Clinical Findings in Diabetes Mellitus

A 45-year-old man presents with a family history of type 2 diabetes mellitus (DM), but he has no history of diabetes himself. His hemoglobin A1c (HbA1c) level is 6.1%. He has a large, protruding belly.

What is the significance of this patient's big belly?

Answer: Central adiposity/big belly may be a giveaway for an elevated risk of type 2 DM.

Most patients presenting with type 2 DM have big bellies, as do those with prediabetes. This patient has prediabetes (HbA1c 5.7-6.4%). In advanced cases, the belly may be protruding to the point where it obstructs the patient's view of the feet on downward gaze.

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A young mother brings her 14-month-old baby to the clinic. She is concerned about the baby having persistent chubby cheeks and thinks her child is at risk for diabetes.

Is there any relation between chubby cheeks and diabetes?

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Answer: Chubby cheeks are strongly associated with increased visceral adiposity.^[1] Increased visceral fat is a marker for insulin resistance and possible risk of DM. However, no studies have been done in babies to determine at what stage chubby cheeks should worry parents. In the images shown, the patient on the left is fat-fit, with a reduced amount of internal fat as compared with the obese control subject on the right.

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An obese 24-year-old man presents to the emergency department (ED) with headache and fatigue. He has no previous history of DM. His blood glucose was 450 mg/dL, and his HbA1c is 12.3%. The physical examination is remarkable for velvety, papillomatous, hyperkeratotic and pigmented lesions in both axillae. The patient had known about the lesions for at least 3 years.

What is the significance of these lesions?

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Answer: The lesions shown are typical of acanthosis nigricans, which is often discernible over the nape of the neck and may also be seen at other sites, such as flexures.^[2]

In an obese patient, acanthosis nigricans lesions indicate insulin resistance, which should raise a red flag for DM or prediabetes. Treatment with metformin or insulin sensitizers (eg, pioglitazone) has been used, with limited success, to delay the onset of diabetes when dietary measures alone have not been effective. Acanthosis nigricans is also seen in patients with hypothyroidism, which must be excluded; the response to therapy can be gratifying.

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An obese 42-year-old man has sleep apnea and newly diagnosed type 2 DM (HbA1c 8.6%). He wants to know whether his sleep apnea contributed to the development of his diabetes.

How would you advise this patient?

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Answer: Sleep apnea necessitating continuous positive airway pressure (CPAP) is often encountered both in prediabetes and in established type 2 DM. Two community-based studies in patients with different ethnic backgrounds have confirmed the relations among sleep-disordered breathing, insulin resistance, and glucose intolerance that are precursors to the development of diabetes.^[3,4] Early resolution of sleep apnea or sleep-disordered breathing should be beneficial, though definitive studies are lacking.

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A 44-year-old man with uncontrolled DM (HbA1c 11%) is seen in your clinic and found to have a positive prayer sign (ie, inability to close the gaps between the two opposed palmar surfaces when an attempt is made to press the hands together).

What is the genesis of this finding?

Answer: A positive prayer sign is typical of diabetic cheiroarthropathy (also known as diabetic stiff hand or limited joint mobility [LJM] syndrome).

Diabetic cheiroarthropathy may be seen in 8-50% of patients with type 1 DM and is also seen in those with type 2 DM.^[5,6] It is associated with and predictive of other microvascular complications. The syndrome is characterized by waxy, thick, and tight skin, similar to that seen in scleroderma. The patient is unable to fully flex or extend the fingers. Diabetic cheiroarthropathy is thought to be secondary to increased glycation of collagen in the skin, as well as decreased collagen degradation. Improvement (shown) may be seen with better glycemic control.

A 53-year-old man with type 2 DM of 8 years' duration presents to the clinic with a history of pain and a catching or locking sensation when attempting to flex the fingers of his right hand. Physical examination reveals a palpable nodule over the fourth and fifth metacarpophalangeal (MCP) joints. In addition, thenar muscle atrophy is present.

What are the likely diagnoses in this scenario?

Answer: Thenar muscle atrophy (arrow) may be seen in advanced diabetic neuropathy and may be a late manifestation of carpal tunnel syndrome (CTS). This patient also has features of flexor tenosynovitis (trigger finger) related to the fourth and fifth fingers of the right hand.

