Tufts OpenCourseware
Authors: Ronald Arky, M.D., Anastassios G. Pittas, M.D.
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1. Goals

To learn the pathophysiology, clinical presentation and management of acute and chronic complications of diabetes

2. Learning Objectives

  • To learn the pathophysiology, clinical presentation and management of the acute complications of diabetes due severe hyperglycemia (diabetic ketoacidosis and hyperglycemic hyperosmolar nonketotic state)
  • To learn the pathophysiology, clinical presentation and management of the chronic complications of diabetes which include macrovascular (coronary artery disease, stroke and peripheral vascular disease) and microvascular (retinopathy and nephropathy) and neuropathy (peripheral and autonomic)
  • To appreciate that macrovascular complications are the main cause of death and the microvascular complications the main cause of morbidity
  • To gain an understanding of the mechanisms that lead to glucose induced vascular damage
  • To appreciate that prevention of vascular complications is possible through frequent screening, tight glycemic control and control of other risk factors for vascular disease

3. Introduction

Complications due to diabetes may be either acute or chronic. Acute complications are due to acute severe hyperglycemia while chronic complications are due to vascular damage. The chronic complications account for the high mortality and severe morbidity of diabetes.

4. Acute Complications of Diabetes

4.1. Diabetic Ketoacidosis (DKA)

Diabetic ketoacidosis results from lack of insulin and it is considered a medical emergency as it has a mortality rate of approximately 5 percent, mostly because of late recognition and frequently suboptimal management. Diabetic ketoacidosis can be the first manifestation of type 1 diabetes in a previously undiagnosed patient or can occur in a patient with type 1 diabetes when insulin requirements rise during medical stress. Noncompliance with insulin administration is another common cause of DKA. Although DKA is much more common in type 1 diabetes, it can also occur in patients with type 2 diabetes who have a predominant insulin secretory defect under severe medical stress.

4.1.1. Pathophysiology

Diabetes is often referred to as "starvation in the midst of plenty" and the progression of events that results from acute insulin deficiency holds this concept to be valid. Insulin deficiency leads to impaired peripheral glucose uptake. In the presence of inadequate insulin, energy stores in fat and muscle are rapidly broken down into fatty acids and amino acids, which are then transported to the liver for conversion to glucose and ketones (beta-hydroxybutyrate and acetoacetate). Counter-regulatory hormones such as glucagon, catecholamines, cortisol and growth hormone rise in an attempt to correct the perceived low glucose levels, further contributing to hyperglycemia and ketonemia. The combination of increased production of glucose and ketones with decreased utilization (due to insulin deficiency) results in high levels of these substances. Hyperglycemia causes osmotic diuresis with an ensuing reduction of intravascular volume, which in turn causes an impairment of renal blood flow and an inability to excrete glucose which worsens the hyperglycemia. Hyperosmolality develops which, when severe (over 320 mosm/kg), can cause severe mental status changes and coma. Compromised renal function also leads to impaired excretion of hydrogen ions, further worsening the metabolic acidosis initially caused by the accumulation of ketones (beta-hydroxybutyrate and acetoacetate). Cardiac output and vascular tone can be greatly diminished by acidemia, thereby leading to shock.

4.1.2. Clinical Presentation and Laboratory Evaluation

Patients are often noted to have a recent history of polyuria, polydipsia, fatigue, nausea, vomiting, and abdominal pain often accompanied by symptoms of an underlying infection, such as urinary tract infection, pneumonia or gastroenteritis. Although symptoms suggestive of uncontrolled diabetes can be present for days, the metabolic changes typical of DKA evolve rapidly (usually within a day). On physical examination, patients with DKA can have signs of dehydration, tachycardia, hypotension, fruity breath (due to acetone) and abdominal tenderness, as well as symptoms and signs specific to the precipitating factor (e.g. infection). Mental status changes may be seen in severe DKA (due to an elevated osmolality). Laboratory evaluation reveals hyperglycemia (usually over 250 mg/dl) and acidemia due to an anion gap metabolic acidosis Serum osmolality is variable. Serum levels of sodium and potassium may be low, normal or high but total body stores of sodium and potassium are depleted.

