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The Etiology of Type 2 Diabetes
Diabetes mellitus is a chronic disease characterized by relative or absolute deficiency of insulin, resulting in glucose intolerance. It occurs in approximately 21 million persons in the United States (approximately 7% of the population). The classic symptoms of diabetes mellitus result from abnormal glucose metabolism. The lack of insulin activity results in failure of transfer of glucose from the plasma into the cells. This situation so called "starvation in the midst of plenty". The body responds as if it were in the fasting state, with stimulation of glucogenolysis, gluconeogenesis and lipolysis producing ketone bodies.
The glucose absorbed during a meal is not metabolized at the normal rate and therefore accumulates in the blood (hyperglycemia) to be excreted in the urine (glycosuria). Glucose in the urine causes osmotic diuresis, leading to increase urine production (polyuria). Stimulation of protein breakdown to provide amino acids for gluconeogenesis results in muscle wasting and weight loss. These classic symptoms occur only in patients with severe insulin deficiency, most commonly in type I diabetes. Many patients with type II diabetes do not have these symptoms and present with one of the complications of diabetes.
Generally, there are two types of diabetes:
-- Type I Diabetes Mellitus (insulin-dependent diabetes mellitus, IDDM)
-- Type II Diabetes Mellitus (non-insulin-dependent diabetes mellitus, NIDDM).
Type I Diabetes Mellitus (insulin- dependent diabetes mellitus, IDDM) is due to destruction of pancreatic B cells. The cause of B cell destruction in type I diabetes is unknown. A few cases have followed viral infections, most commonly with coxsakievirus B or mumps virus. Autoimmunity is believed to be the major mechanism involved. Islet cell autoantibodies are present in the serum of 90% of newly diagnosed cases. Such antibodies are directed against several cell components, including cytoplasmic and membrane antigens or against insulin itself (IgG and IgE antibodies). Sensitized T lymphocytes with activity against B cells have also been demonstrated in some patients.
Plasma insulin levels are very low or even absent in type I diabetes, and ketoacidosis develops if the patients do not receive exogenous insulin. Type I diabetes occurs most commonly in juveniles, with the highest incidence worldwide among the 10- to 14-year-old group, but occasionally occurs in adults, especially the nonobese and those who are elderly when hyperglycemia first appears.
The etiology of type II diabetes mellitus (non-insulin- dependent diabetes mellitus, NIDDM) is even less clearly understood. There are many root causes of this disease, as depicted in the Ishikawa diagram (below), but three factors have been identified:
a) Impaired insulin release - basal secretion of insulin is often normal, but the rapid release of insulin follows a meal is greatly impaired, resulting in failure of normal handling of a carbohydrate load. In most patients, some level of insulin secretion is maintained, so that the abnormality of glucose metabolism is limited and ketoacidosis is uncommon. In these patients, insulin secretion can be stimulated by drugs such as sulfonylureas. Exogenous insulin is therefore not essential in treatment. It also have been suggested that inheritance of a defective pattern of insulin secretion is responsible for the familial tendency of diabetes. The genetic factor is very strong in type II diabetes, with a history of diabetes present in about 50% of first degree relatives.
b) Insulin resistance - a defect in the tissue response to insulin is believed to play a major role. This phenomenon is called insulin resistance and is caused by defective insulin receptors on the target cells. Insulin resistance occurs in association with obesity and pregnancy. In normal individuals who become obese or pregnant, the B cells secrete increased amounts of insulin to compensate. Patients who have genetic susceptibility to diabetes cannot compensate because of their inherent defect in insulin secretion. Thus, type II diabetes is frequently precipitated by obesity and pregnancy. In a few patients with extreme insulin resistance, antibodies against the receptors have been demonstrated in plasma. These antibodies are mostly of the IgG class and act against the insulin receptors, causing the decreased numbers of insulin receptors and defective binding of insulin to receptors.
c) Inflammation - a defect in the tissue response to excess insulin is believed to play a major role. This phenomenon is caused by the increase in insulin resistance. Read below for information about inflammation.
Other specific types of diabetes mellitus includes maturity-onset diabetes of the young (MODY), diabetes due to mutant insulin, diabetes due to mutant insulin receptors, diabetes mellitus associated with a mutation of mitochondrial DNA and obese type 2 patients.
