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- Case report
A 20-year-old man with a 5-year history of Type 1 diabetes presented to hospital 78 h following insulin pump commencement with gross generalized oedema, a 17-kg weight gain and central chest/epigastric discomfort. There was no history of cardiac, hepatic or renal disease. There was a history of persistent sinus tachycardia of unclear aetiology despite investigation; diabetic autonomic neuropathy was a suggested cause, although the patient had no other diabetic microvascular complications. A total daily insulin dose of approximately 100 units was used in the insulin pump compared with a reported use of 123 units per day of basal–bolus insulin (mealtime insulin aspart and nightly insulin glargine). Glycaemic control had been poor with measured HbA1c from the past 3 years all being > 120 mmol/mol (> 13.1%). Blood sugars greatly improved on the insulin pump.
- First description of insulin oedema occurring in the setting of an insulin pump.
- First description of insulin oedema and treatment-induced neuropathy occurring in the same individual.
- Highlights insulin oedema and treatment-induced neuropathy as possible complications of rapid correction of glycaemic control. Suggests caution and the need to monitor for these complications when initiating a treatment approach likely to rapidly improve glycaemic control. Conservative and/or supportive treatment with eventual resolution of symptoms described.
- Computed tomography images and clinical photos of insulin oedema and its subsequent resolution complement the written case.
Physical examination at presentation revealed: sinus tachycardia (rate 102 b min−1) and blood pressure 146/109 mmHg. There was generalized oedema, including abdominal distension. Finger-prick blood glucose was 13.0 mmol/l; ketones were not detected. Results of laboratory investigations are shown in Table 1. Of note, renal function and albumin concentrations were normal, while gamma glutamyl transpeptidase and alanine transferase were elevated; liver function tests had been normal several months prior. Computed tomography scan of the abdomen did not show evidence of venous thrombosis, but hepatomegaly, enlarged and abnormal appearing kidneys, bilateral pleural effusions and extensive subcutaneous oedema were noted (Fig. 1). Spot urinary albumin:creatinine ratio was normal (1.3 mg/mmol). The patient was discharged the next day with arrangements for an outpatient echocardiogram; no new medication was commenced and the insulin pump continued with settings unchanged. Fluid and salt restriction were advised.
Table 1. Laboratory values
| ||Aa||Bb||Cb||Reference range|
|Haemoglobin (g/l)|| 134 || 128 ||152||135–180|
|Creatinine (μmol/l)||36||54||48||< 120|
|Bilirubin (umol/l)||5||6||15||< 20|
|Alkaline phosphatase (U/l)||125||103||101||35–135|
|Gamma glutamyltransferase (U/l)|| 191 || 120 ||22||< 60|
|Alanine aminotransferase (U/l)|| 606 || 164 ||28||< 40|
|Thyroid-stimulating hormone (mU/l)|| ||3.60|| ||0.4–4.0|
|Free thyroxine (pmol/l)|| ||12|| ||9–19|
|Aldosterone (pmol/l)|| < 40 ||134|| ||80–800 Erect|
|Renin (mU/l)|| 52 ||27.2|| ||7–50 Erect|
The patient was reviewed 1 week later. Echocardiogram was normal. At presentation aldosterone had been < 40 pmol/l and renin 52 mU/l. Blood sugars remained normo- to hypoglycaemic. His weight was now 77 kg (61.3 kg had been documented 3 weeks prior); his calculated BMI (based on a dry weight of 61.3 kg) was 17.9 kg/m2. There was generalized oedema involving his face, torso and limbs (Fig. 2). Jugular venous pulsation was 1 cm at 45° with otherwise normal cardiovascular examination. Clinically there were small bilateral pleural effusions. Abdomen was distended with palpable hepatomegaly. Further laboratory results are presented in Table 1.
Figure 2. Examination findings at presentation (a) demonstrating peripheral oedema (left panel) and abdominal distension (right panel) with resolution at 1 month follow-up (b)
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The patient was diagnosed with insulin oedema syndrome. Frusemide 20 mg daily was commenced and the insulin pump basal rate reduced with higher blood sugar targets set. Over the next 1–2 weeks oedema slowly resolved (Fig. 2). Formal ophthalmology review did not demonstrate any significant retinopathy. Liver function tests normalized (Table 1).
On follow-up, the patient's euvolaemic weight plateaued at 70 kg, higher than his pre-pump weight, suggesting non-fluid weight gain since insulin therapy intensification. Unfortunately, however, he developed generalized body pain with neuropathic features. There were no sensory, motor or autonomic neurologic symptoms or signs. The management of this neuropathic pain syndrome became a more challenging task than the management of his insulin oedema. Numerous analgesic combinations were trialled, inpatient management was necessary and pain specialists were involved; symptoms were eventually controlled on a combination of gabapentin, duloxetine and methadone. Eight months following commencement of the insulin pump HbA1c was 55 mmol/mol (7.2%), analgesics were being weaned and oedema had not recurred.
