Type 1 Diabetes Mellitus Clinical Presentation

Author: Romesh Khardori, MD, PhD, FACP; Chief Editor: George T Griffing, MD more...

History
The most common symptoms of type 1 diabetes mellitus (DM) are polyuria, polydipsia, and polyphagia, along with lassitude, nausea, and blurred vision, all of which are due to the hyperglycemia itself. The disease onset may be sudden, with the presentation of an infection. It is not unusual for type 1 DM to present with diabetic ketoacidosis (DKA); it may occur de novo or develop with the stress of illness or surgery. An explosive onset of symptoms in a young lean patient with ketoacidosis always has been considered diagnostic of type 1 DM. Symptoms Symptoms at the time of the first clinical presentation can usually be traced back several days to several weeks; however, beta cell destruction may have started months, or even years, before the onset of clinical symptoms. The following symptoms may be noted with type 1 DM:

Polyuria and thirst: Polyuria is due to osmotic diuresis secondary to hyperglycemia; thirst is due to the hyperosmolar state and dehydration. Polyphagia with weight loss: The weight loss with a normal or increased appetite is due to depletion of water and a catabolic state with reduced glycogen, proteins, and triglycerides. Fatigue and weakness may be due to muscle wasting from the catabolic state of insulin deficiency, hypovolemia, and hypokalemia. Muscle cramps are due to electrolyte imbalance. Older men with impaired fasting glucose and diabetes have accelerated muscle loss, except when diabetes is treated with insulin sensitizers.[21] Nocturnal enuresis: Severe enuresis secondary to polyuria can be an indication of onset of diabetes in young children. Blurred vision is due to the effect of the hyperosmolar state on the lens and vitreous humor; glucose and its metabolites cause dilation of the lens, altering its normal focal length. Gastrointestinal (GI) symptoms: Nausea, abdominal discomfort or pain, and change in bowel movements may accompany acute DKA; acute fatty liver may lead to distention of the hepatic capsule, causing right upper quadrant pain; persistent abdominal pain may indicate another serious abdominal cause of DKA (eg, pancreatitis); chronic GI symptoms in the later stage of DM are due to visceral autonomic neuropathy. Patients may maintain their normal weight or exhibit wasting, depending on the interval between the onset of the disease and initiation of treatment.

Peripheral neuropathy presents as numbness and tingling in both hands and feet, in a glove and stocking pattern; it is bilateral, symmetric, and ascending neuropathy, which results from many factors, including the accumulation of sorbitol in peripheral sensory nerves due to sustained hyperglycemia. Irrespective of autonomic neuropathy, chemosensitivity to hypercapnia is reduced in patients with type 1 diabetes, suggesting microcirculatory damage as cause.[22]

Ask questions about type, duration, and care of diabetes It is important to inquire about the type and duration of the patients diabetes and about the care the patient is receiving for diabetes. Determination of the type of diabetes is based on history, therapy, and clinical judgment. The chronic complications of diabetes are related to the length of time the patient has had the disease. Ask about the type of insulin being used, delivery system (pump vs injections), dose, and frequency. Also ask about oral antidiabetic agents, if any. Patients using a pump or a multiple-injection regimen have a basal insulin (taken through the pump or with the injection of a long-acting insulin analogue) and a premeal rapidacting insulin, the dose of which is determined as a function of the carbohydrate count plus the correction (to adjust for how high the premeal glucose level is). In these patients, ask about the following:

Basal rates (eg, units per hour by pump, generally 0.4-1.5 units/h, may vary based on time of day); total daily dose as basal insulin is a helpful value to know. Carbohydrate ratio (ie, units of insulin per grams of carbohydrate, generally 1 unit of rapid-acting insulin per 10-15 g carbohydrate) Correction dose (ie, how far the blood glucose level is expected to decrease per unit of rapid-acting insulin, often 1 unit of insulin per 50-mg/dL decrease, but individuals with insulin resistance may need 1 per 25-mg/dL decrease) Some patients may be taking premeal pramlintide (amylin analog).