CTS is a consequence of entrapment neuropathy secondary to DM-induced connective-tissue changes.^[7] It may be seen in as many as 20% of diabetic patients. The diagnosis is made on the basis of the history (eg, burning, paresthesia, and numbness in the median nerve distribution [including the first three-and-a-half fingers]) or the clinical findings. Patients with CTS do not have sensory loss in the skin overlying the thenar bulge; this is because the palmar branch of the median nerve branches off and passes over the carpal tunnel. Repetitive hand movements predispose to CTS. It is important to consider other conditions associated with CTS, such as rheumatoid arthritis, acromegaly, hypothyroidism, obesity, previous wrist injury, and pregnancy. Several clinical tests may be helpful in making the diagnosis, including the Phalen maneuver, the Tinel sign, and the Durkan test (see slides 13 and 14).

A 43-year-old woman with DM presents with complaints of left-hand weakness and a sensation of numbness in the left hand along the distribution of the median nerve. She has uncontrolled diabetes (HbA1c 9.6%) and has previously ignored pleas for better glycemic control. Her hand reveals left thenar atrophy, and features of proliferative retinopathy are noted.

What is the likely diagnosis?

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Answer: Left thenar atrophy in DM is commonly a complication of long-standing CTS.^[8]

Diabetes control is important. Because patients with type 1 DM are at higher risk for primary hypothyroidism, thyroid studies are indicated. Acromegaly is associated with CTS, and hyperglycemia may be a consequence.

Three clinical maneuvers facilitate diagnosis of CTS. To perform the Phalen maneuver, gently flex the patient's wrist as far as possible, and hold it there for 60 seconds. Pain and paresthesia will occur in muscle innervated by the median nerve; the quicker the numbness starts, the more advanced the condition. To elicit the Tinel sign, gently tap the skin over the flexor retinaculum; this will induce a pins-and-needles sensation and tingling in the median nerve distribution of the palm. To perform the Durkan test, apply pressure to the palm over the nerve to elicit symptoms.

Using a splint to keep the wrist extended often helps. Because symptoms are worst in the morning, the splint should be worn during the night. For advanced cases, surgery may be considered.

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A 62-year-old woman with a history of type 2 DM, hypertension, and chronic renal insufficiency (stage IV chronic kidney disease) presents with ulcerative lesions of several months' duration located along the inner thighs and dorsal tibial regions. The lesions are firm and calcified along the edges with specks of whitish granular material in the middle of necrotic plaquelike areas. The leg does not appear swollen, and there is no clinically significant regional lymphadenopathy.

What is the most likely diagnosis?

Answer: The lesions are highly suggestive of calciphylaxis, a poorly understood entity of skin necrosis and vascular calcification.^[9-11]

Calciphylaxis is uncommonly seen in uncontrolled diabetic patients, particularly in those with advanced renal complications. Its pathogenesis remains obscure. Hypercalcemia, hyperphosphatemia, chronic renal failure, hyperparathyroid state, vitamin D metabolites, vascular insufficiency, and use of immunosuppressants have all been implicated. The differential diagnosis includes chronic cellulitis, hypersensitivity vasculitis, bullous pemphigoid, brown recluse spider bite, pyoderma gangrenosum, venous ulcers, and Wegener granulomatosis. Mortality is high (60-80%), particularly in those with proximal disease; it is two times higher in those with ulcerative disease. Even though calciphylaxis is often associated with diffuse vascular pathology, it has also been reported with exclusive cutaneous involvement.

A 38-year-old woman with a 14-year history of type 1 DM presents for diabetes management. Physical examination reveals lesions over the shins bilaterally.

What is the likely diagnosis?

Answer: Diabetic dermopathy (shin spots) and necrobiosis lipoidica diabeticorum (NLD) are often seen in patients with DM, possibly reflecting a form of microangiopathy.

Lesions initially appear as small papules that expand rapidly into red-brown to yellow plaques with irregular borders, typically appearing along the anterior aspect of the shin. Telangectasias are visible at the lesion base. These lesions may soon turn into weeping lesions and become superinfected. The prevalence is reported at 1-2% in patients with type 1 DM. The differential diagnosis includes granuloma annulare, erythema nodosum, necrobiotic xanthogranuloma, and sarcoidosis.

A 62-year-old man with poorly controlled type 2 DM (HbA1c 9.2%) wakes up with an inability to lift the right foot against gravity. The patient had been sitting cross-legged while working with his laptop computer.

What is the likely diagnosis?

