin condition termed acanthosis nigricans--a velvety, brown-black skin discoloration, often in skin folds or at the back of the neck.
 
Insulin resistance has important effects on the vascular bed.  It leads to decreased nitric oxide synthesis by endothelial cells with subsequent endothelial dysfunction. Nitric oxide is an important vasodilator that reduces resistance in blood vessels.  This may be one of the mechanisms underlying the hypertension of the metabolic syndrome.

Hyperinsulinism is also responsible for other phenomena not typically associated with carbohydrate metabolism. It produces hyperandogenism in females; hyperinsulinism is a key feature of the polycystic ovarian syndrome, a close relative of the metabolic syndrome. The polycystic ovarian syndrome is a constellation of signs that include insulin resistance, hyperandrogenism, hirsutism, obesity, infertility, and menstrual irregularities.
 
Body fat and insulin resistance
How does body-fat content produce insulin resistance? First, it appears that it is particularly intra-abdominal fat (also termed visceral fat) that is the culprit here. Intra-abdominal fat is adipose tissue associated with the abdominal viscera. Subcutaneous fat is much less of a problem. One hypothesis suggests that a process that is central to the pathogenesis of insulin resistance is fat ectopia. 

In the simplest terms, adipose tissue can only hold a certain amount of fat, and if excessively loaded with fat, there is a spillover or redistribution of lipid to ectopic sites, including liver and skeletal muscle. In support of this, hepatic steatosis is frequently observed in individuals with the metabolic syndrome. Nonalcoholic fatty liver disease has a prevalence of 57% to 74% in obese individuals. It is the most common cause of abnormal liver function tests in the United States. The ectopic triglyceride deposition in non-adipose tissue, such as liver and skeletal muscle, has deleterious effects. There is both tissue damage (lipotoxicity) and the development of insulin resistance.
 
Another aspect of the lipid ectopia hypothesis is that the beta cells themselves are damaged by the deposition of the fat. This results in a gradual failure to produce sufficient insulin, making the insulinopenia worse. The evidence that this hypothesis has some validity comes from rare cases of lipodystrophic diabetes. Congenital lipodystrophies are conditions where body fat is significantly reduced or almost absent. The dearth of normal fat-storage capacity leads to early fat ectopia with deposition of fat (triglycerides) in skeletal muscle and liver and the development of insulin resistance despite the absence of obesity.
 
Conversely, in the Prader-Willi syndrome, where significant obesity is a major feature, insulin resistance is uncommon. These individuals appear to have an expanded capacity to store fat, so their risk of fat ectopia and type 2 diabetes is less than average. Additional support of this hypothesis derives from studies of low-birth-weight infants.

As adults, these individuals are predisposed to insulin resistance. It appears that they have reduced amounts of adipose tissue and, therefore, a reduced capacity to store fat. They are more likely to experience spillover or fat ectopia, according to the hypothesis outlined above. Further evidence comes from the use of a class of drugs termed PPAR-gamma agonists (thiazolidinediones). These compounds stimulate the development of new adipose tissue, allowing the redistribution or normalization of fat stores. Fat leaves the ectopic tissues and re-enters the new adipose tissue. Thiazolidinediones are known to be effective in treating type 2 diabetes.
 
Leptin, resistin, and adiponectin
The hormone leptin may be important in this fat ectopia/lipotoxicity scenario. Leptin is a 167-amino-acid polypeptide with a molecular mass of about 16 kDa that is produced by adipose tissue. It is known to regulate body adipose tissue. The ob/ob mouse is genetically deficient in leptin production, while the db/db mouse or the fa/fa (ZDF) rat have mutations in the leptin receptor.

In these animal models, there is either a deficiency of leptin or there is a nonfunctional leptin receptor. These animals display hyperphagia and obesity as well as steatosis liver, skeletal muscle, and pancreatic islets.  Leptin is believed to reduce appetite and control thermogenesis via actions on the hypothalamus.

Growing evidence suggests that leptin can also act directly on adipose tissue and that this may well be a major site of its action. It has been proposed that, in this setting, leptin normally prevents steatosis in non-adipose tissue--it blocks the ectopic deposition of fat and thus prevents lipotoxicity. In leptin-deficient or leptin-resistant animals, this control is absent and ectopic fat deposition (steatosis) with consequent lipotoxicity continues unabated. 