A focused diabetes history should also include the following questions:

Is the patients diabetes generally well controlled (with near-normal blood glucose levels)? (Patients with poorly controlled blood glucose levels heal more slowly and are at increased risk for infection and other complications.) Does the patient have severe hypoglycemic reactions? (If the patient has episodes of severe hypoglycemia and therefore is at risk for losing consciousness, this possibility must be addressed, especially if the patient drives.) Does the patient have diabetic nephropathy that might alter the use of medications or intravenous radiographic contrast material? Does the patient have macrovascular disease, such as coronary artery disease (CAD), which should be considered in the emergency department (ED)?

Does the patient self-monitor his or her blood glucose levels? (Note the frequency and range of values at each time of day. An increasing number of patients monitor with continuous sensors.) When was the patients hemoglobin A1c (HbA1c) value (an indicator of long-term glucose control) last measured? What was it?

Questions regarding hypoglycemia and hyperglycemia Hypoglycemia and hyperglycemia should be considered. Ask the following questions, as needed:

Does the patient have a history of recent polyuria, polydipsia, nocturia, or weight loss? Has the patient had episodes of unexplained hypoglycemia? If so, when, how often, and how does the patient treat these episodes? Does the patient have hypoglycemia unawareness (ie, does the patient lack the adrenergic warning signs of hypoglycemia)? (Hypoglycemia unawareness indicates an increased risk of subsequent episodes of hypoglycemia.)

Questions regarding microvascular complications Microvascular complications, such as retinopathy and nephropathy, should be considered as well. Consider the following questions:

When was the patients last dilated eye examination? What were the results? Does the patient have known kidney disease? What were the dates and results of the last measurements of urine protein and serum creatinine levels?

Questions regarding macrovascular complications Macrovascular complications should be explored. Questions should include the following:

Does the patient have hypertension? What medications are taken? Does the patient have symptoms of claudication or a history of vascular bypass? Has the patient had a stroke or transient ischemic attack? What are the patients most recent lipid levels? Is the patient taking lipid-lowering medication?

Neuropathy questions Potential neuropathy should be taken into account. Ask whether the patient has a history of neuropathy or symptoms of peripheral neuropathy or whether autonomic neuropathy is present (including impotence if the patient is male). Foot disease questions The possibility of foot disease should be addressed. Inquire as to whether the patient has a history of foot ulcers or amputations or whether any foot ulcers are present.

Go to Diabetic Foot and Diabetic Foot Infections for complete information on these topics. Question about Infections Infections should be considered. Be sure to inquire about whether frequent infections are a problem and, if so, at what sites.

Physical Examination
In new cases of diabetes, physical examination findings are usually normal, except in DKA, wherein signs of Kussmaul respiration, dehydration, hypotension, and, in some cases, altered mental status are present. In established cases, patients should be examined every 3 months for macrovascular and microvascular complications. They should have funduscopic examination for retinopathy and monofilament testing for peripheral neuropathy. A diabetes-focused physical examination includes an assessment of vital signs, funduscopic examination, limited vascular and neurologic examinations, and a foot assessment. Other organ systems should be examined, as indicated by the patients clinical situation. Assessment of vital signs Is the patient hypertensive or hypotensive? Orthostatic vital signs may be useful in assessing the patients volume status, as well as suggesting the presence of an autonomic neuropathy. If the respiratory rate and pattern suggest Kussmaul breathing, DKA must be considered immediately, and appropriate tests obtained. Funduscopic examination Funduscopic examination should include a careful view of the retina, including both the optic disc and the macula. If hemorrhages or exudates are seen, the patient should be referred to an ophthalmologist as soon as possible. Examiners who are not ophthalmologists tend to underestimate the severity of retinopathy, especially if the patients pupils are not dilated. Foot examination The dorsalis pedis and posterior tibialis pulses should be palpated and their presence or absence noted. This is particularly important in patients who have foot infections, because poor lower-extremity blood flow can delay healing and increase the risk of amputation. Documenting lower-extremity sensory neuropathy is useful in patients who present with foot ulcers, because decreased sensation limits the patients ability to protect the feet and ankles. If peripheral neuropathy is found, the patient should be made aware that foot care (including daily foot examination) is very important for the prevention of foot ulcers and lower-extremity amputation.

Go to Diabetic Foot and Diabetic Foot Infections for complete information on these topics.