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- Case report
Insulin oedema may be mild, causing peripheral swelling, or generalized with pleural or pericardial effusions and/or ascites [4, 6, 8]. Reported weight gain has ranged from 1.8 to 20 kg (mean 8.4 kg) [7, 9]. Whilst mostly of short duration, persistent or recurrent insulin oedema can occur . The diagnosis is one of exclusion . In our patient, oedema was generalized with marked weight gain; abdominal distension was prominent. Nephrotic syndrome, cardiac dysfunction, thrombosis and liver failure were excluded as causes. Investigation demonstrated hepatomegaly and hepatic enzyme derangement, which normalized with oedema resolution. Transient hepatic enzyme derangement has been reported previously  and is postulated to be attributable to hepatic congestion. Our patient developed insulin oedema days after commencing an insulin pump. Insulin oedema can occur with insulin regimen intensification, but has not been described in the setting of an insulin pump. Insulin oedema is also associated with hypoglycaemic episodes and diabetic ketoacidosis treatment . At the time of development of insulin oedema, insulin dose has generally been high [6, 10]. This was true in our patient who (with a dry body weight of 61.3 kg) was using approximatley 100 units of insulin per day via his insulin pump; this therapy resulted in a dramatic improvement in glycaemic control, including hypoglycaemic episodes.
Insulin oedema occurs more frequently in patients with Type 1 diabetes, newly diagnosed or with poor glycaemic control, and in patients with poor nutritional status . Our patient had long-standing poor glycaemic control and was underweight. Patients with pre-existing cardiac, hepatic or renal diseases are also at increased risk [4, 13, 14].
Treatment approaches for insulin oedema vary. Even severe oedema may resolve with conservative measures, including compressive stockings, salt and fluid restriction and insulin dose reduction . Loop diuretics, spironolactone and ephedrine have also been utilized with ephedrine reserved for diuretic refractory cases . Our patient was initially managed with salt and water restriction. After 1 week without oedema resolution, higher blood sugar targets (with insulin dose reduction) and diuretic therapy were instituted. As in the majority of cases , oedema in our patient resolved within a matter of weeks; it is difficult to know whether the treatment instituted altered his disease course.
Multiple pathogenic mechanisms for insulin oedema are described. Insulin has a direct anti-natriuretic effect by enhancing renal tubular sodium reabsorption, it causes vasodilation and it increases vascular permeability . Increased transcapillary leakage of albumin has been demonstrated  and may contribute to oedema formation. 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 proposed explanation is that hypoglycaemia stimulates release of counter-regulatory hormones (cortisol, adrenaline, aldosterone, renin and antidiuretic hormone), which retain sodium and water . Insulin oedema occurs in patients with hypoglycaemic episodes, and patients with poor glycaemic control release these counter-regulatory hormones at a higher blood sugar level . Insulin oedema with secondary hyperaldosteronism was reported in one case ; however, this case occurred following treatment of diabetic ketoacidosis. Diabetic ketoacidosis is itself associated with elevated renin and aldosterone  and, in our patient and another , hyperaldosteronism was not demonstrated. Finally, markedly underweight patients with diabetes (patients at higher risk of developing insulin oedema) might have subclinical thiamine deficiency. This deficiency may be unmasked by insulin and dietary carbohydrate intake increasing demand for thiamine. In a thiamine-deficient state, lactate and pyruvate accumulation produce peripheral vasodilation and oedema .
In addition to insulin oedema, our patient developed generalized neuropathic pain several weeks following commencement of his insulin pump. A painful neuropathy preceded by rapid glycaemic control has been described and termed ‘insulin neuritis’  or treatment-induced neuropathy . The syndrome can occur in patients with Type 1 or Type 2 diabetes, with pain occurring in either a length-dependent or, in a smaller number of cases, generalized manner; coexistent autonomic features are common. In a series of 16 patients, generalized pain only occurred in patients with Type 1 diabetes . Worsening of diabetic retinopathy is also reported to occur concurrently  and our patient was screened for this complication. Symptoms of this painful neuropathy are often severe, but generally resolve over months to years. Treatment options to reduce the neuropathic pain include anticonvulsants, antidepressants and opioids. Our patient was treated with a combination of these medication classes.
This case highlights two potential complications of insulin therapy intensification: insulin oedema and treatment-induced painful neuropathy. It demonstrates that these complications may occur in the same individual soon after a rapid improvement in glycaemic control; screening for diabetic retinopathy in these patients is also important. As clinicians, we should be mindful of these potential treatment-related complications, particularly in at-risk patients (such as underweight patients with Type 1 diabetes with poor glycaemic control or in those with other co-morbidities), and consider taking a more gradual approach to blood sugar lowering when insulin therapy is intensified in these circumstances.