The risk of chronic complications increases as a function of the duration of hyperglycemia; they usually become apparent in the second decade of hyperglycemia. Since type 2 DM often has a long asymptomatic period of hyperglycemia, many individuals with type 2 DM have complications at the time of diagnosis. For example, despite long-standing DM, some individuals never develop nephropathy or retinopathy. Many of these patients have glycemic control that is indistinguishable from those who develop microvascular complications, suggesting that there is a genetic susceptibility for developing particular complications
Mechanism of hyper glicemia
One theory is that increased intracellular glucose leads to the formation of advanced glycosylation end products (AGEs) via the nonenzymatic glycosylation of intra- and extracellular proteins. Nonenzymatic glycosylation results from the interaction of glucose with amino groups on proteins. AGEs have been shown to cross-link proteins (e.g., collagen, extracellular matrix proteins), accelerate atherosclerosis, promote glomerular dysfunction, reduce nitric oxide synthesis, induce endothelial dysfunction, and alter extracellular matrix composition and structure.
Intracellular glucose is predominantly metabolized by phosphorylation and subsequent glycolysis, but when increased, some glucose is converted to sorbitol by the enzyme aldose reductase. Increased sorbitol concentration alters redox potential, increases cellular osmolality, generates reactive oxygen species, and likely leads to other types of cellular dysfunction.
A third hypothesis proposes that hyperglycemia increases the formation of diacylglycerol leading to activation of protein kinase C (PKC). Among other actions, PKC alters the transcription of genes for fibronectin, type IV collagen, contractile proteins, and extracellular matrix proteins in endothelial cells and neurons
A fourth theory proposes that hyperglycemia increases the flux through the hexosamine pathway, which generates fructose-6-phosphate, a substrate for O-linked glycosylation and proteoglycan production. The hexosamine pathway may alter function by glycosylation of proteins such as endothelial nitric oxide synthase or by changes in gene expression of transforming growth factor (TGF-) or plasminogen activator inhibitor-1 (PAI-1).
Vascular endothelial growth factor A (VEGF-A) is increased locally in diabetic proliferative retinopathy and decreases after laser photocoagulation. TGF- is increased in diabetic nephropathy and stimulates basement membrane production of collagen and fibronectin by mesangial cells. A possible unifying mechanism is that hyperglycemia leads to increased production of reactive oxygen species or superoxide in the mitochondria; these compounds may activate all four of the pathways described above.
One of the major findings of the UKPDS was that strict blood pressure control significantly reduced both macro- and microvascular complications.
Retinopathy
The gravity of this problem is highlighted by the finding that individuals with DM are 25 times more likely to become legally blind than individuals without DM. Diabetic retinopathy is classified into two stages: nonproliferative and proliferative. Nonproliferative diabetic retinopathy usually appears late in the first decade or early in the second decade of the disease and is marked by retinal vascular microaneurysms, blot hemorrhages, and cotton wool spots (Fig. 338-9). Mild nonproliferative retinopathy progresses to more extensive disease, characterized by changes in venous vessel caliber, intraretinal microvascular abnormalities, and more numerous microaneurysms and hemorrhages. The pathophysiologic mechanisms invoked in nonproliferative retinopathy include loss of retinal pericytes, increased retinal vascular permeability, alterations in retinal blood flow, and abnormal retinal microvasculature, all of which lead to retinal ischemia. The appearance of neovascularization in response to retinal hypoxia is the hallmark of proliferative diabetic retinopathy (Fig. 338-9). These newly formed vessels appear near the optic nerve and/or macula and rupture easily, leading to vitreous hemorrhage, fibrosis, and ultimately retinal detachment. Fluorescein angiography is useful to detect macular edema, which is associated with a 25% chance of moderate visual loss over the next 3 years. Duration of DM and degree of glycemic control are the best predictors of the development of retinopathy; hypertension is also a risk factor. Laser photocoagulation is very successful in preserving vision. Proliferative retinopathy is usually treated with panretinal laser photocoagulation, whereas macular edema is treated with focal laser photocoagulation.
Nephropathy
Diabetic nephropathy is the leading cause of ESRD in the United States and a leading cause of DM-related morbidity and mortality. Both microalbuminuria and macroalbuminuria in individuals with DM are associated with increased risk of cardiovascular disease. Individuals with diabetic nephropathy commonly have diabetic retinopathy.
Like other microvascular complications, the pathogenesis of diabetic nephropathy is related to chronic hyperglycemia. Smoking accelerates the decline in renal function. Because only 20–40% of patients with diabetes develop diabetic nephropathy, additional susceptibility factors remain unidentified. One known risk factor is a family history of diabetic nephropathy.
