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Diabetes is a name for an evolving complex of metabolic derangement's that contribute to a horrendous list of chronic and disabling illnesses. While elevated levels of sugar in the body seem to be the leading edge of the emerging disaster, changes in fat metabolism, liver and kidney function and then circulation impairment add to a cascade of dysfunction. 75% of the early deaths in diabetics are related to coronary artery disease. Play Puzzle Games, online games.

Stephen Gislason MD

The disturbing fact is that most diabetics will develop one or more chronic microvascular and neuropathic complications. These problems include retinopathy, neuropathy, nephropathy (also called the "triopathies") and cardiovascular disease. Hyperglycemia changes cellular metabolism and cumulative changes in macromolecules are responsible for tissue damage. Pathogenic mechanisms include the accumulation of glucose, fructose and sorbitol in tissues and the modification of proteins by glycation. Extraordinaire les machines à sous vous moisit en un seul clic!

Nathan (Harvard Medical School, Diabetes Clinic) stated that: "Non-insulin-dependent diabetes mellitus (NIDDM) may be the most rapidly growing chronic disease in the world. Its long-term complications, including retinopathy, nephropathy, neuropathy, and accelerated macrovascular disease cause major morbidity and mortality... pathogenic mechanisms include the accumulation of sorbitol and other biochemical changes in tissues with aldose reductase, and the modification of proteins by glycation." (Clin Invest Med,(18: 4, 1995 Aug, 332-9 )

Clearly, heroic efforts are more that justified to change life-style determinants of the disease early on so that the terrible consequences of neglected diabetes are avoided.

Adverse Consequences of type 2 Diabetes

This unhappy list of diabetic consequences has been adapted  from the US National Diabetes Information Clearinghouse:

• Heart disease
• Cardiovascular disease is 2 to 4 times more common in people with diabetes.
• Cardiovascular disease is present in 75 percent of diabetes-related deaths.
• Middle-aged people with diabetes have death rates twice as high and heart disease death rates about 2 to 4 times as high as middle-aged people without diabetes.
• Stroke
• The risk of stroke is 2.5 times higher in people with diabetes.
• High blood pressure
• Affects 60 to 65 percent of people with diabetes.
• Blindness
• Diabetes is the leading cause of new cases of blindness among adults 20 to 74 years of age.
• From 12,000 to 24,000 new cases of blindness per year are caused by diabetic retinopathy.
• Kidney disease (treatment by dialysis or transplantation)
• Diabetes is the leading cause of end-stage renal disease, accounting for36 percent of new cases.
• 19,790 new cases occurred in 1992 in people with diabetes.
• 56,059 people with diabetes were undergoing dialysis or transplantation treatment in 1992.
• Nerve disease
• About 60 to 70 percent of people with diabetes have mild to severe forms of diabetic nerve damage (with such manifestations as impaired sensation in the feet or hands, delayed stomach emptying, carpal tunnel syndrome, peripheral neuropathy).
• Severe forms of diabetic nerve disease are a major contributing cause of lower extremity amputations.
• Amputations
• More than half of lower limb amputations in the United States occur among people with diabetes; from 1989 to 1992, the average number of amputations performed each year among people with diabetes was 54,000.
• Dental disease
• Studies show that periodontal disease, which can lead to tooth loss, occurs with greater frequency and severity in people with diabetes. In one study, 30 percent of IDDM patients age 19 years or older had periodontal disease.
• The rate of tooth loss is 15 times higher in Pima Indians with NIDDM, compared to those without diabetes, and the incidence of periodontal disease is 2.6 times higher.
• Pregnancy
• The rate of major congenital malformations in babies born to women with preexisting diabetes varies from 0 to 5 percent in women who receive preconception care to 10 percent in women who do not receive preconception care.
• Three to 5 percent of pregnancies in women with diabetes result in death of the newborn; this compares to a rate of 1.5 percent in women who do not have diabetes.