Infections Seen in Patients With Diabetes

Infections cause considerable morbidity and mortality in patients with diabetes. Infections may precipitate metabolic derangements, and conversely, the metabolic derangements of diabetes may facilitate infection. Hyperglycemia and acidemia exacerbate impairments in humoral immunity and polymorphonuclear leukocyte and lymphocyte functions but are substantially reversed when pH and blood glucose levels return to normal.[23] Although the exact level above which leukocyte function is impaired is not defined, in vitro evidence suggests that glucose levels greater than 200 mg/dL impair leukocytic function.[24] Patients with long-standing diabetes tend to have microvascular and macrovascular disease with resultant poor tissue perfusion and increased risk of infection. The ability of the skin to act as a barrier to infection may be compromised when the diminished sensation of diabetic neuropathy results in unnoticed injury. People with diabetes are susceptible to various types of infections. The most common sites affected are the skin and urinary tract system. Increased risk of staphylococcal follicular skin infections, superficial fungal infections, cellulitis, erysipelas, and oral or genital candidal infections exists. These patients develop frequent lower urinary tract infections and are at increased risk of acute pyelonephritis. A few infections, such as malignant otitis externa, rhinocerebral mucormycosis, and emphysematous pyelonephritis, occur almost exclusively in patients with diabetes. Infections such as staphylococcal sepsis occur more frequently and result in greater mortality rates in patients with diabetes than in others. Infections such as pneumococcal pneumonia affect patients with diabetes and others the same.[25] Ear, nose, and throat infections Malignant or necrotizing otitis externa principally occurs in patients with diabetes who are older than 35 years and is almost always due to Pseudomonas aeruginosa.[26] The term malignant otitis externa has been applied to several different clinical entitiessevere otitis externa, perichondritis, and temporal bone osteomyelitiswhich may coexist. Infection starts in the external auditory canal and spreads to adjacent soft tissue, cartilage, and bone. Patients typically present with severe ear pain and otorrhea. Fever may be absent. Although they often have preexisting otitis externa, progression to invasive disease is usually rapid. Examination of the auditory canal may reveal granulation tissue, but spread of infection to the pinna, preauricular tissue, and mastoid often makes the diagnosis apparent. Involvement of the cranial nerves, particularly the facial nerve, is common; when infection extends to the meninges, it is often lethal. CT or MRI helps to define the extent of disease. Rhinocerebral mucormycosis collectively refers to infections caused by various ubiquitous molds.[27] Invasive disease occurs in patients with poorly controlled

diabetes, especially with DKA. Organisms colonize the nose and paranasal sinuses, spreading to adjacent tissues by invading blood vessels and causing soft tissue necrosis and bony erosion. Patients usually present with periorbital or perinasal pain, swelling, and induration. Bloody or black nasal discharge may be present. Involvement of the orbits, with lid swelling, proptosis, and diplopia, is common. The nasal turbinates may appear dusky red, ulcerated, or frankly necrotic. Black necrotic nasal mucosal or palatal tissue is an important visual clue. The infection may invade the cranial vault through the cribriform plate, resulting in cerebral abscess, cavernous sinus thrombosis, or thrombosis of the internal carotid artery. Wet smears of necrotic tissue often reveal broad hyphae and distinguish mucormycosis from severe facial cellulitis. CT or MRI helps to delineate the extent of disease. Urinary tract infections Patients with diabetes have an increased risk of asymptomatic bacteruria and pyuria, cystitis, and, more important, serious upper urinary tract infection. Intrarenal bacterial infection should be considered in the differential diagnosis of any patient with diabetes who presents with flank or abdominal pain. Emphysematous pyelonephritis is an uncommon necrotizing renal infection caused by Escherichia coli,Klebsiella pneumoniae, or other organisms capable of fermenting glucose to carbon dioxide. The presentation is usually similar to that of uncomplicated pyelonephritis, and the diagnosis is established by identifying renal gas on plain radiography, CT, or sonography. Skin and soft tissue infections Sensory neuropathy, atherosclerotic vascular disease, and hyperglycemia all predispose patients with diabetes to skin and soft tissue infections. These can affect any skin surface but most commonly involve the feet. Go to Diabetic Foot Infections for complete information on this topic. Cellulitis, lymphangitis, and, most ominously, staphylococcal sepsis can complicate even the smallest wound. Minor wound infections and cellulitis are typically caused by Staphylococcus aureus or hemolytic streptococci. Necrotizing infections of the skin, subcutaneous tissues, fascia, or muscle can also complicate wounds and particularly cutaneous ulcers. These infections are typically polymicrobial, involving group A streptococci, enterococci, S aureus, Enterobacteriaceae, and various anaerobes. Radiographs of any spreading soft tissue infection in a patient with diabetes should be obtained to look for the soft tissue gas that characterizes necrosis. Go to Bullous Disease of Diabetes and Diabetic Ulcers for complete information on these topics. Osteomyelitis Contiguous spread of a polymicrobial infection from a skin ulcer to adjacent bone is common in patients with diabetes, particularly from chronic ulcers.