4.1.3. Management

Appropriate treatment of DKA requires restoration of volume and solute homeostasis, correction of insulin deficiency and search for precipitating factors. Management of DKA is summarized in table 1. The details are not important to know, but the concepts underlying treatment are important to understand. The initial treatment for DKA involves fluid resuscitation with normal (0.9%) saline to expand plasma volume to increase renal blood flow and reduce the hyperosmolar state. This measure works to stabilize blood pressure as well as improve the metabolic acidosis with the increased excretion of hydrogen ions. Most adult patients with DKA are thought to have a fluid deficit of 4-5 liters and correcting this deficit appropriately is critical. Shortly after fluid resuscitation is started, a bolus of regular insulin should be administered intravenously followed by a continuous infusion of regular insulin. It is critical to monitor the serum glucose level hourly, as it should not decrease more than 100 mg/dl/hour to prevent cerebral edema. If serum glucose does not fall by 10% during the first hour, then another intravenous bolus of regular insulin can be given. When the blood glucose level reaches 250 mg/dl, intravenous fluids should be changed to D5 0.45% saline to maintain plasma glucose level. This measure helps decrease the chance of cerebral edema as well as hypoglycemia. Insulin infusion should be continued until the ketoacidosis resolves, which usually takes longer than hyperglycemia. Acidosis should not be monitored by the nitroprusside method as this method measures acetoacetate and not beta-hydroxybutyrate. During resolution of ketonemia, beta-hydroxybutyrate is converted to acetoacetate, which may lead to the false belief that acidosis is worsening if the nitroprusside method is used.

Resolution of acidosis should be monitored by following the anion gap. Following resolution of acidosis, subcutaneous insulin is given. In DKA, total body potassium is depleted. It is critical to replete potassium because as the metabolic acidosis is corrected, there is a shift of potassium into the intracellular space with subsequent hypokalemia. Potassium replacement should be held and serum levels closely monitored if there is no change in the serum potassium level and it remains above 5 meq/L or in the setting of renal insufficiency.

Using sodium bicarbonate to correct the metabolic acidosis is a controversial measure because of the potentially deleterious effects of rapid correction of the acidosis. Hypokalemia from rapid intracellular shift of potassium, tissue anoxia from dissociation of oxygen from hemoglobin, and cerebral acidosis all occur if the metabolic acidosis is corrected too quickly. Although serum phosphate may be normal, total body phosphate is depleted in DKA. However, phosphate replacement in DKA is controversial, as no benefit has been shown in randomized trials. Phosphate should be replaced in the setting of severe hypophosphatemia (serum phosphate less than 1 mg/dl) or in patients at risk for cardiac or muscle weakness due to hypoposphatemia.

Essential to the management of DKA is the search for a precipitating cause and an evaluation that includes a chest x-ray, blood cultures, urine cultures, and EKG. If mental status changes are present in the absence of a significant elevation in serum osmolality (over 320 mosm/kg), then other causes for the mental status changes should be entertained

In addition to acute treatment of DKA, patients need to be educated on recognizing symptoms of DKA and preventing its development. Ways to prevent DKA include (1) frequent blood glucose monitoring, (2) continuous insulin administration even when unable to eat (3) knowledge about "sick day" management and (3) monitoring for the presence of ketones. Traditionally, patients are advised to check for urine ketones when their blood glucose is over 250 mg/dl or feeling ill. As noted above, the urine test for ketones has its limitations and it is relatively inconvenient to perform. Currently, patients may evaluate for the presence of acidemia by using glucometers that have the ability to measure beta-hydroxybutyrate from whole blood obtained through a finger stick.

Table 1. Management of diabetic ketoacidosis
Fluid administration
  • Start with 0.9% saline at 15 cc/kg/hr for the first 2 hours, then 0.45% saline at 7.5 cc/kg/hr
  • Decrease the rate as the intravascular volume is repleted
  • Add D5W when the blood glucose level is 250 mg/dl
Insulin replacement
  • Administer an intravenous bolus of 10-20 units of regular insulin initially (0.3 units/kg)
  • Start a continuous intravenous infusion of regular insulin at 0.1 units/kg/hr
  • Monitor serum blood glucose levels hourly and double infusion rate after 2 hours if there is no improvement in serum glucose
  • Glucose levels should not decrease by more than 100 mg/dl per hour to prevent cerebral edema
  • IV infusion of regular insulin should be continued until ketoacidosis resolves, then regular insulin should be given subcutaneously. Dose and frequency of subcutaneous insulin should be calculated based on insulin drip requirements and oral/IV intake
Potassium replacement
  • Serum potassium can be normal or elevated with DKA because of extracellular shifts of potassium with the metabolic acidosis, but total body potassium stores are depleted
  • As the metabolic acidosis is corrected, there is an intracellular shift of potassium and a drop in serum potassium levels
  • If the patient is normokalemic initially, then potassium supplementation should be started at 20 meq/L
  • If the patient is hypokalemic initially, then potassium supplementation should be started at 40 meq/L
  • Potassium replacement should be held in patients with renal failure or persistent hyperkalemia
  • If pH < 7.0 or pH < 7.1 with associated hypotension or arrhythmia, then administer 1 ampule of sodium bicarbonate in D5W or 0.45% saline over 1 hour
  • Do not mix sodium bicarbonate with normal saline
Work-up for precipitating factors
  • CBC, Blood cultures, urine analysis, urine cultures
  • Chest X-ray
  • EKG
  • Further diagnostic testing as needed

