Review article
Clinical approach to the patient with diabetes mellitus and very high insulin requirements

https://doi.org/10.1016/j.diabres.2010.06.025Get rights and content

Abstract

A number of patients with diabetes require very high (>2 U kg−1 day−1), or extremely high (>3 U kg−1 day−1), insulin doses for the management of their hyperglycemia. Unfortunately, many of the physicians who treat these patients limit themselves to prescribing ever higher doses of insulin, without questioning why. Furthermore, when the insulin requirements get to be extreme, demanding an explanation, clinicians are frequently lost in a sea of literature where there is not a single paper dealing with this problem systematically.

A systematic approach to the evaluation of these patients is necessary to facilitate an appropriate diagnosis, select the most reasonable therapy, and hopefully improve the long-term outcome of these patients. This manuscript intends to provide the clinician with a review of the literature pertinent for the differential diagnosis, work-up, and management of these patients.

We will review the definitions of insulin sensitivity during normality, the various degrees or categories of insulin resistance, and the expected insulin requirements during each of these states. Subsequently, we propose a simple alphabetic mnemonic approach to help remember the differential diagnosis, and a clinical algorithm to help guide the work-up of these patients. Lastly, we briefly discuss general management considerations in these conditions.

Introduction

According to the 2005–2006 National Health and Nutrition Examination Survey conducted in the United States, 12.9% of the adult U.S. population aged ≥20 years has diabetes (7.7% previously diagnosed and 5.1% undiagnosed) [1]. Of those with diagnosed diabetes, 26.8% are using insulin, thus, we estimate there are more than 6 million patients receiving insulin therapy in the U.S. alone [2]. Consequently, almost every physician, regardless of specialty, will likely have to manage, or help manage, patients with diabetes on insulin therapy.

Physicians who treat large numbers of patients with diabetes are likely to encounter unusual presentations, including those who will require unusually large amounts of insulin for the management of their hyperglycemia. The purpose of this manuscript is to review the diagnostic and treatment considerations that clinicians must entertain when encountering these unusual cases.

We will first review the definitions of insulin sensitivity during normality, the various degrees or categories of insulin resistance, and the expected insulin requirements during each of these states. Subsequently, we will propose a simple alphabetic mnemonic approach to help guide the clinician through the differential diagnosis in these patients. Lastly, we will briefly discuss the laboratory work-up and the general management of these conditions.

Section snippets

Concept of insulin sensitivity and insulin resistance

Although the concept of insulin sensitivity in diabetes is attributed to Sir Harold Himsworth because he first distinguished between two main types of diabetes, an insulin-sensitive and an insulin-insensitive diabetes, now known as type 1 diabetes and type 2 diabetes respectively [3], the term insulin resistance had been freely used since the discovery of insulin in 1922, but mostly to describe unusual cases of diabetes with very high insulin requirements [3], [4].

Since then, the concept of

Measurement of insulin sensitivity in diabetes

The glucose clamp technique, particularly in its euglycemic version, is the best available method for the measurement of insulin action in vivo, but it is time and technically demanding. Therefore, simpler methods are frequently used to measure insulin sensitivity in the research setting; these include the minimal model approach using the frequently sampled intravenous glucose tolerance test (FSIVGTT), and the homeostatic model assessment (HOMA), amongst many others. Unfortunately, these

Normal insulin sensitivity

Most patients with well-controlled type 1 diabetes demonstrate insulin sensitivities in the range of the average non-diabetic lean individual, i.e. normal insulin sensitivity. However, it is important to note that insulin resistance can occur coincidentally, in subjects with type 1 diabetes, just as it can in the normal, non-diabetic, population. What is more, insulin resistance can also be observed in subjects with sub-optimally controlled type 1 diabetes [8], but this phenomenon can be

Differential diagnosis in patients with diabetes and high insulin requirements

Many cases, but not all, are due to rare disorders leading to severe insulin resistance. The following short alphabetical mnemonic is useful in remembering the major different processes that can lead to high insulin requirements in patients with diabetes (Table 2).

Work-up of patients with diabetes and high insulin requirements

A systematic approach to the differential diagnosis is necessary to arrive to the correct diagnosis, while avoiding unnecessary tests and minimizing empiric treatments that may be futile, and potentially harmful. We propose the following clinical algorithm for the work-up of these patients (Fig. 1).

As usual, the diagnostic work-up is guided primarily by the clinical picture, including a complete history and physical exam, and occasionally some of the following laboratory tests are indicated:

  • -

Management considerations in patients with diabetes and high insulin requirements

The management approach must be individualized and, when possible, aimed at correcting the underlying cause. Unfortunately, many of these conditions are not amenable to cure and must then be dealt with a practical approach.

