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 Table of Contents  
Year : 2022  |  Volume : 2  |  Issue : 1  |  Page : 25-28

Insulin edema in an adolescent girl with newly diagnosed Type 1 diabetes mellitus

Department of Paediatrics, Government Medical College, Thiruvananthapuram, Kerala, India

Date of Submission30-Aug-2021
Date of Decision26-Jan-2022
Date of Acceptance04-Feb-2022
Date of Web Publication25-Feb-2022

Correspondence Address:
Dr. Rekha Krishnan
Adrija, TC 8/864 (3), Elluvila Nagar, Thiruvananthapuram, Kerala
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ipcares.ipcares_270_21

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Background: Insulin edema is a rare complication that can occur following either initiation or intensification of insulin treatment in Type 1 diabetes mellitus (DM). It is an under reported condition. Awareness of this complication among physicians is important for early identification of this condition, and prompt initiation of treatment. Clinical Description: We present an 11-year-old girl with 2-month history of weight loss and 1-month history of polyuria and polydipsia who presented to us in moderate diabetic ketoacidosis. She developed anasarca and pulmonary edema 3 days after starting insulin. She also developed transaminitis a serum serum glutamic-oxaloacetic transaminase of 81 U/L and serum glutamic pyruvic transaminase of 83 U/L. A diagnosis of insulin edema was established after ruling out other causes like severe anemia, renal, cardiac and allergic causes. We also present a brief review of seven similar cases that we identified on a literature search. Management and Outcome: This included salt and fluid restriction along with diuretics. Edema resoled after 4 days of treatment, while transaminitis took 7 days to normalize. Conclusion: This case report highlights the importance of early recognition of the rare complication of insulin edema which can avoid unnecessary anxiety on the part of both treating physicians and parents of patients with Type 1 DM.

Keywords: Adolescent, children, insulin edema, transaminitis, type 1 diabetes mellitus

How to cite this article:
Krishnan R, Bindu S, Riaz I, Preethi M S. Insulin edema in an adolescent girl with newly diagnosed Type 1 diabetes mellitus. Indian Pediatr Case Rep 2022;2:25-8

How to cite this URL:
Krishnan R, Bindu S, Riaz I, Preethi M S. Insulin edema in an adolescent girl with newly diagnosed Type 1 diabetes mellitus. Indian Pediatr Case Rep [serial online] 2022 [cited 2022 May 27];2:25-8. Available from: http://www.ipcares.org/text.asp?2022/2/1/25/338483

Type 1 Diabetes Mellitus (DM) is one of the most common endocrine disorders in children. It is a chronic disorder of autoimmune etiology characterized by hyperglycemia and the consequent osmotic symptoms. Prevalence of Type I DM in the Indian population is increasing with a trend of 3%–5% increase per year. The patients can present with the classical symptoms of polyuria, polydipsia and polyphagia. In many cases these symptoms do not get noticed until the child presents with diabetic ketoacidosis (DKA), a life-threatening condition. Insulin is the main stay of treatment in Type 1 DM that can on occasion lead to side effects like hypoglycemia, weight gain, and local reaction at the injection site.

An uncommon, and relatively less known complication of insulin treatment is insulin edema, which is characterized by the development of generalized or peripheral edema.[1] This can occur either following the initiation of insulin therapy, or during the intensification phase in patients already on insulin.[2],[3] In the majority of cases, edema occurs within 2–4 weeks.[4],[5] The first case of insulin edema was reported in 1928, however since then only a few clinical descriptions have been published in children and adolescents, worldwide [Table 1]. Though mild to moderate edema is the most common presentation, on occasion cardiopulmonary congestion can occur.[6] It can rarely also be associated with transaminitis.[2],[7]
Table 1: Clinical profile of 7 insulin-dependent diabetes mellitus patients with insulin edema

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We present the case of a girl with newly diagnosed Type 1 DM who developed anasarca and transient elevation of liver enzymes on starting insulin. The aim of reporting this case is to create awareness about this rare complication among pediatricians, who frequently manage children with Type 1 DM, and sensitize them about modalities of its management.[6],[7]

  Clinical Description Top

An 11-year-old, previously asymptomatic girl, presented to us with complaints of weight loss and fatigue for 2 months, followed by increased thirst and frequency of urination for a month. The parents had also noticed a voracious increase in appetite for a few days. She did not have any history of fever, cough or breathlessness. There was no significant past history and she had no comorbid illnesses. The child was appropriately immunized for age. Her development had been normal and she was currently studying in the seventh standard with good scholastic performance. She was the only child of nonconsanguineous parents. The only significant family history was that her paternal grandfather had been diagnosed with DM at 51 years of age and was on medication (metformin).