4.2. Hyperglycemic, Hypersmolar Nonketotic State (HHNS)

Hyperglycemia, hyperosmolality and dehydration without ketosis are the hallmarks of the HHNS. It can be precipitated in patients with type 2 diabetes by acute stress (infection, stroke, myocardial infarction, surgery), hyperglycemic-inducing drugs (glucocorticoids, thiazide diuretics), or worsening of concomitant chronic disease (kidney failure). Mortality for HHNS is much higher than DKA (approximately 15%) mainly because of the advanced age of the patients and the presence of comorbid conditions. HHNS associated with congestive heart failure or renal failure carries a worse prognosis. The term "hyperosmolar nonketotic coma" is not used anymore; however, it is important to appreciate that mental status changes, such as lethargy and confusion, develop when the serum osmolality rises over 300 mosm/kg.

4.2.1. Pathophysiology

The basic pathophysiology of HHNS is similar to that of DKA. Deficient insulin action due to insulin deficiency relative to increased insulin resistance reduces glucose uptake by muscle and adipose, increases hepatic gluconeogenesis and increases production of glucagon and other counterregulatory hormones. The resultant hyperglycemia causes glucosuria and osmotic diuresis. However, lipolysis and subsequent ketone production are prevented by the presence of small amounts of insulin in type 2 diabetics. Mental status changes that occur with a rise in serum osmolality can perpetuate the hyperosmolar state if patients' access to free water is compromised. When serum osmolality rises over 320 mosm/kg, severe mental changes characterized by obtundation and coma can occur because of fluid shifts within the brain.

4.2.2. Clinical Presentation and Laboratory Evaluation

Polyuria, polydipsia, generalized weakness, and reduced fluid intake all may herald the onset of HHNS by days. The presence of these non-specific symptoms and the lack of symptoms associated with ketosis such as a "fruity" breath and abdominal pain can confound the diagnosis of HHNS and lead to significant clinical worsening prior to recognition. On physical examination, signs of dehydration (decreased skin turgor, dry mucous membranes, orthostatic hypotension) can be present along with mental status changes. Exceptionally elevated serum glucose levels can be found ranging from 800 to 2400 mg/dl along with hyponatremia. Acidemia is generally not present with HHNS.

4.2.3. Management

Fluid replacement is critical in treating HHNS. Fluid replacement should be done cautiously in patients with cardiac disease to avoid fluid overload Fluid replacement alone can dramatically lower glucose levels. Insulin should be administered judiciously as only small amounts may be required to correct hyperglycemia compared with DKA. Dextrose should be added to the fluids when plasma glucose levels reach 250 mg/dl. Electrolytes should be monitored and repleted (see section on DKA).

As in DKA, essential to the management of HHNS is the search for a precipitating cause and an evaluation that includes a chest x-ray, blood cultures, urine cultures, and EKG. If mental status changes are present in the absence of a significant elevation in serum osmolality (over 320 mosm/kg), then other causes for the mental status changes should be entertained.

4.3. Hypoglycemia

Hypoglycemia is a frequent side effect of diabetes treatment and it is the limiting factor in the glycemic management of diabetes. It is associated with insulin administration in type 1 and type 2 diabetes or use of insulin secretagogues in type 2 diabetes. In addition to potential serious consequences, hypoglycemia can be disturbing and frightening experience for patients and its frequent occurrence may prevent achievement of tight glycemic control. (See lecture on Hypoglycemia for further discussion.)

5. Chronic Complications of Diabetes

The chronic complications of diabetes account for the significant morbidity and mortality of the disease. They can be divided in macrovascular (coronary artery disease, stroke and peripheral vascular disease) which are the main cause of death and microvascular (retinopathy, nephropathy and neuropathy which are the main cause of morbidity (decreased quality of life and disability).

5.1. Macrovascular Complications

The hyperglycemia of diabetes is strongly associated with coronary heart disease, stroke and peripheral vascular disease. In addition to hyperglycemia, excess macrovascular disease, especially coronary heart disease, is also attributed to other risk factors such as dyslipidemia, hypertension and hypercoagulability. These risk factors often cluster together with hyperglycemia (diabetes) in a syndrome known as the metabolic syndrome (see lecture on Pathophysiology of Diabetes).

