The patient should increase her intake of non-caloric beverages to counteract dehydration secondary to persistent hyperglycemia. Reinforce the elements of a diabetic diet, and recommend a low-carbohydrate diet with portion control to help improve glycemic control. Make sure that the patient’s insulin is not expired and is stored according to the manufacturers’ specified conditions to promote consistent pharmacokinetics. Increase her dose of lantus to 65 units twice daily, and increase her dose of aspart to 45 units before each meal with continued glucose monitoring.

A diabetes specialist colleague should be contacted, and if possible, he or she should schedule an appointment for the patient within 3 days.

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The patient was seen by her new diabetes specialist as scheduled. Per the glycemic management consultation note, her blood glucose minimally improved after the previous suggested insulin dose titration. Furthermore, the patient’s insulin was not expired and was stored appropriately. The consultant switched the patient to U-500 regular insulin 29 units before breakfast and 19 units before dinner with continued glycemic monitoring and insulin titration. Her blood glucose level improved to 96-215 mg/dL with return of baseline vision, normal urinary pattern, and decreased thirst.


It is common for primary care clinicians to be contacted by their patients with glycemic management challenges, especially when the specialist caring for them is not available. In this complex patient scenario, the clinician was comfortable with titrating the insulin regimen while scheduling an expedited appointment with a diabetes management specialist. Another option would be to refer the patient to the local emergency room for comprehensive assessment (including stat labs) and management, especially if a specialist was unavailable for a timely follow-up. Prolonged hyperglycemia can potentially result in severe dehydration, compromised renal function, and diabetic ketoacidosis.

Among patients with diabetes who are aged 18 years or older, 14% use insulin exclusively, and another 14.7% use insulin with oral antihyperglycemic agents.1 Within this demographic of insulin-requiring individuals, a subpopulation requires a large amount of insulin supplementation/replacement.

Severe insulin resistance syndrome was reported by the National Institute of Diabetes and Digestive and Kidney Diseases as early as 1975.2 Severe insulin resistance is usually found in patients with diseases that affect glucose metabolism, such as diabetes, acanthosis nigricans, and hyperandrogenism, as well as, hirsutism, oligomenorrhea, amenorrhea, and polycystic ovarian syndrome.3 In this case study, the patient has both diabetes and acanthosis nigricans, which predisposed her to severe insulin resistance, requiring a large amount of insulin supplementation. For other patients, requiring large amounts of insulin may not be related to severe insulin resistance. Some examples include obese patients on weight-based insulin and those with a very high carbohydrate intake.

It is typical for individuals with diabetes and severe insulin resistance to require 200 to 400 units of total daily insulin. Efficient and effective delivery of this large amount of insulin is a challenge. The reservoir limitation and dosing capacity of the modern day insulin pens, syringes, and pumps requires multiple injections or frequent pump reloading. Furthermore, when a large amount of insulin is injected subcutaneously, the pharmacokinetics of the product are more variable.

To overcome these challenges, use a more concentrated form of insulin. There are 2 different insulin concentrations marketed in the United States: U-100 (indicating 100 units of insulin in 1 ml of solution) and U-500 (indicating 500 units of insulin in 1 ml of solution). U-500 insulin is not a novel therapy for patients with diabetes; it was initially used clinically in 1952, and the human form of U-500 was introduced in 1997.2

Although the initiation of U-500 insulin either via multi-dose injection (MDI) or continuous subcutaneous insulin infusion (CSII) would likely be the task of a diabetes specialist, primary care clinicians and other providers should have a general understanding of its indication and usage. Most clinicians are accustomed to prescribing U-100 insulin (glargine, lispro, aspart, premixed insulin, etc.). U-500 regular insulin is the sole U-500 insulin available in the United States at this time and is FDA approved for use as an MDI. Use of U-500 in CSII via an insulin pump is a potentially effective alternative for patients with type 2 diabetes.4 U-500 regular insulin has an onset of action (30 to 60 minutes) and peak (between 2 to 4 hours) similar to U-100 regular insulin. However, U-500 regular insulin has a duration similar to that of basal insulin (up to 24 hours). Frequency of U-500 dosing ranges from twice daily to 4 times daily, usually depending on the amount of insulin needed: the greater the amount, the more frequent the dosing schedule. Note that the risk of hypoglycemia is highest between 18 to 24 hours of U-500 administration.2

In patients who require a large amount of insulin, the CSII insulin pumps have many of the same issues that accompany MDI when using U-100 insulin. Similar to MDI, using U-500 instead of U-100 in CSII mitigates these problems.

Research that has compared the use of U-500 insulin in MDI to its use in CSII found no significant differences in HbA1c improvements, hypoglycemic risk, or weight. However, a nonsignificant trend toward decreased insulin requirements was observed among CSII subjects.4

As demonstrated in this case study, the diabetes management approach for an obese individual requiring a large amount of insulin should include weight reduction interventions, nutrition counseling, and emphasis on increased physical activity. Use of concentrated insulin such as U-500 via MDI or CSII can help patients achieve glycemic control while the modifiable underlying causes are mediated.2

Annie D. Lu, ANP-BC, BC-ADM, practices at the Diabetic Foot and Ankle Center, part of NYU Langone Medical Center’s Hospital for Joint Diseases.


  1. National Diabetes Statistics Report, 2014. Centers for Disease Control and Prevention website. Accessed November 18, 2015.
  2. Cochrane E. U-500 Insulin: When more with less yields success. Diabetes Spectrum. 2009;22(2):116-122.
  3. Savage DB, Semple RK, Chatterjee VK, et al. A clinical approach to severe insulin resistance. Endocr Dev. 2007;11:122-132.
  4. American Association of Clinical Endocrinologists. Consensus Statement by the American Association of Clinical Endocrinologists/American College of Endocrinology Insulin Pump Management Task Force. Endocrine Practice. 2014;20(5):463-489.
  5. More Choices Available for Diabetes Management. FDA website. Accessed November 18, 2015.