Chronic Complications in Diabetes
AGE Products
The two basic mechanisms of secondary complications of diabetes are the polyol pathway and non-enzymatic protein glycosylation. In non-enzymatic protein glycosylation, high amounts of circulating sugars start to attach to proteins, forming a compound called Amadori. After weeks to years, the Amadori product undergoes an irreversible conversion to form a complex compound called Advanced Glycosylation End (AGE) products.
AGE products are found throughout the body but in high levels in connective tissues, blood vessels, the matrix of the renal glomerulus, and the phospholipid component of low-density lipoproteins (LDL). High levels of AGE are associated with structural alterations within the body, including increased vascular permeability, loss of vascular elasticity, reduced clearance of lipoproteins, and altered enzyme function. This reduced clearance of lipoproteins is one of the main contributing factors to the high cardiovascular mortality found in diabetic patients.
AGE products are atherogenic and one of the main contributors to accelerating atherosclerosis in diabetics. Treating hypertension in long-term uncontrolled diabetics can be a very difficult challenge. It is not uncommon for these patients to be on three antihypertensive drugs and still not have adequate control.
Diabetic Retinopathy
Hyperglycemia will eventually cause the retinal cells to have an accumulation of sorbitol through the polyol pathway, which causes an increase in osmosis. The high levels of sorbitol are not easily able to diffuse out of the cell in which it is produced. This causes a high osmotic swelling, in which water will enter the cell. Due to the buildup of water pressure in the cell, valuable antioxidants, such as glutathione and myoinositol, are pushed out and thereby free radical damage occurs within the eye. This causes diabetic retinopathy.
The progression of diabetic retinopathy may actually begin without any overt symptoms. Eye exam will initially reveal visible lesions. Micro-aneurysms on the terminal capillaries of the retina form quite similarly to balloons. They inflate but burst very easily. The increased fragility and weakness of the capillaries start to leak proteinaceous fluid, thereby causing hard exudates. The leaking of red blood cells form hemorrhages. In itself, this process does not cause visual impairment. New capillaries do not form and the condition is thus coined non-proliferative retinopathy.
This differs from proliferative retinopathy, in that the retinal vessels further deteriorate to the point of ischemia (arterial narrowing and blockage). The resultant ischemia causes new vessels to compensate for the lack of blood flow to the retina. Unfortunately, these vessels are very weak and tend to burst easily, causing hemorrhage into the preretinal areas or vitreous, causing significant vision loss. Diabetic macular edema occurs when fluid from abnormal vessels leaks into the macula. Retinal detachment is a medical emergency and needs to be treated by eye surgeons as soon as possible.
Progression of Diabetic Retinopathy
Name of condition Eye Exam
Nonproliferative diabetic retinopathy Retinal micro-aneurysms
Proliferative diabetic retinopathy New vessels on the disc
High risk proliferative retinopathy New vessels with vitreous as hemorrhage
Diabetic macular edema Hard exudates < 2 disc
Diabetic Neuropathy
Diabetic neuropathy and retinopathy both have something in common: accumulation of sorbitol. Nerve damage (neuropathy) is an easily treatable condition when one understands its pathology. The polyol pathway happens also in the capillaries of the retina as in the Schwann cells of the nerves. Neuropathy and vascular disease account for the high incidence of diabetic foot amputations.
The most common type of neuropathy is distal symmetrical polyneuropathy, which involves loss of vibration in the toes and loss of ankle reflexes. This can be found on a routine physical exam. Many drugs inhibit the absorption of vitamin B-12 and can cause vitamin deficiency-induced neuropathy that must be differentiated from hyperglycemia-induced neuropathy. Symptoms include numbness and paresthesias that may cause severe burning and prickling sensations. Pathological examination shows axonal destruction due to the complications of sorbitol buildup.
Mononeuropathies come on with a sudden onset and leave usually spontaneously. They may affect the third, fourth, sixth, and seventh cranial nerve. Truncal neuropathy in the T4 -T12 area also exists. The pain is constant, unrelenting, worse at night, and is often confused with cardiac or gastrointestinal disease.