5.1.1. Coronary Heart Disease

Coronary heart disease (CHD) accounts for the majority of diabetic deaths. Certain features of CHD and diabetes include:

  • Adjusted for age, myocardial infarction is 2-5 times more frequent in patients with diabetes. Indeed, a patient with diabetes without previous myocardial infarction (MI) has as high a risk for MI as a patinet without diabetes and a previous MI.
  • Patients with diabetes who have an MI have a lower survival rate compared to patients without diabetes and MI.
  • There is a geatly increased incidence of "Silent MI" (40% of patients). This may be due to sensory neuropathy.
  • Silent MI may present as new onset of CHF without pain.
  • Small vessel disease with relatively patent coronary arteries appears to be more common.

Because of this high risk of MI, diabetes has been designated as CHD-equivalent, meaning that patients with diabetes should be treated aggresively for "secondary" prevention of CHD.

5.1.2. Cerebrovascular Disease

Diabetes results in diffuse atherosclerosis in the large peripheral arteries, especially at the bifurcation of vessels. Carotid stenosis is more common in patients with diabetes and stroke is almost always due to occlusive vascular disease. Stroke carries a three times higher mortality in diabetes compared to non-diabetics.

5.1.3. Peripheral Vascular Disease

Special characteristics of diabetic peripheral vascular disease:

  1. Location: tibial and popliteal arteries, rarely aorto-ilio-femoral
  2. Extent: multi-segmental occlusions
  3. Progression: accelerated progression compared to non diabetics.
  4. Gangrene: risk is increased 53X in men and 71X in women compared to non diabetics over 40 years of age

Lower extremity vascular disease greatly predisposes a patient to ischemic foot ulcers. Gangrene occurs as result of arterial occlusion. With infection is "wet" gangrene. It most often occurs in conjunction with peripheral neuropathy so that patient develops small painless ulceration, e.g. from poorly fitting shoes, that goes unnoticed and untreated it progresses to gangrene. Patients with diabetes should be counseled on proper foot care and avoidance of agents that reduce peripheral blood flow, such as tobacco.

5.1.4. Prevention and Treatment of Macrovascular Complications

Although epidemiologic studies strongly suggest a relationship between persistent hyperglycemia and macrovascular complications, control of glycemia alone has not been convincingly shown to decrease macrovascular complications in randomized trials. Therefore, although near euglycemia is desirable for decreasing microvascular complications (see below), it may not reduce cardiovascular risk alone. That observation implies that the other components of the metabolic syndrome need to be optimally managed as well to decrease risk. As mentioned previously, diabetes is currently considered to be a CHD-equivalent and as such, treatment guidelines for diabetes are similar to those of secondary prevention of CHD. The goals for diabetes management in relation to vascular disease are summarized in table below.

Table 2. Recommendations for adults with diabetes
Glycemic Control, Hemoglobin A1c < 7 %
Blood Pressure < 130/80 mmHg
  • LDL
  • Triglycerides
  • HDL
  • < 100 mg/dl
  • < 150 mg/dl
  • > 40 mg/dl
Aspirin 81-320 mg daily

Frequent examination of feet by the patient (small sores, fissures and blisters) and the health care provider (quality of pulse, pressure sensation, temperature, hair loss) is of paramount importance in early identification of peripheral complications. Prompt referral to a podiatrist (for proper fitting of shoes, nail care) and to vascular surgeon of management of ulcers is important. Surgical procedures, such vascular bypass, can be done in selected patients to improve blood flow. Amputation of an infected extremity is a last resort.

5.2. Microvascular Complications

5.2.1. Retinopathy

Diabetic retinopathy is the most common cause of blindness in the U.S. in adults between ages 20 and 74. Among all complications of diabetes, retinopathy carries the highest correlation with the severity and duration of diabetes. The Wisconsin Epidemiological Study of Diabetic Retinopathy (WESDR) showed that 3.6% of patients with diabetes who were under 30 years of age and 1.6% of patients over 30 years of age at time of diagnosis were legally blind. After 20 years of diabetes, almost all patients with type 1 diabetes and over 60% of type 2 diabetes patients have evidence of retinopathy.