In one study, osteomyelitis was found in the bone under 68% of diabetic foot ulcers, and findings on physical examination and plain radiographs did not help in diagnosing one half of the cases.[28] Unfortunately, these diagnostic modalities are often the only ones available in the ED, and the diagnosis might be suspected but not established. MRI, if available on an emergent basis, has better sensitivity and specificity in diagnosing osteomyelitis.[29] Cultures from superficial wound swabs often fail to identify the causative organism. Cultures from biopsy or curettage of the debrided ulcer base are preferred. Other infections Although cholecystitis is probably no more common in patients with diabetes than in the general population, severe fulminating infection, especially with gas-forming organisms, is more common. The early clinical manifestations of emphysematous cholecystitis are indistinguishable from those of usual cholecystitis. The diagnosis can be made by finding gas in the gallbladder lumen, wall, or surrounding tissues. Gallstones are present in only approximately 50% of cases. Perforation is common, and even with immediate surgery, the rate of mortality is high. Infection is typically polymicrobial. Clostridial species are found in more than 50% of cases. The incidence of staphylococcal and K pneumoniae infections are greater in people with diabetes than in people without diabetes. Diabetes is a risk factor for reactivation of tuberculosis; however, a study from Denmark, a country with low tuberculosis burden, found no evidence of association between tuberculosis and dysglycemia.[30] Cryptococcal infections and coccidioidomycoses are more virulent in patients with diabetes.

Diabetes-Related Ophthalmologic Complications

Diabetes can affect the lens, vitreous, and retina, causing visual symptoms that may prompt the patient to come to the ED. Visual blurring may develop acutely as the lens changes shape with marked changes in blood glucose concentrations. This effect, which is caused by osmotic fluxes of water into and out of the lens, usually occurs as hyperglycemia increases, but it also may be seen when high glucose levels are lowered rapidly. In either case, recovery to baseline visual acuity can take up to a month, and some patients are almost completely unable to read small print or do close work during this period. Patients with diabetes tend to develop senile cataracts sooner than persons without diabetes, though this is not related to the degree of glycemic control. Rarely, patients with type 1 diabetes who are in extremely poor control (eg, those with frequent episodes of DKA) can acutely develop a snowflake (or metabolic) cataract. Named for their snowflake or flocculent appearance, these cataracts can progress rapidly and create total opacification of the lens within a few days. In the retina, DM causes diabetic retinopathy. It is the leading cause of blindness in the United States in people younger than 60 years and affects the eyes in the following different ways:

Background retinopathy is due to retinal small vessel abnormality leading to hard exudates, hemorrhages, and microaneurysms; it does not affect acuity. Proliferative retinopathy is due to extensive proliferation of new retinal small blood vessels; a sudden loss of vision can occur due to vitreous hemorrhage from proliferating new vessels or retinal detachment. Maculopathy is due to edema and hard exudate or retinal ischemia. It causes a marked reduction of acuity. Cataracts occur frequently in people with diabetes. Glaucoma relates to the neovascularization of the iris, rubeosis iridis.

