Abstract
Insulin oedema is a rare complication of insulin treatment characterised by an absence of heart, liver and renal involvement. Insulin oedema typically develops in the lower extremities or, less frequently, as generalised oedema after initiation of insulin therapy. We report a 59-year-old man with poorly controlled type 2 diabetes who developed oedema in his penis and scrotum accompanied by weight gain following intensive insulin therapy. His oedema improved after reduction of the daily insulin injection dose and treatment for urinary retention. Penile and scrotal oedema is a rare physical finding for the patient with diabetes. Therefore, in patients with poorly controlled diabetes who have started insulin therapy, physicians should pay attention to urinary retention and do not miss changes in weight gain or oedema in the lower body, including the perineal region.
Keywords: endocrine system, diabetes, drugs: endocrine system
Background
Insulin oedema is a rare complication of insulin treatment characterised by an absence of heart, liver and renal involvement. Insulin oedema typically develops in the lower extremities or, less frequently, as generalised oedema after initiation of insulin therapy.1
Case presentation
The patient was a 59-year-old Japanese man admitted to our hospital for an intractable ulcer in both of his lower extremities. He was diagnosed with diabetes at 55 years of age. He had stopped going to the hospital. Except for diabetes, his medical history was unremarkable.
His family never had the same illness. He lived together with his mother, wife, daughter and daughter’s husband.
His body mass index was 20.4 kg/m2. He had attenuation of the Achilles’ tendon reflection. Physical examination demonstrated an ulcer and erosion in both lower limbs and an ulcer on the left hallux, but the remaining general examination includng lower leg oedema was unremarkable.
The ulcer and erosion in both lower extremities were treated with debridement and antibiotic treatment of cefmetazole sodium and vancomycin.
A total daily dose of 16 units of insulin aspart and insulin degludec was initiated on admission, which was increased to a total daily dose of 32 units due to his glucose levels. His weight suddenly increased by 4 kg and bilateral lower limb oedema was observed on day 14. Furthermore, he experienced swelling in his penis and scrotum without pain, a fever, and acute urinary retention happened suddenly.
Investigations
Laboratory findings on admission disclosed the following: white blood cell count was 12.7×109/L, neutrophil rate of 82.0%, C reactive protein was 2.58 mg/dL, postprandial plasma glucose level was 295 mg/dL and haemoglobin A1c was 11.7%. Methicillin-resistant Staphylococcus aureus (MRSA) was detected from the ulcer.
Table 1 shows biochemical and hormonal data taken at time of oedema. Complete blood counts were within normal limits. Cardiac enzyme, liver enzyme, renal function and electrolyte levels were also within normal limits or slightly high. Brain natriuretic peptide (BNP) level was 109 pg/mL (<18.4). Urinary protein excretion was 0.44 g/day. We had also checked an ECG, chest X-rays and a CT scan.
Table 1.
Laboratory data from a patient with bilateral lower limb oedema and penile and scrotal oedema
| CBC | |
| WBC (×109/L) | 8.2 (3.9–9.8) |
| RBC (×109/L) | 3.34 (4.27–5.70) |
| Hb (g/L) | 106 (135–176) |
| Ht (%) | 31.2 (39.8–51.8) |
| Platelets (×109/L) | 361 (131–362) |
| Urinalysis | |
| u-protein | 3+ |
| u-glucose | – |
| u-blood | 3+ |
| u-ketone body | – |
| Triglyceride (mg/dL) | 66 (30–149) |
| T-Cho (mg/dL) | 204 (140–219) |
| HDL-Cho (mg/dL) | 105 (40–99) |
| CRP (mg/dL) | 0.57 (0.00–0.30) |
| PSA (ng/mL) | 0.33 (0.0–4.0) |
| Glucose metabolism | |
| HbA1c (%) | 11.5 (4.6–6.2) |
| PG (fasting) (mg/dL) | 205 (70–110) |
| IRI (ng/mL) | 2.0 (2.2–12.4) |
| C-peptide (ng/mL) | 0.98 (0.5–2.0) |
| GAD-Ab (U/mL) | <5.0 (<5.0) |
| Biochemistry | |
| BUN (mg/dL) | 11.9 (8.0–22.0) |