Answer: Right foot drop may be noted in a patient with type 2 DM and peroneal nerve neuropathy, and in this case, compression or mechanical trauma to the common peroneal nerve is the most likely etiology.^[12]

The common peroneal nerve is a branch of the sciatic nerve (L4-5, S1-3). After leaving the popliteal fossa, it crosses behind the head of the fibula and passes laterally around the neck of the fibula. It is here that the peroneal nerve is most vulnerable to compression. Foot drop is more common in diabetic patients because they already have subclinical ischemia, which is exacerbated by mechanical trauma. Males are affected more commonly than females are. The condition is often seen after sports injury, hip or knee replacement, or large weight loss (eg, after bariatric surgery). In peripheral compressive neuropathy, recovery is expected in about 3 months. The differential diagnosis includes lumbar radiculopathy, motor neuron disease, a parasagittal or subcortical cerebral lesion, Charcot foot, and habitual crossing of the legs.

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A 56-year-old man with type 2 DM (HbA1c 8.8%) of 24 years' duration presents with burning, lancinating pain in the right buttock, thigh, and legs. Over the preceding 3 months, he has lost 15 lb in weight. On physical examination, there is wasting of the thigh muscles on the right side, with occasional involuntary twitching.

What is the likely diagnosis?

Answer: Right proximal motor neuropathy (previously designated as diabetic amyotrophy).

First described in 1890 by Bruns, and given the name diabetic amyotrophy in 1955 by Garland, proximal motor neuropathy (also referred to as lumbosacral plexopathy) occurs in both type 1 and type 2 DM, with a peak incidence in the sixth decade of life. Weakness and atrophy of the pelvic girdle and thigh muscles are characteristic. Rapid weight loss and worsening glycemic control are common. Often, this condition is accompanied by polyneuropathy. Involuntary twitching or fasciculation may be seen. Weight gain and improved glycemic control often reduce symptom intensity. Nerve biopsies have tilted the view toward an immune mechanism that leads to endoneural vasculitis, which in turn leads to ischemia. Immunosuppressants have been used in its management.^[13]

A 56-year-old man with type 2 DM of 24 years' duration (HbA1c 9.8%) presents with ulcerative lesions on the soles of both feet.

What is the diagnosis?

Answer: Diabetic foot ulcers with asymmetric peripheral vascular disease, often seen in patients with DM.^[14,15]

The foot lesions shown provide an excellent illustration of asymmetrical vasculopathy and bilateral peripheral neuropathy in a diabetic patient. The ulcers at the base of the first and second toes are strongly suggestive of neuropathic ulcers (pressure points). On the left foot, there is also an ischemic ulcer at the tip of the big toe. No erythema or red flare is seen. This is highly suggestive of concomitant vascular disease. Notice also that the left foot appears pale. On the other side, the right foot has a pinkish hue, and there is a red flare surrounding the ulcers and extending deeper and inward; this reflects the inflammation that would be seen when circulation is preserved.

A 72-year-old man with long-standing uncontrolled diabetes and autonomic neuropathy presents to you with a painful and warm left foot.

What is the most likely diagnosis for this patient?

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Answer: Charcot foot (also known as Charcot neuroarthropathy).

Diabetic neuropathy is the leading cause of Charcot foot.^{[16, 17]} The foot is warm as a consequence of increased blood flow occurring in association with autonomic dysfunction. The foot is insensate, and multiple ulcerations may be seen. The medial arch is collapsed, and the foot feels like a "bag of worms." Charcot foot may also be seen in other neuropathic states, such as tabes dorsalis, leprosy, spinal cord compression, multiple sclerosis, and syringomyelia.

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A 72-year-old man with a history of type 2 DM and hypertension presents with a complaint of having awakened with headache and nausea. His right eye shows clinically remarkable findings (shown).

What is the likely diagnosis?

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Answer: Right third cranial neuropathy (oculomotor nerve palsy).

This neuropathy is signaled by mild ptosis, abduction of the eye, and downward displacement of the eye or failure to converge. Pupillary dilatation may be seen, but it may be absent (pupillary sparing) if the lesion is recovering.^[18,19] The eye is thus displaced outward and downward. Isolated third-nerve palsy secondary to vascular disease is the most common cranial neuropathy seen in patients with DM. Hypertension may be an independent cause in some patients. Isolated third-nerve palsy is also seen in upper midbrain vascular accidents, in demyelinating lesions, and peripherally as a result of compression by carotid and posterior communicating artery aneurysms, parasellar neoplasms, sphenoidal wing neoplasms, and neoplasms of the base of the skull. With diabetes, often the recovery is complete. In this patient, symptoms reflect a cerebrovascular accident.