Insulin Resistance, Beta Cell Dysfunction & Inflammation
Type 2 diabetes is more than a “blood sugar” disease! It is a combination of insulin resistance, beta cell dysfunction, and inflammation. Insulin resistance and inflammation prevent your body’s cells from effectively using the insulin produced by the pancreas. That is, the insulin receptors on the surface of each cell are damaged (inflamed), ignoring the presence of insulin in your blood and refusing to allow glucose from your blood to enter your cells. The cells in your body require the glucose (as fuel) in order to produce energy. Without this fuel, your cells cannot produce energy and you will feel tired. This is one of the primary reasons why many diabetics lack the energy to exercise or feel the need to take a nap in the middle of the day.
Under normal circumstances, when you eat food, it is broken down and converted to glucose, and the glucose level in your blood begins to rise. This signals the pancreas to secrete insulin into your bloodstream. The cells in your body, such as the fat cells and muscle cells, contain these “doors” (insulin receptors) that sense the presence of insulin. Insulin acts like a “key” and causes these “doors” in the cell membranes to open. When these “doors” open, the glucose in your blood is transported into your cells and processed to provide you with energy. Any extra glucose is stored as glycogen in your liver and muscle cells for future use (e.g. exercise). At this point, the glucose level in your blood lowers and returns to normal, usually within 2 hours after eating.
But, that isn’t what happens when you are a diabetic. Everything is the same up to the point when these “doors” (insulin receptors) sense the presence of insulin. At that point, the damaged cell “doors” do not respond to the “key” insulin and do not open and let in the glucose. Although some of the glucose is stored as glycogen by the liver and muscle cells, the majority of the glucose begins to “back up” in the blood causing the blood glucose level to continue to rise. The pancreas senses that the blood glucose level is still rising, so the pancreas ramps up and secretes more and more insulin to try to “push” the glucose into the cells and bring the glucose level down.
As the glucose level continues to rise, the liver and muscle cells, due to a limited storage capacity, are unable to store any more glucose and become resistant to insulin. Consequently, the extra glucose is converted to fat by the liver and stored throughout the body in places that do not have limited storage capacities: the abdomen, hips, waist, and the blood (as triglycerides). In the meantime, the kidneys try to help by removing glucose from the blood. This leads to frequent urination, which leads to a strong thirst and constant drinking, which leads to more urination and a depletion of vitamins and minerals.
The high levels of insulin in the body trigger the increase in fat storage -- especially in the abdomen area, which includes the omentum layer of fat surrounding the bowel. The high levels of insulin also inhibit the metabolism (breakdown) of fat as the amount of fat and the number of fat cells in the body continues to increase. The excess fat cells release chemicals called cytokines that block the insulin receptors, leading the pancreas to churn out two to three times more insulin. After years of high insulin levels force-feeding the glucose into the resistant cells, some of the insulin-producing beta cells in the pancreas may burn out. This, in turn, causes insulin levels to fall, leading to a further rise in the glucose level. And, as the glucose level rises even more, this can eventually lead to further cell membrane damage, cell starvation, severe dehydration, and organ shutdown triggering a coma state.
As depicted in the following diagram, the lack of communicative response from the damaged (inflamed) cell receptors (“doors”) to open up and let in the glucose leads to low energy, fatigue and an increased resistance to insulin. This ongoing insulin resistance and inflammation leads to an increase of oxidation (free radical damage), inflammation (cell membrane/tissue damage), and toxicity (poisoning and acidity).
In addition, ongoing diabetes leads to the following problems:
- A depletion of vitamins (B-complex, Vitamin C, Vitamin E) and minerals (calcium, potassium, magnesium, chromium), many of which are excreted in the urine due to the kidneys trying to get rid of the excess glucose. The loss of these nutrients prevents proper carbohydrate/protein/fat metabolism, electrolyte balance, nerve protection, insulin regulation, muscle relaxation, and antioxidant protection from free radicals.
- An increase in the production of cholesterol by the liver due to the insulin activating the HMG-CoA reductase enzyme.
- A conversion of the extra glucose to fat, increasing the triglycerides, LDL cholesterol, and blood viscosity (thickness).
- A prevention of the breakdown of homocysteine, causing an increase of cell inflammation leading to a buildup of plaque in the artery walls, which become rigid, thicker and more narrow.
- An increase of inflammation markers such as homocysteine, C-reactive protein (CRP), fibrinogen, and lipoprotein(a), leading to thick, sticky and slow moving blood.
- An increase in advanced glycated end products (AGEs), which are formed when glucose damages the protein in the cells, preventing the normal function of those cells and accelerating the aging of the cells.