| Creatinine (mg/dL) | 0.67 (0.60–1.00) |
| Na (mEq/L) | 139 (135–149) |
| K (mEq/L) | 4.0 (3.5–4.9) |
| Cl (mEq/L) | 103 (96–108) |
| Total protein (g/dL) | 5.8 (6.7–8.3) |
| Albumin (g/dL) | 2.6 (4.0–5.0) |
| AST (IU/L) | 14 (13–33) |
| ALT (IU/L) | 11 (8–42) |
| γ-GTP (IU/L) | 268 (10–47) |
| Amylase (U/L) | 44 (37–135) |
| Endocrine | |
| TSH (µU/mL) | 1.8 (0.50–4.20) |
| FT4 (ng/dL) | 1.4 (0.7–1.5) |
| FT3 (pg/mL) | 2.2 (2.4–4.1) |
| ACTH (pg/mL) | 64.0 (7.2–63.3) |
| Cortisol (µg/dL) | 11.2 (4.5–21.1) |
| PRA (ng/mL/hour) | 0.2 (0.2–3.9) |
| PAC (pg/mL) | 59 (35.7–240) |
| Epinephrine (ng/mL) | 0.01 (<0.10) |
| Norepinephrine (ng/mL) | 0.09 (0.10–0.50) |
| Dopamine (ng/mL) | 0.01 (<0.03) |
| BNP (pg/mL) | 109 (<18.4) |
ACTH, adrenocorticotropic hormone; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BNP, brain natriuretic peptide; BUN, blood urea nitrogen; CBC, complete blood count; Cl, chloride; CRP, C reactive protein; FT3, free tri-iodothyronine; FT4, free thyroxine; GAD-Ab, glutamic acid decarboxylase antibody; GTP, gamma-glutamyl transpeptidase; Hb, hemoglobin; HbA1c, haemoglobin A1c; HDL-Cho, HDL cholesterol; Ht, hematocrit; IRI, immunoreactive insulin; K, potassium; Na, sodium; PAC, plasma aldosterone concentration; PG, plasma glucose; PRA, plasma renin activity; PSA, prostate-specific antigen; RBC, red blood cell; T-Cho, total cholesterol; TSH, follicle-stimulating hormone; WBC, white blood cell.
Differential diagnosis
The differential diagnosis of the oedema included renal, hepatic and cardiac disease. An ECG on admission showed sinus rhythm and complete right bundle branch block with no ST-T changes. Chest X-rays were negative for cardiomegaly or pleural effusion. There were no findings of pulmonary congestion or pleural and ascites fluid on the chest CT scan. Echocardiography also showed no congestive and ventricular asynergy, so cardiac failure was deemed clinically improbable.
A further possibility was hepatic disease, including cirrhosis, but relatively normal liver function tests and abdominal CT scan made these unlikely. Nephrotic syndrome present with marked oedema, proteinuria, hypoalbuminemia and often hyperlipidaemia. In the absence of such a condition, nephrotic syndrome is ruled out. The diagnosis of insulin oedema was made because of the appearance of oedema when the insulin dose was increased during the course of treatment.
Furthermore, the differential diagnosis of the urine retention included prostatic, bladder, urethra, nervous disease. A CT scan of the abdomen and pelvis revealed bilateral hydronephrosis, cystectasia, oedema of the penis and scrotum, but no prostatic hypertrophy, inguinal hernia, varicocele or testicular tumours (figure 1). Urethral dilatation was observed via the internal to external urethral opening. Urinary retention was suggested to be related to mechanical obstruction by penile oedema.
Figure 1.
Abdominal CT scan findings.
Treatment
Figure 1 shows his clinical course.
There was 200 mL of residual urine after the patient had urinated 900 mL himself. His urinary retention improved with a urethra indwelling catheter, but his oedema was not improved (figure 2). Linagliptin and metformin were added for reduction of total daily insulin levels and his daily insulin dose was reduced from 36 units to 22 units per day. His oedema started to improve, and over the next week, the patient’s oedema slowly resolved. Abdominal CT scan on day 30 showed improvement of hydronephrosis, cystectasia and penile and scrotum oedema. His body weight returned to his initial weight of administration on day 32. Echocardiography showed no abnormalities in cardiac function, but his BNP level improved slightly to 78 pg/dL during the treatment for oedema.
Figure 2.
Clinical course.
Finally, the MRSA-infected diabetic foot infection was healed and his daily insulin dose was reduced to 10 units per day. Oedema and dysuria were not observed on removal of the indwelling catheter in the outpatient clinic after discharge.