Up to 20% of patients with type 2 diabetics have some degree of retinopathy at the time of diagnosis, suggesting that the disease has gone unrecognized for some time. The progression of retinopathy is well defined and it is a function of the severity of baseline retinopathy and the severity of glycemia, as shown by the WESDR Study. Classification and Pathophysiology of Diabetic Retinopathy

  • Non proliferative diabetic retinopathy (NPDR): increased vascular permeability, venous dilation, microaneurysms, intraretinal hemorrhage, fluid leakage and retinal ischemia. After fluid leakage, when water is reabsorbed, lipid and protein form hard exudates. Generally, these changes do not cause vision problems unless they affect the macula.
  • Proliferative diabetic retinopathy (PDR): neovascularization (which is disordered), vitreous hemorrhage and fibrous proliferation (scarring).

Diabetic retinopathy leads to vision loss via various mechanisms such as:

  • Central vision impairment by macular edema or capillary
  • Vitreous hemorrhage from neovascularization
  • Retinal detachment due to traction from scarring

Hyperglycemia is the primary cause of diabetic retinopathy but the specific pathophysiologic mechanisms are not well understood. One of the earliest defects induced by hyperglycemia is thought to be death of microvascular contractile cells (pericytes) and the loss of intracellular contacts which leads to microaneurysms and leakage. Certain growth factors have been implicated in the development of the next phase - proliferative retinopathy. The most studied one is Vascular Endothelium Growth Factor (VGEF). The absence of other factors that inhibit neovascularization may also play a role. Please see below for other proposed mechanisms of hypergycemia-induced vascular damage. Prevention and Treatment of Diabetic Retinopathy

Once developed, there is no effective treatment that reverses diabetic retinopathy. Therefore, efforts have been concentrated at preventing development and progression of retinopathy by tight glycemic control. In the Diabetes Control and Complications Trial (DCCT), intensive glycemic control with insulin in type 1 diabetes patients reduced the development of retinopathy by 76% and progression by 54 percent. Statistically significant reductions, although more modest, were also seen in the United Kingdom Prospective Diabetes Study (UKPDS) which examined tight glycemic control in type 2 diabetes. Intensive glycemic treatment early in the course of the disease is most effective, but the intervention is beneficial over the entire spectrum of retinopathy. Hypertension and hypercholesterolemiacan also worsen retinopathy and therefore, controlling these factors is important in the prevention of retinopathy.

Once developed, diabetic retinopathy can progress to vision loss. Laser photocoagulation therapy has been shown in large randomized trials to prevent loss of vision in patients with moderate to severe diabetic retinopathy. The effectiveness of photocoagulation is attributed to decreased metabolic requirements of the retina.

  • Focal and grid photocoagulation that destroys only vessels responsible for leakage is used for diabetic macular edema
  • Panretinal photocoagulation is used for severe NPDR and PDR. Adverse effects of panretinal laser treatment include decreased peripheral and night vision

For advanced retinopathy not amenable to photocoagulation therapy, vitrectomy (removal of scar tissue and replacement with saline) is an alternative treatment modality.

Given the orderly progression of diabetic retinopathy, the overwhelming evidence that near euglycemic control can prevent or delay the progression of diabetic retinopathy and the existence of effective management modalities that can prevent loss of vision, yearly screening for retinopathy in patients with diabetes is well accepted. Fundus photography through a dilated pupil is the most sensitive way to detect retinal disease. If fundus photography is not available, then a dilated retinal examination by an ophthalmologist or optometrist experienced in diabetic retinopathy is recommended. As retinopathy may worsen during pregnancy, an ophthalmologic examination is indicated prior to conception and during the 1st trimester in pregnant women with pre-existing diabetes.

5.2.2. Nephropathy

Diabetic nephropathy is the leading cause of kidney failure in the U.S. accounting for approximately 40% of new cases.. Non-white Americans with type 2 diabetes have a much higher risk of developing diabetic nephropathy than white Americans. Genetic predispotition is very important in determining who will develop nephropathy. Patients with diabetes on dialysis have a higher mortality compared to those without diabetes. Classification and Pathophysiology of Diabetic Nephropathy

Similar to retinopathy, the progression of nephropathy is well defined and consists of the following clinical stages:

  • Increased glomerular filtration rate (GFR) >150 ml/min
  • Microalbuminuria (30 - 300 mg/24hrs)
  • Clinical albuminuria, also called macroalbuminuria (>300 mg/24 hours)
  • Worsening of clinical proteinuria, hypertension and decrease in GFR
  • Kidney failure occurs when GFR falls to approximately 10ml/min

Pathophysiologically, there are various types of nephropathy that are seen in patients with diabetes:

  • Nodular Glomerulosclerosis (Kimmelstiel-Wilson Disease). This is the only type of nephropathy that is relatively specific for diabetes. Nodules containing glycoproteins, lipids, reticulin, hyaline, located at the periphery of the glomerular capillary tufts.
  • Diffuse Glomerulosclerosis - thickening of basement membrane of capillaries. It may be a precursor of nodular and often found in conjunction with nodular. More common than nodular (in 25% of nephropathy of diabetics), being present in about 75% of nephropathy of diabetics.
  • Exudative Glomerulosclerosis - fibrinoid material within the glomerular capillaries - a late stage, perhaps an end stage. Material is not that of the nodular and diffuse types and may represent a superimposed process.
  • Arteriosclerosis - similar process to other tissues. In diabetes, it characteristically affects afferent arterioles.
  • Pyelonephritis. Incidence probably is increased compared to nondiabetics. Silent infection may cause worsening of diabetic control.
  • Papillary Necrosis - uncommon. It is a combination of ischemic papilla and coexistent severe infection. Clinically, it presents as pain, fever, dysuria, hematuria, and sloughing of tip of papilla and can see tissue in urine. Often associated with increasing BUN and renal failure. May occur completely silently and be found on autopsy.
  • Acute renal failure following intravenous contrast. Diabetics who have modest renal insufficiency are at high risk to develop acute renal failure (which is often reversible but not always) following procedures which utilize the intravenous injection of contrast dyes (e.g. arteriograms, IVP, C-T scans). Prevention and Treatment of Diabetic Nephropathy

Both the DCCT and the UKPDS showed that near euglycemia can decrease the development of microalbuminuria and progression of diabetic nephropathy. However, tight glycemic control has no effect in reducing proteinuria or improving GFR if clinical nephropathy is present. Therefore, early recognition of nephropathy is crucial.

In addition to hyperglycemia, hypertension is another risk factor for nephropathy. In patients with type 1 diabetes, hypertension is often caused by underlying diabetic nephropathy. In patients with type 2 diabetes, hypertension is often present at time of diagnosis of diabetes as a component of the metabolic syndrome. There is abundant evidence from epidemiologic and prospective trials that aggressive blood pressure management delays the progression of nephropathy and reduces the need for dialysis or transplantation. For non pregnant diabetic patients, the goal blood pressure should be <130/80.

Based on evidence from numerous randomized controlled trials, inhibition of the renin-angiotensin system is the best way to decrease progressions on nephropathy. Angiotensin-converting enzyme inhibitors (ACE-I) appear to have a selective renoprotective effect beyond what one would expect from their antihypertensive efficacy alone and have emerged as the oral antihypertensive agents of choice in diabetics. It is now recommended that ACE-I be started in all diabetics with microalbuminuria or advanced nephropathy. Angiotensin receptor blockers (ARB) can be used as initial monotherapy if ACE-I are not tolerated. The beneficial effects of ACE-I and ARB appear to be class effects and there is little evidence to support favoring a specific ACE-I or ARB over another. Non-dihydropyridine calcium channel blockers (diltiazem) have been shown to decrease albumin excretion in short termstudies and can be used as an alternative to ACE-I or ARB.

Other recommended interventions that slow the progression of renal disease include correction of dyslipidemia and smoking cessation. Given the orderly progression of diabetic nephropathy, the overwhelming evidence that near euglycemic control can prevent or delay its progression and the presence of effective anti-hypertensive agents that can delay development or progression, screening for nephropathy in patients with diabetes is well accepted. An algorithm for screening for albuminuria is shown in Figure 1. It is not clear whether additional treatment modalities such as protein restriction have a role in the management of nephropathy.

Figure 1. Screening for nephropathy in patients with diabetes
DM Complications (Figure)

5.2.3. Neuropathy

Neuropathy is a common and frustrating long-term complication of diabetes. Diabetic neuropathy can present as mononeuropathy or polyneuropathy and can also be divided in sensory, motor and autonomic.

The pathogenesis is not well elucidated, but it is believed that the mononeuropathies, such as the acute cranial nerve palsies and diabetic amyotrophy, are due to ischemic infarction of the peripheral nerves. The peripheral sensori-motor neuropathies and autonomic neuropathies may be caused by a metabolic factor or osmotic toxicity secondary to hyperglycemia. Peripheral Sensory Polyneuropathy [very common]

It often presents with numbness, tingling, itching and lancinating pain which can be disabling. Symptoms slowly progress to sensory loss which is generally symmetric with a "stocking glove" distribution in the distal legs and arms. Even before symptoms develop, physical findings may be present which include decreased proprioception and vibration, delayed ankle reflexes and decreased sensation. Decreased sensation together with poor blood supply place patients at increased risk for development of foot ulcers and infection which may lead to limb amputation. Decreases pain sensation in joints can also lead to progressive joint deformity - Charcot joint.

