Insulin oedema David J. Evans, Kathryn Pritchard-Jones and Beatrice Trotman-Dickenson
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Insulin oedema
David J. Evans, Kathryn Pritchard-Jones and Beatrice Trotman-Dickenson
John Radeliffe Hospital, Headington, Oxford, UK.
Summary: A 35 year old markedly underweight woman presented with uncontrolled diabetes.
Following insulin therapy she developed gross fluid retention with extensive peripheral oedema, bilateral
pleural effusions and weight gain of 18.8 kg in 22 days, accompanied by a fail in plasma albumin. She
responded well to treatment with diuretics and salt-poor albumin, losing 10.3 kg in 6 days without
recurrence of oedema. Severe insulin oedema is an uncommon complication of insulin therapy and may be
due to effects of insulin on both vascular permeability and the renal tubule.
Introduction
Extensive oedema formation is an uncommon com- creatinine (64 pmol/l), urea (6.3 mmol/l) and elec-
plication of insulin therapy and has been termed trolytes normal. Plasma albumin was 34 g/l (normal
'insulin oedema' (Leifer, 1928). It must be differen- range 35-50), total protein 69 g/l and liver function
tiated from other causes of oedema such as cardiac or tests normal. A midstream urine sample was without
renal disease, which may themselves arise independen- proteinuria, and chest X-ray and electrocardiograph
tly or as a complication ofthe diabetic state. We report were normal. Islet cell antibodies were positive, choles-
the case of a markedly underweight woman newly terol, triglycerides, iron, iron binding capacity, red cell
presenting with diabetes in whom extensive fluid folate, transketolase (84 IU/1), and transketolase plus
retention accompanied by large bilateral pleural thiamine pyrophosphate (105 IU/l), all normal. There
effusions followed the initiation of insulin therapy. were no muscle fibres or fat globules in the stool.
She was initially treated with an intravenous in-
fusion of insulin and normal saline (3 litres in 24
Case report hours). Treatment was continued with twice daily
Actrapid and Insulatard insulin totalling 40 units/day,
A 35 year old woman presented with a 2-year history increasing over the next 3 weeks to a maximum of 110
of general malaise, weight loss of 13 kg and amenorr- units/day to maintain blood glucose between 8 and
hoea. Increased thirst, polyuria and polydipsia had 16 mmol/l (Figure 1). Mild bilateral pitting ankle
been present for 3 months and a painful swelling of the oedema was first noted on day 13 and progressed over
left foot for 6 weeks. Both maternal grandparents had the next week. By day 22 she complained ofbreathless-
diabetes mellitus. Examination revealed a markedly ness on exertion and had marked fluid retention with
underweight, mildly dehydrated woman (weight elevated jugular venous pressure, tender hepatomegaly,
38.2 kg, height 1.727 m, body mass index 12.8) with gallop rhythm, extensive peripheral pitting oedema,
several areas of necrobiosis lipoidica on her shins. She facial puffiness and large bilateral pleural effusions
was apyrexial and had a sinus tachycardia of 120/min, (Figure 2). Echocardiography showed good left ven-
with blood pressure of 110/80mm Hg. There was a tricular function and no cardiac abnormality other
glove and stocking neuropathy for all modalities of than a small pericardial effusion. A diagnostic pleural
sensation extending to the wrists and knees, and tap showed a protein content of 21 g/l. She had
ophthalmoscopy showed a severe background retin- gained 18.8 kg in weight since admission and plasma
opathy. Initial investigations were as follows: plasma albumin had fallen to 25 g/l. She was treated with
glucose 29.4 mmol/l; venous pH 7.35; plasma ketones frusemide and salt-poor albumin over the next 2 days
(ketostix, Ames) + +; urine glucose and ketones with a good diuresis and rise in albumin, but regained
+ + +. Haemoglobin 10.9 g/dl; haematocrit 0.348; weight on discontinuing this therapy. Re-introduction
white cell count 13.9 x 109/1 (neutrophil leucocytosis); of diuretic and albumin resulted in a further diuresis
with weight loss of 10.3 kg in 6 days. The body mass
Correspondence: D.J. Evans, B.Sc., M.B., M.R.C.P., Sheikh index was now 15.7. Frusemide was discontinued on
Rashid Diabetes Unit, Radcliffe Infirmary, Oxford day 32, by which time the fluid retention had com-
OX2 6HE, UK. pletely resolved and did not recur throughout her
Accepted: 3 January 1986 admission. Repeated urinary protein estimations were
() The Fellowship of Postgraduate Medicine, 1986Downloaded from http://pmj.bmj.com/ on February 4, 2015 - Published by group.bmj.com
666 CLINICAL REPORTS
Spironolactone 100 mg o.d.