At presentation she was conscious and well oriented. There was no fever, and she had a pulse rate of 108 beats per minute, respiratory rate of 24 breaths per minute and blood pressure that was 106/60 mm of Hg (<50th centile for age). Anthropometric examination was normal with a weight of 25 kg (Z score-1.2), height of 142 cm (Z score-0.17), and body mass index of 12.4 kg/m2 (Z score-1.6). The only salient general physical examination finding was the presence of some dehydration. The respiratory, cardiovascular, abdominal and central nervous system examinations were with in normal limits.

Since the clinical history was highly suggestive of DM, her blood sugar level was checked immediately, and found to be 560 mg/dl. As per standard protocol for detecting DKA, we did a venous blood gas analysis which revealed a pH of 7.29 and bicarbonate of 6.7 mEq/L. She also had ketonuria (urinary ketones 3+). Thus, a diagnosis of DM with moderate DKA was established, and standard treatment initiated with intravenous (IV) fluids and insulin infusion.[8] Her baseline investigations (blood counts, Erythrocyte Sedimentation Rate, liver and renal function tests, urine albumin and microscopy) were within normal limits at admission [Table 2]. There was no evidence of sepsis; the C reactive protein (CRP) was negative, and blood and urine cultures were sterile. The glycosylated Glycated Hemoglobin (HbA1c) was highly elevated (15%).
Table 2: Lab parameters of the child at admission and at the onset of edema

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  Management and Outcome Top

The metabolic acidosis got corrected within 6 h of starting treatment. After this she was started on subcutaneous insulin (1 unit per kg/day in 3 divided doses). The next day she was shifted to a split mix regimen of insulin with Neutral Protamine Hagedorn (NPH) insulin twice a day, along with regular insulin thrice daily before meals (total dose of 1U/kg/d). 2 days after starting NPH insulin facial puffiness and bilateral pitting pedal edema were noted that progressively increased and became generalized within 24 h. This was reflected in an increase in weight of 1.5 kg over the same duration. Abdominal examination detected clinical indicators of ascites. Despite these fresh clinical issues, her glycemic control continued to exhibit improvement.

All the usual causes of generalized edema were systematically excluded by history, examination and relevant tests. The child remained hemodynamically stable. There were no clinical features indicative of infection such as fever, diarrhea, abdominal pain, or tenderness. This was supported by blood counts and CRP levels that remained normal. There was no jaundice or liver enlargement, but the liver function test identified some minor abnormalities; elevation of transaminases on the day of onset of edema (serum serum glutamic-oxaloacetic transaminase of 81 U/L and serum glutamic pyruvic transaminase of 83 U/L. with normal bilirubin levels). The total protein was 6 g/dL and serum albumin 3.8 g/dL. The prothrombin time/International normalized ratio was 1. These indicated normal hepatic synthetic function and absence of hypoproteinemia as the underlying cause of the anasarca. Also typical symptoms and signs of congestive heart failure (CHF) were absent. An underlying renal cause was also ruled out as there was no oliguria, hematuria, frothy urine or past history of renal disease. The urine microscopy was also normal, without proteinuria. Her blood urea was 25 mg/dL, and serum creatinine 0.8 mg/dL. There were no features suggestive of an acute hypersensitivity reaction like urticaria or rashes. A normal thyroid-stimulating hormone level (2.27 mIU/L) excluded hypothyroidism.

Thus, by excluding all the probable causes of edema (acute renal failure, nephrotic syndrome, CHF, liver dysfunction, allergy and hypothyroidism) a diagnosis of insulin edema was made. The child was administered Furosemide (1 mg/kg) per orally, stat. After 4 h there was sudden deterioration with tachycardia and elevation in jugular venous pressure. The oxygen saturation levels remained maintained in room air. The appearance of decreased air entry on the right side and bilateral basal crepitations, suggested acute development of pulmonary edema. IV furosemide (1 mg/kg) was given, following which there was clinical improvement within an hour. At that point, a chest X-ray, N-terminal pro–B-type natriuretic peptide, electrocardiogram, and echocardiography were done and found to be normal, confirming the absence of an underlying cardiac cause. Following oral fluid restriction (two-third maintenance), continuation of furosemide, and salt restriction, the anasarca gradually decreased, with complete resolution within 4 days. The transaminitis normalized after 1 week.

  Discussion Top

Insulin edema is an uncommon complication of insulin therapy. We reviewed the clinical details of 7 reported cases of insulin edema among Type 1 DM patients [Table 1]. Of these six occurred among newly diagnosed cases and one was observed following the restart of therapy in a poorly compliant 20-year-old female. Six out of the seven patients were females with a mean age group of 13.2 years (range 9.5–20 years). Female preponderance has been noted earlier; female to male ratio of 2.75 reported in a review of 15 cases.[3] Among the 7 cases we reviewed [Table 1], 3 had isolated peripheral edema and 4 generalized edema. There was one patient with additional pulmonary edema.[2] The presence of pulmonary edema (as in this case) though uncommon, has been reported previously.[9] Edema occurred 3 days after the start of insulin (2 days after starting NPH) in our patient. In our review, we noted that the occurrence of edema ranged between 1 and 8 days, after commencing/intensifying insulin. Transient elevation of transaminases that corresponded with the onset of edema was observed in 1 case. It is also an uncommon event that has been reported earlier.[2],[7] In our review of 7 patients we noted that edema resolved in a span of 7–14 days, and in most cases only salt and fluid restriction was used in the management. In fact, in 3 cases oedema resolved without treatment [Table 1].[6],[10] In the review of 15 cases by Derya et al., only 5 required medical treatment.[3]