- An increase in blood pressure due to the hyperinsulinemia, thicker blood and narrowed, more rigid arteries.
- An increase in blood pressure due to the retention of salt and water and poor filtering of the blood by the kidneys, which may stimulate the liver to produce more cholesterol.
- A gradual development of pancreatic beta cell dysfunction.
Development of blood clots due to the thicker, sticky blood, eventually leading to strokes and heart attacks.
Also, the extra insulin drives the glucose level down too low triggering hormonal hunger – this is why diabetics feel tired (low glucose level) and hungry (hormonal hunger). If the pancreas does not secrete enough glucagon to counter-balance the extra insulin, the glucose level is driven down too low, and may trigger an attack of low blood sugar.
When the blood glucose level rises too high and remains too high, the glucose molecule attaches itself to cells permanently and is eventually converted to a poison called sorbitol that destroys the cells. This process gradually leads to blurred vision, burning foot syndrome, tingling, and the loss of feeling in the extremities.
Inflammation
In recent years, it has been theorized that chronic, low-grade tissue inflammation related to obesity contributes to insulin resistance, the major cause of Type 2 diabetes. In research done in mouse models, the UCSD scientists proved that, by disabling the macrophage inflammatory pathway, insulin resistance and the resultant Type 2 diabetes can be prevented.
The findings of the research team, led by principle investigators Michael Karin, Ph.D., Professor of Pharmacology in UCSD's Laboratory of Gene Regulation and Signal Transduction, and Jerrold Olefsky, Distinguished Professor of Medicine and Associate Dean for Scientific Affairs, will be published as the feature article of the November 7 issue of Cell Metabolism.
"Our research shows that insulin resistance can be disassociated from the increase in body fat associated with obesity," said Olefsky.
Macrophages, found in white blood cells in the bone marrow, are key players in the immune response. When these immune cells get into tissues, such as adipose (fat) or liver tissue, they release cytokines, which are chemical messenger molecules used by immune and nerve cells to communicate. These cytokines cause the neighboring liver, muscle or fat cells to become insulin resistant, which in turn can lead to Type 2 diabetes.
The UCSD research team showed that the macrophage is the cause of this cascade of events by knocking out a key component of the inflammatory pathway in the macrophage, JNK1, in a mouse model. This was done through a procedure called adoptive bone marrow transfer, which resulted in the knockout of JNK1 in cells derived from the bone marrow, including macrophages.
With this procedure, bone marrow was transplanted from a global JNK1 knockout mouse (lacking JNK1 in all cell types) into a normal mouse that had been irradiated to kill off its endogenous bone marrow. This resulted in a chimeric mouse in which all tissues were normal except the bone marrow, which is where macrophages originate. As a control, the scientists used normal, wild-type mice as well as mice lacking JNK1 in all cell types. These control mice were also subjected to irradiation and bone marrow transfer.
The mice were all fed a high-fat diet. In regular, wild-type mice, this diet would normally result in obesity, leading to inflammation, insulin resistance and mild Type 2 diabetes. The chimeric mice, lacking JNK1 in bone marrow-derived cells, did become obese; however, they showed a striking absence of insulin resistance -- a pre-condition that can lead to development of Type 2 diabetes.
"If we can block or disarm this macrophage inflammatory pathway in humans, we could interrupt the cascade that leads to insulin resistance and diabetes," said Olefsky. "A small molecule compound to block JNK1 could prove a potent insulin-sensitizing, anti-diabetic agent."
The research also proved that obesity without inflammation does not result in insulin resistance. Olefsky explained that when an animal or a human being becomes obese, they develop steatosis, or increased fat in the liver. The steatosis leads to liver inflammation and hepatic insulin resistance.
The chimeric mice did develop fatty livers, but not inflammation. "Their livers remained normal in terms of insulin sensitivity," said Olefsky, adding that this shows that insulin resistance can also be disassociated from fatty liver.
"We aren't suggesting that obesity is healthy, but indications are promising that, by blocking the macrophage pathway, scientists may find a way to prevent the Type 2 diabetes now linked to obesity and fatty livers," Olefsky said.
Note: This research was supported by National Institutes of Health grants ES004151, ES006376, DK033651 and DK074868.
Note: For more information about the science of Type 2 diabetes, go to the following links:
-- The Pathophysiology
-- The Pathogenesis
-- The Epidemiology
-- Overview of Diabetes