There is no specific treatment for peripheral sensory neuropathy. Treatment is symptomatic with tricyclic antidepressants, such as amitryptylline 25-50 mg at bedtime, used more commonly as first line pharmacotherapy. Effectiveness of the pharmacotherapy is variable. Some patients report a remarkable improvement in their symptoms within several days, possibly due to improved sleeping patterns and modulation of nociceptive C fibers. If there is no improvement, tricyclics should be discontinued. Other medications which have been used with modest success include local capsaicin, carbamazepine, phenytoin and gabapentin. Medications that target the underlying process of microvascular complications are in clinical trials (see Pathophysiologic Mechanisms of Hyperglycemia-Induced Glycemic Damage). Regular foot examination, foot protection, and podiatric evaluation as needed are all essential components of diabetic foot care. Special shoes can also be made to distribute weight over the insensitive foot especially those deformed by surgery, fractures, or Charcot's joints. Motor Mononeuropathy [uncommon]

Motor mononeuropathy [uncommon] involve cranial nerve and peripheral (peroneal, median) nerves. The most common cranial nerves affected are the third and sixth. The acute mononeuroapthies are likely caused by ischemic infarction of the involved nerve. Radiculopathy with pain in the distribution of the affected dermatome may also be seen. Clinical onset of mononeuropathies is abrupt and may involve pain, sensory loss or weakness. Recovery is common for both the acute cranial nerve palsies (within weeks) and diabetic amyotrophy (within months). This may be the presenting symptom of diabetes in some patients. Amyotrophy [rare]

Amyotrophy [rare] is manifested as acute pain and weakness of the thigh muscles and involves combined muscle and nerve disease. Autonomic Neuropathy [very common]

Autonomic neuropathy [very common] can affect multiple organ systems and generally occurs in patients with long-standing diabetes. Gastroparesis, orthostatic hypotension, bowel and bladder disorders and erectile dysfunction can all be caused by autonomic dysfunction. Treatment can be difficult and not always effective. Gastroparesis

Gastroparesis should be suspected in patients with nausea, vomiting or unexplained post-prandial abdominal discomfort. Gastroparesis may cause an erratic nutrient absorption due to stomach stasis, therefore, in the absence of abdominal symptoms, gastroparesis should also be suspected in patients with unexplained post-prandial hypoglycemia or hyperglycemia. Management of gastroparesis includes dietary modifications followed by pharmacotherapy. Metoclopramide has been used but its efficacy decreases over time and its potential for side effects is limiting. Cisapride with meals and at bedtime has also been used to improve gastric emptying. Access of cisapride is restricted in the U.S. due to arrhythmia. Erythromycin has also been used in effort to remove residue from stomach. Orthostatic Hypotension

Orthostatic hypotension is one of the most undesirable neuropathies. Treatment includes non-pharmacologic approaches (lower extremity stockings, increased salt intake, slow postural changes), or pharmacotherapy with mineralocorticoids (fludrocortisone 0.1-0.5 mg daily). Erectile Dysfunction

Erectile dysfunction affects a large percentage of diabetic men and is associated with poor quality of life. Prevalence ranges from 6% in men aged 20-24 to 52% in diabetic men aged 55-59. Obesity, tobacco use, poor glycemic control and duration of disease all increase the development of erectile dysfunction. Penile erection requires numerous neural and hormonal factors, but it is primarily a vascular phenomenon. It has been shown that diabetic men have narrowing of the penile arteries with cavernous arterial insufficiency. Erectile dysfunction can also be caused by somatic and autonomic dysfunction with the parasympathetic nerves of the pelvis very susceptible to damage early in the course of diabetic neuropathy. Other mediators of erectile function such as nitric oxide, endothelins, and prostaglandins have been shown to be lower in diabetics. Inhibitors of the enzyme phosphodiesterase-type 5 which metabolizes cGMP, such as sildenafil can be effective in diabetic erectile dysfunction. Higher cGMP levels lead to higher levels of nitric oxide which maximizes penile blood flow and erection. Sildenafil is contraindicated when nitrates are used concomitantly. Other treatment modalities for erectile dysfunction include vacuum-constriction devices that increase corporeal blood flow, prostaglandin intraurethral suppositories, and intracavernosal injections.