Diabetic neuropathy, like all illnesses, can cause depression. Diabetic neuropathic cachexia involves neuropathy along with symptoms of anorexia and depression. Autonomic neuropathy, including both sympathetic and parasympathetic nerves, can cause a variety of problems, including resting tachycardia, postural hypotension, bladder dysfunction, and lack of peristalsis in the stomach (gastroparesis).
Diabetic Nephropathy
Diabetic nephropathy is the leading cause of end-stage renal disease. It goes through a very predictable pattern of five stages. Cardiovascular disease and mortality are a great risk for patients suffering from diabetic renal disease. Nephropathy leads to systemic hypertension because of hyperlipidemia and a decreased clearance of atherogenic advanced glycosylation end products.
Progression of Renal Disease in Insulin-Dependent Diabetes
| Stage | Onset | Lab | Risk Factors | Treatment |
| 1. Early Hypertrophy and Hyperfunction | Initial diagnosis | Increased glomerular filtration rate | Hyperglycemia
Hypertension Stress homocysteine Hypoantioxidants Pharmaceuticals Protein diet Smoking Insulin resistance |
Decrease:
Hyperglycemia Hypertension Replace: Kidney toxic pharmaceuticals with natural medicine if possible Increase: Antioxidants Herbal kidney support ACE inhibitors |
| 2. Renal Lesions | 3 years after diagnosis | Increased glomerular filtration rate | As above | As above |
| 3. Incipient Nephropathy | 7-15 years after diagnosis | Glomerular filtration rate beginning to decline. Albumin found in urine more than 0.03 g/daily. | As above | As above |
| 4. Clinical Diabetic Nephropathy | 10-30 years after diagnosis | Glomerular filtration rate continues to decrease. Urinary albumin continues to increase. | As above | As above |
| 5. End-stage Renal Disease | 20-40 years after diagnosis | Glomerular filtration rate very low. Increased serum creatinine. | As above | As above, dialysis |
(Adapted from Selby JV, Fitzsimmons SC, Newman JM, et al. The natural history and epidemiology of diabetic nephropathy: Implications for prevention and control. JAMA 1959;263;1954-59)
Infections
Patients with undiagnosed high blood sugar may come into the office for the treatment of an infection. Infections are more likely in diabetic patients due to glycosylation of tissues that causes irritation and increases susceptibility to infection. Diabetics have an abnormal white blood cell defense, in which polymorphonuclear white blood cells have a decreased ability to perform chemotaxis, a reduced ability to degranulate, and a decreased production of free radicals that destroy infections. This makes diabetics more prone to infections, chiefly Staphylococcus, Streptococcus, and Candidiasis.
Foot Infections and Amputation
Diabetics are especially prone to foot infections. As many as 25% of all diabetics will develop severe foot problems at some point in their lifetime. Half of all amputations in the United States result from diabetes.
Diabetic foot infections are generally more severe and more difficult to treat than infections in non-diabetics. This is due to impaired microvascular circulation, neuropathy, anatomical alterations, and impaired immune capacity in diabetic patients. Most moderate-to-severe soft-tissue diabetic foot infections are polymicrobial (i.e., due to gram-positive, gram-negative, aerobic, and anaerobic pathogens).
Early detection and prompt attention by checking for signs of infection will significantly decrease the risk of serious complications. Although one would think that the vascular insufficiency is the main cause of diabetic foot ulcerations, it is actually the neuropathy. It is speculated that uneven pressure on the plantar side of the foot leads to microtrauma to the tissues, which allows the bacteria to enter and start reproducing. The patient will have no pain due to the neuropathy and thus continues to walk on it, further aggravating the condition. This eventually results in deep soft tissue and/ or bone infections.
Cardiovascular Disease
Cardiovascular disease and mortality are a great risk for patients suffering from diabetic renal disease. Nephropathy leads to systemic hypertension because of hyperlipidemia and a decreased clearance of atherogenic advanced glycosylation end products. In a study of NIDDM in Pima Indians, it was found that diabetics who had albumin in the urine (indicating renal disease) had 3.5 times greater risk for cardiovascular disease and overall mortality than the ones who had no albumin in the urine.
