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Home , Insulin resistance

e116 Care Volume 39, August 2016

Management of in Cemre Robinson,1,2 Elaine Cochran,3 Phillip Gorden,3 and Severe Resistance Rebecca J. Brown3 Diabetes Care 2016;39:e116–e118 | DOI: 10.2337/dc16-0635

Syndromes of severe insulin resistance developed fatigue, malaise, and Kussmaul and escalating doses of insulin with- (IR) include mutations of or autoanti- respirations. out improvement (A1C 12% [108 bodies to the and lipo- He presented to an outside hospital mmol/mol]). dystrophy (1). Diabetic ketoacidosis with DKA with a pH of 7.08, partial pres- Six months after diagnosis, she pre- (DKA), although rare, can occur in these sure CO2 of 27 mmHg, and bicarbonate sented to an outside hospital with an- patients, even in the context of hyper- of 8 mmol/L. He received fluid resusci- orexia, fever, tachycardia, and tachypnea. insulinemia, due to impaired insulin tation for an estimated 10% dehydration. Exam showed uveitis, severe diffuse acan- signaling. DKA can be extremely chal- In collaboration with National Institutes thosis nigricans, and multiple granulating lenging to treat, and few clinicians are of Health (NIH) physicians, an insulin drip perineal and gluteal abscesses. experienced or comfortable in using was started at 100 units/h that was grad- She was in DKA with a venous pH of the high doses of insulin required. We ually increased to 1,000 units/h on the 6.95, partial pressure CO2 of 17 mmHg, describe aggressive management of first day and 2,000 units/h on the second and bicarbonate of 4 mmol/L. Her serum DKA in three patients with syndromic day, without improvement of acidosis was 359 mg/dL. Because of se- severe IR. (Fig. 1A). Because of the lack of improve- vere dehydration, she received 14 L of ment despite massive doses of insulin fluid in the first 72 h. In collaboration CASE 1 (.50,000 units/day) and intravenous an- with NIH physicians, she was treated An 18-year-old man with compound tibiotics, bicarbonate was given and den- with an insulin drip plus subcutaneous heterozygous mutation of the insulin re- tal extraction performed. He improved U-500 insulin, which was slowly in- ceptor presented with DKA. He had thereafter on 2,000 units/h of insulin, creased from 2 mL (1,000 units) to poorly controlled diabetes (A1C 14% which was gradually weaned to 500 9 mL (4,500 units) every 6 h (maximum [130 mmol/mol]) treated with U-500 in- units/h. Acidosis resolved and he was insulin .18,000 units/day). The workup sulin (1,500 units/day), metreleptin (re- transitioned back to subcutaneous insu- revealed a group B Streptococcus aga- combinant human methionyl as lin, 500 units t.i.d. lactiae urinary tract infection and multi- an experimental drug), and ple methicillin-resistant Staphylococcus (2 g/day). CASE 2 aureus (MRSA) abscesses, the likely trig- Two weeks prior, he underwent a root A 20-year-old woman with an autoanti- gers of her DKA. She was treated with canal for an abscessed tooth but did not body to the insulin receptor (type B IR) intravenous antibiotics. She improved

OBSERVATIONS take the prescribed antibiotics. Antibi- presented to an outside hospital with dramatically following aggressive fluid – otics were subsequently initiated. One DKA (2). Six months prior, she presented resuscitation and bicarbonate adminis- day after discharge, he developed abdom- with a 35-lb and severe hy- tration. Insulin drip was discontinued inal pain,nausea, vomiting, andworsening perglycemia (.500 mg/dL). She was and she continued subcutaneous insu- e-LETTERS jaw pain and swelling. Two days later, he treated with metformin, , lin, 4,500 units every 6 h.

1Section on Skeletal Diseases and Mineral Homeostasis, Craniofacial and Skeletal Diseases Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 2Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 3Diabetes, , and Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD Corresponding author: Rebecca J. Brown, [email protected]. Received 22 March 2016 and accepted 4 May 2016. © 2016 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. care.diabetesjournals.org Robinson and Associates e117