Outcome and follow-up
Owing to reduction of total daily insulin levels, his oedema started to improve, and on day 30, the patient’s oedema slowly resolved.
Discussion
This case involved insulin oedema and urine retention after rapid improvement of glucose levels in a patient with type 2 diabetes. His oedema improved after reduction of the daily insulin injection dose and treatment for urinary retention. Expansion of the daily insulin injection dose may be a risk for oedema and urinary retention in patients with poorly controlled diabetes. Insulin oedema is a syndrome occurring in patients with either type 1 or type 2 diabetes after intense insulin treatment.2–4 The severity of insulin oedema varies from mild peripheral oedema to cardiac failure and massive effusions. Insulin oedema should be differentiated from other causes of oedema secondary to renal, hepatic or cardiac failure, as well as from drug-induced oedema.1 Insulin oedema develops in the lower extremities in most cases, but this is the rare case to report urinary retention associated with penile oedema.
In regards to the pathogenesis of insulin oedema, two effects of insulin treatment, antinatriuresis and increased capillary permeability, have been reported.5 Insulin has a direct antinatriuretic effect by enhancing renal tubular sodium reabsorption, causing vasodilation, and increased vascular permeability. Chronic hyperglycaemia is also associated with increased capillary permeability, which may explain the increased frequency of insulin oedema in patients with poor glycaemic control.
Another mechanism is that hypoglycaemia stimulates release of counter-regulatory hormones (cortisol, epinephrine, aldosterone, renin and antidiuretic hormone), which keep sodium and water.5 Insulin oedema occurs in patients with hypoglycaemica and with poor glycaemic control releases these counter-regulatory hormones at a higher blood sugar level.6 Insulin oedema with secondary hyperaldosteronism was reported in one case7; however, in our patient hyperaldosteronism was not demonstrated.
Treatment approaches for insulin oedema vary. Generally, oedema may resolve with conservative managements, including compressive stockings, salt and fluid restrictions, insulin dose reduction and changing insulin type. In severe cases, loop diuretics and spironolactone may be used. In cases of oedema resistant to diuretics, ephedrine has also been used.5 Our patient was managed with insulin dose reduction.
Painless swelling of the penis and scrotum can be caused by harmless conditions or can be a sign of something more serious. Several causes are hydrocele, inguinal hernia, varicocele, spermatocele, haematocele, oedema and testicular cancer.8 9 Medical examination and CT scan were helpful in diagnosing that the patient’s penile and scrotal oedema, accompanied by urine retention, was induced by insulin oedema syndrome. His bladder and ureter were stuffed without prostatic hypertrophy, and his urinary retention improved with a urethra indwelling catheter. Diabetic cystopathy is a well-recognised complication of diabetes neuropathy and is observed in 43%–87% of insulin dependent diabetics.10 This patient had the potential to progress to temporary bladder dysfunction due to rapid improvement of glucose levels, considering his clinical course. The cause of urine retention was considered a urethral stenosis in the distal prostate urethra. Oedema surrounding the external genitalia due to insulin oedema may exacerbate urethral stenosis.
In conclusion, after exclusion of common causes of oedema, a physician should consider insulin oedema syndrome in patients with oedema following insulin therapy. If a patient is treated with increasing the dose of insulin, reduction of the dosage along with the addition of oral hypoglycaemic agents may be a solution to reduce oedema. Increasing the dose of insulin induces insulin oedema. Therefore, after initiating insulin therapy in a patient with poorly controlled diabetes, the physician should watch for changes in weight and oedema and check for urinary retention.
Patient’s perspective.
I developed urinary retention at the same time as the lower leg oedema, which made me very anxious. But the treatment improved my urinary retention, and then I reduced my insulin and the oedema improved as well. Fortunately, I did not have any other complications of insulin oedema, such as heart failure.
Learning points.
After exclusion of common causes of oedema, a physician should consider insulin oedema syndrome in patients with oedema following insulin therapy.
Increasing insulin dose induces insulin oedema, so insulin reduction may be a treatment.
Insulin oedema can rarely result in urinary retention and urine output should be monitored.
Acknowledgments
I would like to thank Shigehara K and Aono D for useful discussions. I would also like to take this opportunity to thank TY for years of collaboration and advice.
Footnotes
Contributors: Report was written by YT and SK, supervised by MK and TY. Patient was under the care of YT.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Provenance and peer review: Not commissioned; externally peer reviewed.
Ethics statements
Patient consent for publication
Obtained
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