A few mechanisms have been proposed for insulin edema, but the exact pathogenesis remains unclear. The most favored explanation is the consequences of fluid resuscitation in the setting of DKA,[7] especially since the edema resolves with salt and fluid restriction and diuretics, but the reason for the late onset remains unresolved. Transient hyperaldosteronism with increase in secretion of anti-diuretic hormone resulting from the osmotic diuresis that occurs secondary to hyperglycemia is another explanation that has been suggested.[5] Insulin mediated sodium retention can occur due to the direct action of insulin on the renal tubules. Sodium absorption is increased in the proximal convoluted tubules during insulin treatment via the stimulation of Na+/K+-ATPase, as well as the expression of Na+/H + exchanger.[5] When reintroduced into the insulin-deficient state seen in DM, insulin promotes sodium retention and inhibits natriuresis by suppressing glucagon. The decreased glucagon in turn leads to decreased inhibition of aldosterone, and increased sodium retention. Arteriolar vasodilatation may have a pathogenic role,[7] as evidenced by the efficacy of ephedrine (a vasoconstrictor) in insulin edema. The transient elevation of liver enzymes has rarely been described in literature. This may be attributed to the insulin mediated increase in glycogen storage.

Despite this condition being described for almost a century, there is high probability that it is being under recognized and under-reported. International societies of clinicians dealing with DM are yet to release standardized guidelines for investigating and managing insulin edema. There is a strong felt need for this, as well as future research regarding the etiopathogenesis, and a possible genetic predisposition. This case is being reported to create awareness among physicians about early recognition of this rare complication of insulin treatment in Type 1 DM. This will avoid unnecessary anxiety of the treating team and parents, and; reduce duration of hospital stay and unnecessary investigations, thus reducing expenses. Given the female predisposition, insulin edema should be especially looked for among adolescent girls with newly detected Type 1 DM.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

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Conflicts of interest

There are no conflicts of interest.

  References Top

Hursh BE, Dedhar A, Panagiotopoulos C. Case 2: Generalized swelling in a child with newly diagnosed diabetes mellitus. Paediatr Child Health 2014;19:233-4.  Back to cited text no. 1
Adamo L, Thoelke M. Generalised insulin oedema after intensification of treatment with insulin analogues. BMJ Case Rep 2013;2013:bcr2012007037.  Back to cited text no. 2
Derya Bulus A, Andiran N, Osman Köksal A. Insulin edema in type 1 diabetes mellitus: Report of a case and brief review of the literature. Iran J Pediatr 2016;26:e5077.  Back to cited text no. 3
Mamoulakis D, Bitsori M, Galanakis E, Raissaki M, Kalmanti M. Insulin induced oedema in children and adolescents. J Paediatr Child Health 2006;42:655-7.  Back to cited text no. 4
Kalambokis GN, Tsatsoulis AA, Tsianos EV. The edematogenic properties of insulin. Am J Kidney Dis 2004;44:575-90.  Back to cited text no. 5
Mantadakis E, Thomaidis S, Triantafyllou P. Insulin edema in a AQ6 girl with newly diagnosed diabetes mellitus type I. Hippokratia 2013;17:382.  Back to cited text no. 6
Olsson R, Wesslau C, William-Olsson T, et al. Elevated aminotransferases and alkaline phosphatases in unstable diabetes mellitus without ketoacidosis or hypoglycemia. J Clin Gastroenterol 1989;11:541-5.  Back to cited text no. 7
Wolfsdorf JI, Glaser N, Agus M, et al. ISPAD Clinical Practice Consensus Guidelines 2018: Diabetic ketoacidosis and the hyperglycemic hyperosmolar state. Pediatr Diabetes 2018;19 Suppl 27:155-77.  Back to cited text no. 8
Lee P, Kinsella J, Borkman M, et al. Bilateral pleural effusions, ascites, and facial and peripheral oedema in a 19-year-old woman 2 weeks following commencement of insulin lispro and detemir – An unusual presentation of insulin oedema. Diabet Med 2007;24:1282-5.  Back to cited text no. 9
Baş VN, Çetinkaya S, Ağladıoğlu SY, et al. Insulin oedema in newly diagnosed type 1 diabetes mellitus. J Clin Res Pediatr Endocrinol 2010;2:46-8.  Back to cited text no. 10


  [Table 1], [Table 2]


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