severe IR raise safety concerns for pro- viders not experienced with severe IR. At very high doses, the dose-response curve for insulin is extremely shallow (Fig. 1B) (5), requiring aggressive dose increases. The first case clearly demon- strates that despite a 10-fold increase in the hourly rate of insulin infusion, from 100 units/h to 1,000 units/h over less than 24 h, the patient’sacidosisdid not resolve. The primary safety concern with high-dose insulin is ; however, patients with severe IR are at very low risk for this during DKA. If hy- poglycemia occurs, it can be managed with intravenous dextrose. Because of the rarity of DKA in severe IR, there is no information regarding other potential toxicities of very high-dose insulin use. Two patients required bicarbonate therapy during their DKA management as insulin alone failed to correct the ac- idosis. Bicarbonate therapy is not indi- cated in mild to moderate forms of DKA as metabolic acidosis will correct with insulin (3). Proponents of bicarbonate therapy point to the potential deleteri- — Figure 1 A: Relationship between the serum pH value and the insulin dose per hour adminis- ous effects of acidosis on cardiac hemo- tered during the management of DKA for a patient with mutation of the insulin receptor (Rabson-Mendenhall syndrome). Insulin dose (solid line, squares) was aggressively increased dynamics (4). in the first 36 h from 100 to 2,000 units/h. Acidosis (represented by pH [dashed line, triangles]) Infection is a common precipitating did not improve despite insulin until dental extraction was performed (black arrow) for dental factor for DKA and was present in two abscess, the inciting event for DKA. B: Theoretical total body insulin dose-response curve for of these patients. Despite massive insu- insulin administration. Representative dose ranges of daily insulin administration to achieve lin doses, acidosis did not resolve with- target goals are shown for (DM) (solid line) and (dashed line) (both derived from the literature) and syndromic IR (dotted line) (taken from our own experi- out treatment of the underlying cause of ence). Note that much higher doses of insulin are required to achieve or approach target goals as DKA. In patients with severe IR, prompt the dose response at the target levels are markedly attenuated. Panel B is reprinted with evaluation and treatment of infections permission from Cochran et al. (5). are important to reduce the risk of DKA, as once DKA occurs, management is ex- tremely challenging. Relapsing DKA may occur if patients are transitioned to sub- CASE 3 on U-500 insulin, 1,000 units q.i.d., cutaneous insulin at inadequate doses. A 63-year-old man with history of type 2 with glucose levels of 130–180 mg/dL. These cases highlight the importance diabetes, managed with metformin for A precipitating factor for DKA was not of aggressive management of DKA in 8 years, presented to an outside hospital identified. severe IR, including high-dose insulin, with weakness, fatigue, polyuria, an- fluids, bicarbonate, and treatment of orexia, and 20-lb weight loss. A recent CONCLUSIONS underlying infection. Cooperation be- A1C was 13.4% (123 mmol/mol). He We describe three cases demonstrating tween critical care physicians and endocri- was acidotic with a pH of 7.1, bicarbon- the complexity of managing DKA in pa- nologists is essential for safe and effective ate of 9 mmol/L, and serum glucose tients with severe IR. High doses of in- management. .600 mg/dL. He was managed with intra- sulin, elimination of the inciting triggers, venous insulin, 40 units/h, but attempts to and aggressive fluid resuscitation are transition him to subcutaneous insulin re- keys to management. sulted in recurrent DKA. The workup re- Insulin treatment in DKA has evolved Acknowledgments. The authors thank Drs. Kevan Akrami (The Eunice Kennedy Shriver vealed type B IR, and he was transferred from the use of high-dose insulin, up to National Institute of Child Health and Human to NIH. 100 units/h, to lower doses of 5–10 Development), Keisha Bell (LifeBridge Health The patient was maintained on an in- units/h (0.1 units/kg/h) (3,4). However, Center), Andrea Cuviello (LifeBridge Health Cen- sulin drip at 40 units/h while subcutane- low doses of insulin used in standard ter), Kelli Dunn (Carolinas Healthcare System), fi Michael Monroe (Carolinas Healthcare System), ous insulin (U-500), 1,000 units t.i.d., was DKA protocols are not suf cient for pa- Todd Brown (Johns Hopkins University), and initiated. Insulin drip was successfully tients with severe IR. The unusually high Silpa Gadiraju (Johns Hopkins University), who weaned on day 3, and he was maintained doses of insulin required for DKA in cared for these patients. e118 DKA in Severe Insulin Resistance Diabetes Care Volume 39, August 2016

Funding. This work was supported by the intra- access to all the data in the study and takes 3. Gosmanov AR, Gosmanova EO, Dillard- mural research programs of the National In- responsibilityfortheintegrityof the dataandthe Cannon E. Management of adult diabetic ketoa- stitute of Diabetes and Digestive and Kidney accuracy of the data analysis. cidosis. Diabetes Metab Syndr Obes 2014;7: Diseases, the Eunice Kennedy Shriver National 255–264 Institute of Child Health and Human Develop- 4. Kitabchi AE, Umpierrez GE, Fisher JN, ment, and the NIH Clinical Center. References Murphy MB, Stentz FB. Thirty years of personal Duality of Interest. No potential conflicts of 1. Semple RK, Savage DB, Cochran EK, Gorden experience in hyperglycemic crises: diabetic interest relevant to this article were reported. P, O’Rahilly S. Genetic syndromes of severe ketoacidosis and hyperglycemic hyperosmolar Author Contributions. C.R. researched the insulin resistance. Endocr Rev 2011;32:498– state. J Clin Endocrinol Metab 2008;93:1541– data and wrote the manuscript. E.C. and R.J.B. 514 1552 researchedthedataandreviewedandeditedthe 2. Malek R, Chong AY, Lupsa BC, et al. Treatment 5. Cochran E, Musso C, Gorden P. The use manuscript. P.G. contributed to the discussion of type B insulin resistance: a novel approach to of U-500 in patients with extreme insulin and reviewedand editedthemanuscript. R.J.B.is reduce insulin receptor autoantibodies. J Clin resistance. Diabetes Care 2005;28:1240– the guarantor of this work and, as such, had full Endocrinol Metab 2010;95:3641–3647 1244