Whether patients develop diabetic retinopathy depends on the duration of their diabetes and on the level of glycemic control.[31, 32] The following are the 5 stages in the progression of diabetic retinopathy: 1. Dilation of the retinal venules and formation of retinal capillary microaneurysms 2. Increased vascular permeability 3. Vascular occlusion and retinal ischemia 4. Proliferation of new blood vessels on the surface of the retina 5. Hemorrhage and contraction of the fibrovascular proliferation and the vitreous The first 2 stages of diabetic retinopathy are known as background or nonproliferative retinopathy. Initially, the retinal venules dilate, then microaneurysms (tiny red dots on the retina that cause no visual impairment) appear. The microaneurysms or retinal capillaries become more permeable, and hard exudates appear, reflecting the leakage of plasma. Rupture of intraretinal capillaries results in hemorrhage. If a superficial capillary ruptures, a flame-shaped hemorrhage appears. Hard exudates are often found in partial or complete rings (circinate pattern), which usually include multiple microaneurysms. These rings usually mark an area of edematous retina. The patient may not notice a change in visual acuity unless the center of the macula is involved. Macular edema can cause visual loss; therefore, all patients with suspected macular edema must be referred to an ophthalmologist for evaluation and possible laser therapy. Laser therapy is effective in decreasing macular edema and preserving vision but less effective in restoring lost vision. Preproliferative and proliferative diabetic retinopathy are the next stages in the progression of the disease. Cotton-wool spots can be seen in preproliferative retinopathy. These represent retinal microinfarcts due to capillary occlusion and appear as off-white to gray patches with poorly defined margins. Proliferative retinopathy is characterized by neovascularization, or the development of networks of fragile new vessels that often are seen on the optic disc or along the main vascular arcades. The vessels undergo cycles of proliferation and regression. During proliferation, fibrous adhesions develop between the vessels and the vitreous. Subsequent contraction of the adhesions

can result in traction on the retina and retinal detachment. Contraction also tears the new vessels, which hemorrhage into the vitreous. Using nailfold video capillaroscopy, a high prevalence of capillary changes is detected in patients with diabetes, particularly those with retinal damage. This reflects a generalized microvessel involvement in both type 1 and type 2 diabetes.
[33]

Go to Diabetic Retinopathy and Macular Edema, Diabetic for complete information on these topics.

Diabetic Nephropathy
Microvascular disease is a significant feature of diabetes and causes multiple pathological complications. Hyaline arteriosclerosis, a characteristic pattern of wall thickening of small arterioles and capillaries is widespread and is responsible for ischemic changes in the kidney, retina, brain, and peripheral nerves. In the kidneys, this wall thickening leads to diabetic nephropathy, which is characterized by proteinuria, glomerular hyalinization (Kimmelstiel-Wilson), and chronic renal failure. About 2030% of patients with type 1 develop evidence of nephropathy[34] and all patients with diabetes should be considered to have the potential for renal impairment unless proven otherwise. The use of contrast media can precipitate acute renal failure in patients with underlying diabetic nephropathy. Although most recover from contrast medium induced renal failure within 10 days, some have irreversible renal failure. Chronically elevated blood pressure contributes to the decline in renal function. Go to Diabetic Nephropathy for complete information on this topic.

Diabetic Neuropathy
In the peripheral nerves, diabetes causes peripheral neuropathy. Four types of diabetic neuropathies develop, as follows:

Peripheral distal symmetrical polyneuropathy, predominantly sensory Autonomic neuropathy Proximal painful motor neuropathy Cranial mononeuropathy (ie, III, IV, VI)

Sensory and autonomic neuropathy are due to axonal degeneration and segmental demyelination. Motor neuropathy and cranial mononeuropathy are due to vascular disease in blood vessels supplying nerves. Of the 4 types of diabetic neuropathy, distal symmetric sensorimotor polyneuropathy (in a glove-and-stocking distribution) is the most common.[35] Besides causing pain in its early stages, this type of neuropathy eventually results in the loss of peripheral sensation. The combination of decreased sensation and peripheral arterial insufficiency often leads to foot ulceration and eventual amputation.

Acute-onset mononeuropathies in diabetes include acute cranial mononeuropathies, mononeuropathy multiplex, focal lesions of the brachial or lumbosacral plexus, and radiculopathies. Of the cranial neuropathies, the third cranial nerve (oculomotor) is most commonly affected, followed by the sixth nerve (abducens) and the fourth nerve (trochlear). Patients can present with diplopia and eye pain. In diabetic third-nerve palsy, the pupil is usually spared, whereas in thirdnerve palsy due to intracranial aneurysm or tumor, the pupil is affected in 80-90% of cases. It is important to consider nondiabetic causes for cranial nerve palsies, including intracranial tumors, aneurysms, and brainstem stroke.[36] Therefore, evaluation should include nonenhanced and contrast-enhanced CT or, preferably, MRI. Neurologic consultation is recommended. Acute cranial-nerve mononeuropathies usually resolve in 2-9 months. Acute thrombosis or ischemia of the blood vessels supplying the structure involved is thought to cause these neuropathies. Go to Diabetic Lumbosacral Plexopathy and Diabetic Neuropathy to see complete information on these topics.