5.2.4. Pathophysiologic Mechanisms of Hyperglycemia-induced Vascular Damge

There are various mechanisms that have attempted to explain how hyperglycemia causes the vascular and neuropathic complications of diabetes, summarized below: Aldose Reductase Pathway

Intracellular hyperglycemia activates the aldose reductase pathway which uses NADPH to reduce glucose to sorbitol. Intracellular sorbitol has been postulated to cause osmotic cellular damage and that may the mechanism explaining the formation of cataracts in diabetics. The decline in cellular NADPH may also affect other significant cellular process leading to cell death. Although inhibitors of the aldose reductase pathway showed promising results in animal studies, they did not show efficacy in human trials. Reactive Oxygen Species

That diabetes causes an elevated oxidative stress milieu is one of the oldest theories for hyperglycemia-induced vascular damage. The oxidation of glucose releases free radicals which may account for a number of cellular dysfunctions. Unfortunately, in recent human trials, the promise of antioxidants (such as vitamin C and vitamin E) in reducing diabetic complications did not materialize. Advanced Glycation Endproducts Theory

Hyperglycemia causes increased glycation of proteins. There is a variety of extracellular and intracellular products of glycation that have been termed advanced glycation endproducts (AGE). Extracellular AGE may alter protein function and intracellular AGE may alter gene expression, the net result being abnormal cellular and vascular function. Inhibitors of AGE have been used in animal studies but their efficacy was limited by toxicity in clinical trials. Protein Kinase C (PKC) Theory

Diacylglycerol (DAG) PKC is an important intracellular signaling molecule that regulates many vascular functions including permeability, endothelial activation and growth factor signaling. Pathologic activation of PKC is seen in diabetes, specifically in blood vessels from retina, kidney and nerves. PKC activation may produce vascular damage and disordered vascular proliferation. Inhibitors of specific PKC isoforms have shown promising results in animals in terms of preventing or reversing diabetic retinopathy, nephropathy and neuropathy. PKC inhibitors are currently in clinical trials for retinopathy and nephropathy. If the trials are successful, these will be the first medications that may prevent or reverse the chronic complications of diabetes even in the presence of hyperglycemia.

6. Infections

Patients with diabetes may be more prone to infection, especially in the setting of hyperglycemia. The mechanism is thought to be inhibition of phagocytosis and leukocyte mobilization by hyperglycemia. Because of vascular compromise and other factors, infections may be more difficult to control and may be more severe. Also, certain infections may be more common, as described below.

6.1. Urinary Tract Infections

Usually in association with bladder neuropathy and/or catheterization. Severe infection combined with renal vascular disease may be associated with renal papillary necrosis. Emphysematous pyelonephritis occurs when the gram-negative facultative organism produces gas - usually seen only in diabetics. Therapy - as for non-diabetics - 1 oral drug for cystitis but parenteral therapy with two drugs for pyelonephritis associated with sepsis.

6.2. Gram-negative Bacteremia

More common in diabetic and associated with increased mortality due to poorly understood host factors.

6.3. Soft Tissue Infections

Gangrene and leg infections in part due to vascular disease and neuropathy (do not feel trauma). Staphylococci Group A beta hemolytic streptococci and anaerobes are frequently isolated from foot ulcers. Usually a mixed infection. Local care is usually all that is needed unless signs of invasion are present, e.g. erythema, tenderness, fever and leukocytosis, in which case systemic antibiotics should be used. Other staphyloccal skin infections also occur at an increased frequency in diabetes.

6.4. Tuberculosis

Occurs at increased frequency in diabetics. Diabetics with a positive intermediate PPD are candidates for prophylactic INH.

6.5. Fungal Infections

Candida - especially in vagina, mouth and in skin folds (e.g. under breasts and in groin) - usually seen with poor diabetic control. Prevention of skin maceration and topical mystatin usually control infection. Mucormycosis - involve the paranasal sinuses and meninges. Almost always occurs in setting of diabetic ketoacidosis. High mortality and most diagnoses early by biopsy. Therapy includes surgical debridment and amphotericin.

6.6. Malignant External Otitis

Due to pseudomonas aeruginosa. Have symptoms of pain and severe tenderness of tissues around ear and mastoid along with persistent drainage and presence of granulation tissue in external ear in an elderly diabetic. Untreated patients develop spread of infection to deep soft tissues, necrosis of cartilage and bone and fatal outcome. Isolation of pseudomonas and clinical picture demands vigorous systemic antibiotic therapy.

7. References

  • Pittas, AG and Greenberg AS. Contemporary Diagnosis and Management of Diabetes. Handbooks in Health Care, Newtown, PA. 2003.
  • Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus, Diabetes Care 24 (suppl. 1): 2003.