A similar situation is found in individuals with congenital lipodystrophies. In the latter case, the lack of adipose tissue is responsible for the leptin deficiency. In human diet-induced obesity, leptin levels initially are high, preventing ectopic fat deposition. Resistance to leptin ultimately occurs, however, and control over the ectopic deposition of fat is lost.
 
How does leptin exert its action to prevent steatosis? It enhances fatty-acid oxidation by tissues, leading to the generation of both ATP and heat.  It also reduces de novo fatty acid biosynthesis and reduces synthesis of triglycerides. In the absence of leptin, these processes are blocked and triglycerides accumulate in non-adipose tissue.

Furthermore, these metabolic studies have shed light on the lipotoxicity of ectopic fat deposition. In the absence of leptin, and when intracellular triglycerides accumulate, fatty acids enter a pathway of non-oxidative metabolism.  This leads to increased ceramide formation. Ceramide is a sphingolipid, derived from sphingosine (an amino alcohol) joined to a fatty acid. Ceramide promotes apoptosis (programmed cell death).
 
Recent studies in adipose tissue biology have lead to the discovery of a another new hormone (termed resistin) that (like leptin) is produced by adipose tissue. Initial evidence pointed to resistin playing a major role in the pathogenesis of insulin resistance by virtue of its ability to oppose certain actions of insulin. This was supported by the observation that thiazolidinedione drugs that activate the transcription factor PPAR-gamma decrease adipose tissue resistin secretion and, therefore, help to reverse insulin resistance. Since its initial description, the role of resistin has been somewhat less clear cut with conflicting reports in the literature. A study published in 2002 showed, however, that the removal of visceral fat from Zucker diabetic rats prevented the development of insulin resistance, and that resistin expression in visceral fat was much higher than subcutaneous fat. The role of resistin in human biology however, remains rather uncertain.
 
Adiponectin is yet another adipose tissue-derived protein with endocrine effects.  Adiponectin is a 244-amino-acid protein (30 kDa) with a collagen-like domain. Part of the molecule shares structural similarities with the cytokine tumor necrosis factor-alpha (TNF- alpha). Plasma concentrations of adiponectin are lowered in obesity and insulin resistance, in contrast to many other adipose-derived cytokines. Adiponectin production is associated with insulin sensitivity; conversely, low adiponection concentrations produce insulin resistance. Adiponectin also stimulates fatty-acid oxidation and lowers plasma triglycerides.

In addition, adiponectin appears to have antiatherogenic effects. When adiponectin "knock-out" mice were given high-fat, high-sucrose diets, they developed insulin resistance. Of relevance to the metabolic syndrome, visceral fat accumulation is associated with lowered adiponectin concentrations. TNF-a, which is also known to be associated with insulin resistance, inhibits adiponectin gene expression.
 
Islet amyloid
Another development in the field of type 2 diabetes has been the identification of islet amyloid and its relationship to beta-cell failure. The standard model of type 2 diabetes, as described above, raises the question: Is the beta-cell failure that occurs as the disease advances simply a result of cell exhaustion? Is it due to the lipotoxicity described above? There is evidence that islet amyloid may be important, too, although it is probably not the only factor. Amyloid is a proteinaceous fibrillary deposit that is seen in tissues during certain pathologic processes and that can fold into beta-pleated sheets. Amyloid has a characteristic electron-microscopic appearance, as well as a green birefingence in polarizing light microscopy when stained with Congo Red. Islet amyloid is a form of local amyloidosis, since it is confined to the islets of Langerhans.
 
Islet amyloidosis is frequently observed in individuals with type 2 diabetes mellitus. The amyloid appears to promote beta-cell damage and death. Is there any connection with insulin resistance? There may well be. A major component of islet amyloid is a 37-amino-acid polypeptide termed islet amyloid polypeptide (IAPP) or amylin, produced and secreted by the islet beta cells. In the setting of insulin resistance, not only does insulin secretion by the beta cell increase, IAPP production follows suit. Although the IAPP sequence is normal, the high polypeptide concentrations promote amyloid fibril formation, leading to localized islet amyloidosis. This ultimately may contribute to beta-cell failure. Thus, insulin resistance leads to islet amyloid, which, in turn, promotes insulin lack of.
 