Diabetic patients have a fourfold chance of having both macrovascular and microvascular disease. Smoking, dyslipidemia, insulin resistance, homocysteine levels, emotional stress, and lack of general antioxidants due to the oxidation of LDL and low levels of vitamin E all need to be considered when treating diabetic patients with high cardiovascular risk factor.
The clinical signs of ischemic heart disease in diabetic patients are different than in other patients. This is one reason that thyroid hormone therapy has to be used cautiously with diabetics, due to its potential of increasing cardiac blood flow. Diabetic patients often will have a silent ischemia, making it more difficult to diagnose. Patients may have no pain, just nausea or sweating.
Furthermore, hyperinsulinemia and insulin resistance are independent risk factors for the development of atherosclerosis.
Gestational Diabetes
Gestational diabetes (GDM) is diagnosed in pregnancy and limited to pregnancy. GDM affects 5% to 7% of women during their pregnancies. It is defined as abnormally high blood sugar levels after a meal. The usual diagnosis of GDM is by a 3-hour glucose tolerance test, whereby the mother drinks a 100 g sugar solution. The standard criteria is: Fasting levels < 105 mg/dl, 1 hour > 190, 2 hours > 165, 3 hours > 145 mg/dl. If a women is higher at any two time points, she is diagnosed with GDM.
Risk factors include a family history of diabetes, body weight above 115% of ideal, and poor dietary patterns. Babies born to mothers with gestational diabetes may be abnormally large, may suffer from jaundice, may have low blood sugar and low calcium, and may experience traumatic births. Women with gestational diabetes are more likely to become diabetic after pregnancy.
Pregnancy is a complex metabolic state. There is a dramatic alteration in hormone levels, including increased levels of cortisol, progesterone, prolactin, estrogen, and human chorionic gonadotropin. The high levels of circulating hormones have been shown to decrease insulin receptor binding. Human chorionic gonadotropin and human placental lactogen also decrease post receptor effects of insulin. Needless to say, there is also an increased demand of fuel from the fetus. This makes it very difficult for the mother to keep up with all the hormonal changes.
From 20 weeks onward into pregnancy, insulin resistance is common. In normal pregnancy, maternal secretion of insulin increases in late second and third trimesters to compensate for insulin resistance. Glucose not only alters during pregnancy, but triglycerides, cholesterol, and free fatty acids are also increased in the blood, as commonly found in insulin resistance.
Risks
The immediate risks of gestational diabetes to the mother include increased hypertension and preeclampsia; the later risk is developing diabetes itself.
The risk to the fetus is fetal macrosomia (increased fetal size).The postulated mechanism for this is due to the high levels of fuels, such as glucose, amino acids, lipids, and insulin. Congenital abnormalities from diabetes in the early era were about 33%, but now with drug treatment and insulin only 1.6% to 2% of diabetic pregnant women have children with congenital abnormalities.
Secondary Diabetes
Diabetes can be secondary to liver disease, due to the liver’s role in producing hepatic insulin sensitizing substrate. Diabetes can also be secondary to other diseases, such as pancreatectomy, hemochromatosis, cystic fibrosis, and chronic pancreatitis. Endocrinopathies, such as acromegaly, pheochromocytoma, Cushing’s syndrome, primary aldosteronism, and glucagonoma, are all potential causes of diabetes as well.
Iatrogenic Diabetes
Antihypertensive drugs, thiazide diuretics, glucocorticoids, estrogens, psychoactive medications, and pentamidine all can be causes of impaired glucose tolerance. Virtually all non-controlled diabetic patients end up on antihypertensive drugs due to diabetic induced high blood pressure, and many will need thiazide diuretics due to congestive heart failure initiated by the hypertension. Antihypertensive and thiazide diuretics drugs intensify insulin resistance, thereby further intensifying diabetic illness.