Glomerular hyperperfusion and renal hypertrophy occur in the first years after the onset of DM and are associated with an increase of the glomerular filtration rate (GFR). During the first 5 years of DM, thickening of the glomerular basement membrane, glomerular hypertrophy, and mesangial volume expansion occur as the GFR returns to normal. After 5–10 years of type 1 DM, ~40% of individuals begin to excrete small amounts of albumin in the urine. Microalbuminuria is defined as 30–300 mg/d in a 24-h collection or 30–300 mg/mg creatinine in a spot collection (preferred method). Although the appearance of microalbuminuria in type 1 DM is an important risk factor for progression to overt proteinuria (>300 mg/d), only ~50% of individuals progress to macroalbuminuria over the next 10 years. In some individuals with type 1 diabetes and microalbuminuria of short duration, the microalbuminuria regresses. Once macroalbuminuria is present, there is a steady decline in GFR, and ~50% of individuals reach ESRD in 7–10 years. Once macroalbuminuria develops, blood pressure rises slightly and the pathologic changes are likely irreversible. Some individuals with type 1 or type 2 DM have a decline in GFR in the absence of micro- or macroalbuminuria and this is the basis for assessing the GFR on an annual basis using serum creatinine. Finally, it should be noted that albuminuria in type 2 DM may be secondary to factors unrelated to DM, such as hypertension, congestive heart failure (CHF), prostate disease, or infection.
Type IV renal tubular acidosis (hyporeninemic hypoaldosteronism) may occur in type 1 or 2 DM. These individuals develop a propensity to hyperkalemia, which may be exacerbated by medications [especially angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs)]. Patients with DM are predisposed to radiocontrast-induced nephrotoxicity. Risk factors for radiocontrast-induced nephrotoxicity are preexisting nephropathy and volume depletion.
The recommended strategy for detecting microalbuminuria is outlined in Fig. 338-11 and includes annual measurement of the serum creatinine to estimate GFR.
Screening for microalbuminuria should be performed in patients with type 1 diabetes for more tan 5 years, in patients with type 2 diabetes, and during pregnancy
Non-diabetes-related conditions that might increase microalbuminuria are urinary tract infection, hematuria, heart failure, febrile illness, severe hyperglycemia, severe hypertension, and vigorous exercise
During the phase of declining renal function, insulin requirements may fall as the kidney is a site of insulin degradation. Furthermore, many glucose-lowering medications (sulfonylureas and metformin) are contraindicated in advanced renal insufficiency. pressure should be maintained at <130/80 style="background: yellow none repeat scroll 0% 0%; -moz-background-clip: -moz-initial; -moz-background-origin: -moz-initial; -moz-background-inline-policy: -moz-initial;">macroalbuminuria.
The ADA suggests modest restriction of protein intake in diabetic individuals with microalbuminuria (0.8 g/kg per day) or macroalbuminuria (<0.8>, which is the adult Recommended Daily Allowance, or ~10% of the daily caloric intake).
Neuropathy
Additional risk factors are BMI (the greater the BMI, the greater the risk of neuropathy) and smoking. The presence of cardiovascular disease, elevated triglycerides, and hypertension is also associated with diabetic peripheral neuropathy. The ADA recommends screening for distal symmetric neuropathy beginning with the initial diagnosis of diabetes and screening for autonomic neuropathy 5 years after diagnosis of type 1 DM and at the time of diagnosis of type 2 DM. All individuals with diabetes should then be screened annually for both forms of neuropathy.
Polyneuropathy/Mononeuropathy
The most common form of diabetic neuropathy is distal symmetric polyneuropathy. It most frequently presents with distal sensory loss, but up to 50% of patients do not have symptoms of neuropathy. Hyperesthesia, paresthesia, and dysesthesia also may occur. Any combination of these symptoms may develop as neuropathy progresses. Symptoms may include a sensation of numbness, tingling, sharpness, or burning that begins in the feet and spreads proximally. Neuropathic pain develops in some of these individuals, occasionally preceded by improvement in their glycemic control. Pain typically involves the lower extremities, is usually present at rest, and worsens at night. Both an acute (lasting <12>. As diabetic neuropathy progresses, the pain subsides and eventually disappears, but a sensory deficit in the lower extremities persists. Physical examination reveals sensory loss, loss of ankle reflexes, and abnormal position sense.
Diabetic polyradiculopathy is a syndrome characterized by severe disabling pain in the distribution of one or more nerve roots. It may be accompanied by motor weakness. Intercostal or truncal radiculopathy causes pain over the thorax or abdomen. Involvement of the lumbar plexus or femoral nerve may cause severe pain in the thigh or hip and may be associated with muscle weakness in the hip flexors or extensors (diabetic amyotrophy).
Mononeuropathy (dysfunction of isolated cranial or peripheral nerves) is less common than polyneuropathy in DM and presents with pain and motor weakness in the distribution of a single nerve. A vascular etiology has been suggested, but the pathogenesis is unknown. Involvement of the third cranial nerve is most common and is heralded by diplopia. Physical examination reveals ptosis and ophthalmoplegia with normal pupillary constriction to light. Sometimes other cranial nerves IV, VI, or VII (Bell's palsy) are affected. Peripheral mononeuropathies or simultaneous involvement of more than one nerve (mononeuropathy multiplex) may also occur.
Autonomic
Autonomic neuropathies affecting the cardiovascular system cause a resting tachycardia and orthostatic hypotension. Reports of sudden death have also been attributed to autonomic neuropathy. Gastroparesis and bladder-emptying abnormalities are often caused by the autonomic neuropathy seen in DM (discussed below). Hyperhidrosis of the upper extremities and anhidrosis of the lower extremities result from sympathetic nervous system dysfunction. Anhidrosis of the feet can promote dry skin with cracking, which increases the risk of foot ulcers. Autonomic neuropathy may reduce counterregulatory hormone release, leading to an inability to sense hypoglycemia appropriately (hypoglycemia unawareness).
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