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Other studies have enabled researchers to piece together a scenario for the causes of diabetic nephropathy, where glycosylation of proteins, abnormal clotting factors, abnormal platelets, antibodies to glycosylated proteins, and so on, join together to injure glomerular capillaries. Early injury may only cause reduction of electrical charge on the pores. As a result, negatively charged proteins such as albumin leak through the pores and appear in the urine. Glycosylated proteins leak through pores much earlier than normal proteins. High blood pressure, and especially high serum insulin levels, can increase GFR and force even more protein to leak through the pores. If some of these proteins are glycosylated, they will stick to the mesangium, the tissue between the capillaries. Examination of diabetic glomeruli indeed discloses large deposits of glycosylated proteins and antibodies to glycosylated proteins in capillary walls and mesangium. As these deposits increase, the mesangium compresses the capillaries, causing pressure in the capillaries to increase and larger proteins to leak from the pores. This leads to more thickening of the mesangium, more compression of the capillaries, and acceleration of destruction. Eventually the mesangium and capillaries become a mass of scar tissue. Independently of this, both high blood sugars and glycosylated proteins cause mesangial cells to produce type IV collagen, a fibrous material that further increases their bulk.

Many studies performed on humans show that when blood sugars improve, GFR improves and less protein leaks into the urine. When blood sugars remain high, however, there is further deterioration. There is a point of no return, where a glomerulus has been so injured that no amount of blood sugar improvement can revive it.

Nowadays many diabetics who have lost all kidney function are treated by artificial kidneys (dialysis machines) that remove nitrogenous wastes from the blood. In order to reduce the weekly number of dialysis treatments, which are costly and unpleasant, patients are severely restricted in their consumption of dietary protein. Instead of using large amounts of carbohydrate to replace the lost calories, many dialysis centers now recommend olive oil to their diabetics. Olive oil is high in monounsaturated fats, which are believed to lower the risk of heart disease.

In summary: Diabetic nephropathy does not appear if blood sugar is kept normal. Dietary protein does not cause diabetic nephropathy, but can possibly (still uncertain) accelerate the process once there has been a considerable amount of kidney damage. Dietary protein has no substantial effect upon the GFR of healthy kidneys, certainly not in comparison to the GFR increase caused by elevated blood sugar levels.*

Restrictions on Salt Intake: Are They Reasonable for All Diabetics?

People with advanced glomerulopathy will inevitably develop hypertension in part because GFR is severely diminished. These people cannot make enough urine, and therefore retain water. Excessive water in the blood causes elevated blood pressure. There are many other ways hypertension can be caused by high blood sugars.

The mere presence of high blood sugar will cause water to leave tissues and enter the bloodstream, even experimentally in nondiabetics. It is not unusual to observe reduction in blood pressure concomitant with control of blood sugar. Studies have shown that many, and possibly most, hypertensive nondiabetics are insulin-resistant, and therefore have high serum insulin levels. In addition to causing elevation of serum triglycerides and reduction in serum HDL in nondiabetics, high serum insulin levels have long been known to foster salt and water retention by the kidneys. Furthermore, excessive insulin stimulates the sympathetic nervous system, which in turn speeds up the heart and constricts blood vessels, causing further increase in blood pressure. Thus Type II diabetics who eat lots of carbohydrate, and therefore will tend to make excessive insulin, can readily develop hypertension. Type I diabetics treated with the usual industrial doses of insulin to cover high-carbohydrate diets are likewise more susceptible to hypertension. One dramatic study showed that in hypertensive individuals, blood pressure is directly proportional to serum insulin level. A report from Nottingham, England, showed that a brief infusion of insulin and glucose would increase blood pressure in normal men without changing their blood sugars.

Why don't all diabetics on high-carbohydrate diets or all poorly controlled diabetics have hypertension?

One reason is that the body has several very efficient systems for unloading sodium (a component of salt) and water. One of the more important of these systems is controlled by a hormone manufactured in the heart called atrial naturietic factor (ANF). When the heart is expanded by even a slight fluid overload, it produces ANF. The ANF then signals the kidneys to unload sodium and water. Hypertensive individuals, and the children of two hypertensive parents, tend to produce much lower amounts of ANF than do normal people. Nonhypertensive diabetics apparently are able to produce enough ANF to control the blood pressure effects of high blood sugars and high serum insulin levels, provided they do not have moderately advanced kidney disease. Indeed, a study, in which some of my patients participated, showed that diabetics with high blood sugars produce significantly more ANF than those with lower blood sugars.

How does all this apply to you? First, you and your physician should know if you have glomerulopathy. This is readily determined if the tests suggested in Chapter 2 are performed. If these tests are abnormal, your physician may advise you to reduce your salt intake.

Whether your renal risk profile is normal or abnormal, your resting blood pressure should also be measured. A proper measurement requires that you first be seated in a quiet room, without conversation, for 15–30 minutes. Blood pressure should be measured every 5 minutes, until it drops to a low value and then starts to increase. The lowest reading is the significant one. If you get nervous in the doctor's office, then you should measure your own blood pressure at home in a similar fashion. Repeated measurements, with low values just exceeding 135/85, suggest that your blood pressure is "borderline." (The American Diabetes Association suggests that 120/80 be considered borderline for younger diabetics.) You may benefit from dietary salt reduction. The only way to find out is to check your blood pressure while on your current salt intake, and again after following a low-salt (sodium) diet for at least three weeks. Your physician can give you guidelines for such a diet, and you can consult nutritional tables such as those in the books listed in Chapter 3. I would suggest that resting blood pressures be measured several times a day, and at the same hours each day, throughout the study. Blood pressures can then be averaged, and the averages compared. If your blood pressure drops significantly on the low-salt diet, your physician may urge you to keep the salt intake down. Alternately, he may want you to take small amounts of supplemental potassium, which tends to offset the effects of dietary salt on blood pressure. Recent studies suggest that as many as 40 percent of hypertensive patients (the so-called low-renin hypertensives) may show lower blood pressures when they take calcium supplements.

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