In addition to individualized diet and lifestyle recommendations, when appropriate, the following is a list of some of the treatments available that may be useful when dealing with patients requiring large insulin doses, with some general comments:

  • -

    Metformin and/or one of the

Conclusion

A small, but significant, number of patients with diabetes will require very high (>2 U kg−1 day−1), or extremely high (>3 U kg−1 day−1), insulin doses for the management of their hyperglycemia. A systematic approach to the evaluation of these patients is necessary to determine the cause. In turn, an accurate diagnosis will help the clinician select the most appropriate therapy, and hopefully improve the long-term outcome of these patients.

Although, we still have much to learn about the etiology and

Conflict of interest

The authors declare that they have no conflict of interest.

References (77)

  • P. Dandona et al.

    Low-dose insulin infusions in diabetic patients with high insulin requirements

    Lancet

    (1978)
  • M.A. Hussain et al.

    Treatment of type A insulin resistance with insulin-like growth factor-I

    Lancet

    (1993)
  • R. Azziz

    The hyperandrogenic-insulin-resistant acanthosis nigricans syndrome: therapeutic response

    Fertil Steril

    (1994)
  • K.E. Elkind-Hirsch et al.

    Insulin resistance improves in hyperandrogenic women treated with Lupron

    Fertil Steril

    (1993)
  • J.C. Pickup et al.

    Aprotinin and insulin resistance

    Lancet

    (1980)
  • C.C. Cowie et al.

    Full accounting of diabetes and pre-diabetes in the U.S. population in 1988–1994 and 2005–2006

    Diabetes Care

    (2009)
  • D.M. Mann et al.

    Trends in medication use among US adults with diabetes mellitus: glycemic control at the expense of controlling cardiovascular risk factors

    Arch Intern Med

    (2009)
  • C.M. MacBryde

    Insulin resistance in diabetes mellitus

    Arch Intern Med

    (1933)
  • American Diabetes Association

    Consensus development conference on insulin resistance

    Diabetes Care

    (1998)
  • G.M. Reaven

    Banting lecture 1988. Role of insulin resistance in human disease

    Diabetes

    (1988)
  • R.A. DeFronzo et al.

    Insulin resistance is a prominent feature of insulin-dependent diabetes

    Diabetes

    (1982)
  • J.M. Olefsky et al.

    Insulin resistance in non-insulin dependent (type II) and insulin dependent (type I) diabetes mellitus

    Adv Exp Med Biol

    (1985)
  • E. Cochran

    U-500 insulin: when more with less yields success

    Diabetes Spectrum

    (2009)
  • E. Cochran et al.

    The use of U-500 in patients with extreme insulin resistance

    Diabetes Care

    (2005)
  • W. Crasto et al.

    Insulin U-500 in severe insulin resistance in type 2 diabetes mellitus

    Postgrad Med J

    (2009)
  • A. Vidal-Puig et al.

    Insulin resistance: classification, prevalence, clinical manifestations, and diagnosis

  • C.R. Kahn et al.

    The syndromes of insulin resistance and acanthosis nigricans. Insulin-receptor disorders in man

    N Engl J Med

    (1976)
  • N.A. Tritos et al.

    Clinical review 97: syndromes of severe insulin resistance

    J Clin Endocrinol Metab

    (1998)
  • E.N. Mendenhall

    Tumor of the pineal body with high insulin resistance

    J Indiana State Med Assoc

    (1950)
  • S.M. Rabson et al.

    Familial hypertrophy of pineal body, hyperplasia of adrenal cortex and diabetes mellitus; report of 3 cases

    Am J Clin Pathol

    (1956)
  • D.E. Moller et al.

    Insulin resistance—mechanisms, syndromes, and implications

    N Engl J Med

    (1991)
  • E. Arioglu et al.

    Clinical course of the syndrome of autoantibodies to the insulin receptor (type B insulin resistance): a 28-year perspective

    Medicine (Baltimore)

    (2002)
  • J.S. Flier et al.

    Acanthosis nigricans in obese women with hyperandrogenism. Characterization of an insulin-resistant state distinct from the type A and B syndromes

    Diabetes

    (1985)
  • H. Globerman et al.

    Analysis of the insulin receptor gene tyrosine kinase domain in obese patients with hyperandrogenism, insulin resistance and acanthosis nigricans (type C insulin resistance)

    Int J Obes Relat Metab Disord

    (1998)
  • N. Hashimoto et al.

    Type C insulin resistance

    Nippon Rinsho

    (1994)
  • F. Nakamura et al.

    Familial type C syndrome of insulin resistance and short stature with possible autosomal dominant transmission

    Endocrinol Jpn

    (1989)
  • M.K. Pandit et al.

    Drug-induced disorders of glucose tolerance

    Ann Intern Med

    (1993)

    • Cited by (0)

    View full text
    Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.