In the course of a normal physiologic response to starvation, free fatty acids or FFA have a carbohydrate-sparing effect so that glucose can be preserved for oxidation by the central nervous system. Fatty acids are also elevated in obese individuals, and these have direct effects on carbohydrate metabolism. Fatty acids decrease glucose uptake, glycogen synthesis, and glycolysis, effects normally promoted by insulin. The evidence from the original studies suggested the effect of fatty acids to be at the level of glucose transport or phosphorylation. (18) Furthermore, fatty acids inhibit insulin suppression of hepatic glucose production, leading to increased hepatic glucose production.

Pathogenesis of Type 2 Diabetes
The pathological sequence for type 2 diabetes is complex and entails many different elements that act in concert to cause that disease. One of the flow charts (below) proposes a sequence of events and how the disease progresses in the human body.

A genetic predisposition must exist, although to date very little is known about specific genetic defects in this disease. Whether the diabetes phenotype will occur depends on many environmental factors that share an ability to stress the glucose homeostasis system, with the current explosion of obesity and sedentary lifestyle being a major cause of the worldwide diabetes epidemic.

We also propose that a lowered beta-cell mass either through genetic and/or beta-cell cytotoxic factors predisposes for glucose intolerance. As the blood glucose level rises even a small amount above normal, then acquired defects in the glucose homeostasis system occur -- initially to impair the beta cell's glucose responsiveness to meals by impairing the first phase insulin response -- and cause the blood glucose level to rise into the range of impaired glucose tolerance (IGT).

This rise in blood glucose, now perhaps in concert with the excess fatty acids that are a typical feature of obesity and insulin resistance, cause additional deterioration in beta-cell function along with further insulin resistance, and the blood glucose levels rise to full-blown diabetes. This sequence also provides insight into how to better prevent or treat type 2 diabetes, by studying the molecular basis for the early defects, and developing targeted therapies against them.

Candida Problems

If you have diabetes, chances are good you will also have problems with a bacteria known as candida. Why? Because every living human has candida in his or her system. Usually the "friendly bacteria" keep the non-friendly candida at bay, but certain factors can allow the candida to flourish -- factors that are often brought on by diabetes.

For example, candida is a cause of vaginal yeast infections in women, and while yeast infections are very common, they are even more common among women with diabetes. This is because diabetes impairs the body's immune system and its ability to fight infections. Candida growths that would be taken care of naturally in non-diabetic people become problematic in people with diabetes.

In addition, a high blood sugar level makes the mucous membranes more sugary, which is a perfect environment for yeasts to grow in.

Foods that can trigger candida include sugar, flour, alcohol, corn, potatoes, pasta, rice, bread and other processed foods that contain sugar or flour. By eliminating these foods, most people can get rid of their candida. Ironically, these are the same foods that diabetics need to avoid to better control their blood glucose levels. Focus on periodic detox and eating more yogurt and vegetables, especially those that inhibit the growth of candida, i.e. cabbage, raw garlic, onions, broccoli, turnip, kale.

Summary and Conclusion
In this review, we have examined the phenomenon of insulin resistance, a central manifestation of the metabolic syndrome. While it is by no means clear-cut, many new and exciting hypotheses have been proposed to explain this puzzling and enigmatic phenomenon. These studies have also led to a new way of looking at adipose tissue -- it is no longer a passive repository of fat. It now actually appears to be a very active endocrine organ. A disturbance in this endocrine function helps contribute to the metabolic syndrome.

For more information about the science of Type 2 diabetes, go to the following links:
-- The Epidemiology
-- More Facts & Figures
-- The Etiology
-- Overview of Diabetes
-- Medical Sciences
-- Nutritional Science

Note: For more details about repairing and healing the body from the damage caused by the diabetes (and the drugs), refer to Repairing & Healing web page.

Note: If you concerned about what the drugs are doing to you, follow these steps to get started today on your journey to wellness.

Note: If you want to to learn more about diabetes and if you're serious about defeating your diabetes, request a free copy of the author's research paper titled The 7 Mistakes That Diabetics  Make.

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BG-Insulin Graph: Beat, Reverse & Cure Your Diabetes! 

Diabetes Pathology at Celular Level: Beat, Reverse & Cure Your Diabetes!

Diabetes Pathology -- Cellular Level: Beat, Reverse & Cure Your Diabetes!

The Pathogenesis of Type 2 Diabetes
Pathogenesis: Beat, Reverse & Cure Your Diabetes!


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