Notes From the 56th annual meeting and scientific sessions of the American Diabetes Association, San Francisco, CA June 10, 1996

Dr. Michael Brownlee of the Albert Einstein Medical College (New York) described how sugar-modified proteins or Advanced Glycation End-Products (AGEs) appear to damage tissues in three ways:

1. The  intracellular production of AGEs can cause immediate protein dysfunction.
2. AGE receptors on cells may be activated, resulting in the alteration of gene expression and an increased production of cytokines including TNF, IL-1 and IGF-1. These may induce the proliferation of the cellular matrix. The activation of endothelial AGE receptors may cause expression of endothelin, which can cause vasoconstriction and thrombosis, and may play a role in acute MIs in diabetic patients.
3. AGEs that bind to extracellular matrix molecules can alter the cell matrix. This may result, for example, in an increase permeability to albumin (FEBS Letts 1995;375:41)

Current Research

Several strategies have been developed to block the activity or development of AGEs. For example:

• Compounds that inhibit the crosslinking of AGEs and proteins and the development of "crosslink breakers" such as n- phenacyl-thiazoliuum bromide, designed to break apart crosslinked macromolecules.
• AGE formation inhibitors - aminoguanidine ( pimagedine).

Aminoguanidine reacts with 3-deoxyglucosone, a major precursor for AGE. This reaction forms substituted triazine compounds that are harmlessly excreted in the urine. In animals, aminogunaidine has been shown to limit the development of diabetic retinopathy and to reduce the incidence of microaneurysms by 85%. It has also been shown to prevent diabetic nephropathy by minimizing the fractional mesangial volume, which is elevated in diabetic patients. Furthermore, in animals, albumin excretion is reduced by 85% following treatment with aminoguanidine. Preliminary evidence indicates that nerve conduction can be restored in diabetic animals treated with this drug. Clinical studies are currently underway looking at the effects of aminoguanidine on diabetic nephropathy. These are enrolling patients with both type I and type II diabetes, and results should be available within the next 2 to 4 years. To date, preliminary analyses indicate that doses of 150 to 300 mg bid are well tolerated, although their effectiveness has not yet been determined.

Douglas Greene, MD discussed new treatments for patients with peripheral neuropathy. In these patients, progressive nerve fiber damage and loss occurs, and the Diabetes Control and Complication Trial (DCCT) showed that intensive treatment with insulin resulting in tight glycemic control could reduce the incidence of this neuropathy by 60%.

One approach has been to target the polyol pathway. In this pathway, glucose is converted to sorbitol by aldose reductase; sorbitol is then converted to fructose, which serves as a substrate for glycation and crosslinking. Aldose reductase inhibitors (ARIs), which block the conversion of glucose to sorbitol, may limit the formation of products that induce cellular changes associated with neuropathy. To date, the experience with ARIs has been variable. He noted that the new agent FK366 can induce dose-related decreases in nerve sorbitol content and is the first agent in this class to decrease sorbitol content by 85% at the higher doses (600 mg). Previous ARIs were able to decrease sorbitol levels by only 50%. Because new techniques are now available to more accurately characterize nerve function, Dr. Greene was enthusiastic about new research into the ARIs. For example, zopolrestat has been shown in man to significantly improve nerve conduction velocity after 12 weeks of treatment.

Other approaches include the use of antioxidants such as alpha- lipoic acid. In high IV doses, this compound decreased nerve pain scores for burning, paresthesia, and numbness in patients with diabetes. Also, evening primrose oil has been shown to increase gamma-linoleic acid levels, which in turn improves nerve function.

Elevated Blood Fats

Some of the vascular disease can be explained as atherosclerosis and attributed to abnormalities in blood fats. A high sugar and  fat in the diet of diabetics is a lethal combination. More than 60 % of non-insulin dependent diabetes have elevated blood fat levels.

Cholesterol - Total	increased	Goal
LDL	increased	<2.5
HDL	decreased	>1.1
Triglycerides	increased	<2.0
apo lipoprotein B	increased

Return to Diabetes Center   See Lipid Abnormalities

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