Macrovascular Complications of Diabetes

People with diabetes experience accelerated atherosclerosis, affecting the small arteries of the heart, brain, lower extremity, and kidney. Coronary atherosclerosis Coronary atherosclerosis often occurs earlier and is more severe and extensive than in those without diabetes, increasing the risk of ischemic heart disease. Atherosclerosis of the brain Atherosclerosis of the internal carotid and vertebrobasilar arteries and their branches predisposes to cerebral ischemia. Lower-extremity atherosclerosis Severe atherosclerosis of the iliofemoral and smaller arteries of the lower legs predisposes to gangrene. Ischemia of a single toe or ischemic areas on the heel are characteristic of diabetic peripheral vascular disease; this is due to the involvement of much smaller and more peripheral arteries. Renal atherosclerosis Atherosclerosis of the main renal arteries and their intrarenal branches causes chronic nephron ischemia. It is a significant component of multiple renal lesions in diabetes. Nephropathy is a significant life-threatening complication and is due to the adverse effects of glucose-induced preglomerular vasodilation on glomerular hemodynamics. Glomerulosclerosis is initiated early in the course of diabetic nephropathy by exacerbated expression of cytokines such as tumor growth factor beta 1. However, not all people with type 1 DM are at risk of nephropathy because of some polymorphisms in the various factors involved in its pathogenesis, which can modulate the course of this disease from one person to the other. Although end-stage renal disease (ESRD) is one of the most severe complications of type 1

DM, the incidence of ESRD has been very low: 2.2% at 20 years after diagnosis and 7.8% at 30 years after diagnosis.[37] A study by the DCCT/EDIC Research Group et al found that long-term risk of an impaired glomerular filtration rate was significantly lower in persons treated with intense insulin therapy early in the course of disease compared with those who received conventional therapy. Risk factors of macrovascular disease Macrovascular disease is the leading cause of death in patients with diabetes, causing 65-75% of deaths in this group, compared with approximately 35% of deaths in people without diabetes. Diabetes increases the risk of myocardial infarction (MI) 2-fold in men and 4-fold in women, and many patients have other risk factors for MI as well. HbA1c value per se rather than self-reported diabetes status and/or other established risk factors robustly predicts MI odds. Each 1% increment in HbA1c independently predicts 19% higher odds for MI.[38] The risk of stroke in patients with diabetes is double that of nondiabetic people, and the risk of peripheral vascular disease is 4 times that of people without diabetes. Patients with diabetes may have an increased incidence of silent ischemia.[39] Diastolic dysfunction is common in patients with diabetes and should be considered in the patient with symptoms of congestive heart failure and a normal ejection fraction.

Diagnostic Considerations
The following conditions and factors should be taken into account in considering a diagnosis of type 1 diabetes mellitus (DM):

Monogenic DM[18] , previously known as maturity-onset diabetes of youth (MODY), a rare autosomal dominant condition found primarily in whites Secondary hyperglycemia Disorders of target tissues (liver, muscles, adipose tissue) Endocrine disorders - Endocrine tumor causing increased production of growth hormone, glucocorticoids, catecholamines, glucagon, and somatostatin; Addison disease; Graves disease; Hashimoto thyroiditis; acanthosis nigricans (genetic disorders with insulin resistance) Drugs - Thiazide diuretics, phenytoin, glucocorticoids Chronic pancreatitis Cystic fibrosis Prader-Willi syndrome - Mental retardation, muscular hypotonia, obesity, short stature, and hypogonadism associated with DM Nondiabetic glycosuria Renal glycosuria - Glucose appears in urine despite normal glucose concentration in blood. This glucose may be due to an autosomal genetic disorder or dysfunction of the proximal renal tubule (eg, Fanconi syndrome, chronic renal failure), or it may be due to increased glucose load on tubules by the elevated glucose filtration rate during pregnancy.

Peripheral neuropathy due to alcohol and vitamin B-12 deficiency

Differentials

Diabetes Mellitus, Type 2 Diabetic Ketoacidosis Diabetic Nephropathy Diabetic Ulcers Insulin Resistance Lead Nephropathy