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A 24-year-old male with uncontrolled type 1 DM (HbA1c 11%) presents with diabetic ketoacidosis (DKA). He also demonstrates features of cranial nerve neuropathy.

What is the likely diagnosis, and what is the prognosis?

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Answer: Left seventh-nerve palsy (Bell palsy).

Bell palsy may be seen in patients with DM, including those with acute decompensation such as is seen in DKA.^[20-23] It is most often unilateral. There is a significant correlation between HbA1c level and Bell palsy; no such relation exists with hypertension or dyslipidemia. Use of statins has been linked with Bell palsy. Complete recovery is seen in almost all cases, commonly within 6 months. The postonset course of the disease in patients with DM is similar to that in patients without DM. Occasionally, bilateral Bell palsy is seen in patients with DM, but this is an exceedingly rare occurrence. When present, bilateral Bell palsy often implies a serious underlying disorder, such as Guillain-Barre syndrome, multiple cranial neuropathies, basilar meningitis (neoplastic or infectious), leukemia, syphilis, sarcoidosis, Lyme disease, HIV infection, or mononucleosis (to name only a few).

Image courtesy of Wikimedia Commons (left, right—Patrick J. Lynch; illustrator; C. Carl Jaffe; MD; cardiologist Yale University Center for Advanced Instructional Media).

A patient with uncontrolled DM (HbA1c 10.4%) undergoes anterior eye chamber examination. The iris appears as shown on the slide. The patient denies experiencing any acute pain or systemic symptoms.

What is the diagnosis?

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Answer: Rubeosis iridis (vascular invasion/neovascularization of the iris).

This condition is seen in uncontrolled DM and may precipitate glaucoma. Symptoms are usually related to glaucoma. Rubeosis iridis is usually associated with a disease process in the retina that entails the retina becoming ischemic and releasing a variety of angiogenesis factors, such as vascular endothelial growth factor (VEGF). These factors promote angiogenesis in areas that do not normally have vessels, such as the iris. In the early stages, neovascularization can be reversed by means of prompt panretinal photo coagulation (PRP) or injection of anti-VEGF medications.^[24]

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A young female patient with DM (HbA1c 8.9%) of 8 years' duration undergoes a physical examination, the results of which are completely normal. Her primary care provider asks you take a look at the patient's most recent photograph (shown), which, he thinks, demonstrates an abnormality that was not seen earlier.

What is the diagnosis, and how is it linked to diabetes?

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Answer: Heterochromia iridum (dissimilar colors of the irises).

This condition may be seen in DM after inflammation of iris in patients with rubeosis iridis or glaucoma; it may also be seen in patients with glaucoma who are using latanoprost eyedrops.^[25,26] The treated eye shows increased pigmentation. Heterochromia of the iris can also be a benign congenital condition seen in as many as six of every 1000 eyes examined. It is often subtle and may go unnoticed. Acquired iris heterochromia is always due to disease affecting eyes or loss of sympathetic innervation on the affected side.

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Some patients with DM show a clinical picture similar to the one shown on the slide, in which a right miotic irregular pupil does not react to direct light (pupillary reaction) but responds to accommodation.

What is this phenomenon called?

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Answer: Argyll Robertson pupil (ARP).

ARP is characterized by a small pupil, failure of pupillary constriction (pupillary response) in response to light, and preservation of accommodation response.^[27] Initially considered pathognomonic for neurosyphilis, ARP has since been observed in sarcoidosis, multiple sclerosis, and occasionally DM. The pupil's better response to accommodation than to light stimuli is a reflection of a vascular lesion that affects more dorsally located fibers that subserve the light response. Two mnemonics may be helpful for remembering the characteristics of this condition: The acronym ARP can also be thought of as short for "accommodation reflex present," and if it is reversed, the resulting acronym, PRA, can be thought of as short for "pupillary reaction (to light) absent."

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Gustatory sweating (sweating of the face, head, and neck at the sight or smell of food) may be seen in patients with DM and autonomic neuropathy, in whom it is a relatively common phenomenon.^[28,29] Its presence indicates possible concurrent diabetic complications. Glycemic control is not related to the severity of symptoms. Reversal of gustatory sweating has been reported with renal transplantation in those with end-stage diabetic nephropathy; it has been reported in the absence of nephropathy as well.

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