+" i "+*+" Frusemide ; = 40 mg
M
m] Cm Salt-poor albumin
00 *D
4-
0
3. 00
00
* .. .*
'so . 0*- ** 0 *0* 0
@0
co 0*
O 0 00
E. 4U 0 0 0 0
0
2 E_2 32; 0
0
241
c
=
:3(A :
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Figure 1 Body weight, plasma albumin and insulin dose following admission.Downloaded from http://pmj.bmj.com/ on February 4, 2015 - Published by group.bmj.com
CLINICAL REPORTS 667
relation to the low body weight. Peripheral oedema is a marked reduction in the intravascular pool of
associated with chronic insulin overtreatment in albumin and so plasma volume (Gundersen & Chris-
young diabetic subjects (Rosenbloom & Giordano, tensen, 1977). Increased vascular permeability in our
1977), and may also occur in young or middle-aged subject is suggested by the relatively high protein
insulin-treated diabetic women (Lawrence & Dun- content of the pleural effusion in relation to the low
nigan, 1979). Increased endogenous plasma insulin plasma albumin, in the absence of infection. The low
levels are associated with moderate fluid retention albumin might have reflected a dilutional effect,
both in 'idiopathic oedema' (Shaw et al., 1968) and in failure of hepatic synthesis of albumin, or its increased
the 'refeeding oedema' accompanying carbohydrate loss other than via the kidney, as by increased
ingestion after starvation (Kolanowski et al., 1972), degradation. After albumin infusion, plasma levels
which may progress to frank cardiac failure and rose but soon fell rapidly despite continued diuresis
pulmonary oedema in severely malnourished children and weight loss, thus excluding the first two pos-
(Patrick, 1977). The apparently increased incidence of sibilities as major causes of the low serum albumin.
insulin oedema in Africa may thus be due to the more The high protein content of the pleural fluid supports
common occurrence of under-nutrition, which may the possibility of an increase in vascular permeability,
also have been important in our patient. rather than a primary increase in albumin degrada-
At least two possible mechanisms to produce fluid tion, as the cause of the decreased serum albumin.
retention after insulin treatment exist. Sodium reten- Secondary hypo-albuminaemia would then have con-
tion in the treatment of diabetic keto-acidosis with tributed to the fluid retention by a reduction in plasma
preceding salt depletion has long been recognized oncotic pressure.
(Nabarro et al., 1952), and may largely explain the Other mechanisms which have been proposed to
moderate fluid retention encountered in this situation. contribute to the development of insulin oedema
Sodium retention may also occur during insulin include thiamine deficiency with high output cardiac
treatment of non-ketoacidotic diabetic patients, even failure (Deckert, 1958; Shaper, 1966), excluded in our
in the absence of salt depletion (Saudek et al., 1974). case, or an increase in glycogen-associated water
Insulin has a direct sodium-retaining effect on the stores (Leifer, 1928; Shaper, 1966). Glycogen stores in
kidney in both man and experimental animals (De- muscle and liver may vary by up to 500 g, each gram of
Fronzo et al., 1975; Rostand et al., 1980), most marked glycogen being associated with 4 g of water (Olsson &
in diabetic animals with preceding insulin deficiency Saltin, 1970), so this mechanism may contribute to the
and independent of changes in renal blood flow or the lesser degrees ofweight gain associated with improved
renin-aldosterone axis. Insulin oedema may thus be at diabetic control but cannot explain the marked expan-
least partly secondary to sodium retention resulting sion of extracellular volume seen in patients with
from a direct action of insulin on the renal tubule, and severe insulin oedema.
leading to an expansion of interstitial and plasma Regardless of the responsible mechanisms, the
volumes. possibility of severe fluid retention should be borne in
A second possible mechanism is an increase in mind during the introduction of insulin therapy in
vascular permeability (Bleach et al., 1979). Insulin severely malnourished diabetic patients.
increases the permeability of subdermal vessels in
response to injected irritants in both normal and
diabetic rats (Garcia-Leme et al., 1973; Goth et al., Acknowledgements
1957). Endothelial junctions are narrowed in the
insulin deficient animals and this change is corrected We thank Dr T.D.R. Hockaday for permission to report this
after insulin treatment (Garcia-Leme et al., 1974). In case and for helpful discussions during the preparation of the
diabetic men, intravenous injection of insulin leads to manuscript.
References
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Downloaded from http://pmj.bmj.com/ on February 4, 2015 - Published by group.bmj.com
Insulin oedema.
D. J. Evans, K. Pritchard-Jones and B.
Trotman-Dickenson
Postgrad Med J 1986 62: 665-668
doi: 10.1136/pgmj.62.729.665
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