Irl B. Hirsch, MD, Editor
In 1979, the National Diabetes Data Group and in 1980 the World Health Organization recognized two major forms of diabetes.1,2 One type was termed insulin-dependent diabetes mellitus (IDDM, or type 1 diabetes) and the other non-insulin-dependent diabetes (NIDDM, or type 2 diabetes). Unfortunately, the terms IDDM and NIDDM are confusing and resulted in classifying individuals based on treatment rather than on their etiology.
Furthermore, the pathogenesis of both major forms of diabetes has become more clear. It is now appreciated that type 1 diabetes is usually due to an autoimmune process resulting in complete -cell destruction. Islet cell antibodies (ICAs), glutamic acid decarboxylase antibody (GADA), insulin autoantibodies, or autoantibodies to tyrosine phosphatases are present in the majority of people with type 1 diabetes. For a minority of people with type 1 diabetes, there is no evidence of autoimmunity, but it is clear that complete insulin deficiency exists. On the other hand, those with type 2 diabetes are resistant to the effects of insulin. Although a -cell defect is required for the development of hyperglycemia in those with type 2 diabetes, complete insulin deficiency does not occur, and there is no evidence for an autoimmune process.
With this understanding, an international committee sponsored by the American Diabetes Association published in 1997 new recommendations for the diagnosis and classification of diabetes.3 The new nomenclature eliminated the terms IDDM and NIDDM, and stipulated that the terms type 1 diabetes and type 2 diabetes were to be used with Arabic numerals only. The report also mentioned that often in adults the -cell destruction may be slow, and indeed, sufficient insulin secretion may be present for years before the development of ketoacidosis.
How, then, do busy clinicians differentiate an adult with an autoimmune process, type 1 diabetes, but significant -cell function from one with insulin resistance and type 2 diabetes? Furthermore, what difference does it make, especially if the patient's blood glucose is controlled?
Certainly, obese patients with a strong family history of type 2 diabetes and acanthosis nigricans on the back of the neck (usually from hyperinsulinemia) strongly suggest type 2 diabetes. Although there are exceptions, Hispanic, American Indian, African-American, Asian, and Pacific Islander patients seen in our clinics usually have type 2 diabetes. Patients with a good response to metformin (Glucophage) or a thiazolidinedione also most likely have insulin resistance and a type 2 process occurring.
Unfortunately, despite the above generalizations, the identification of the disease process causing hyperglycemia is often unclear, especially in adults with an autoimmune process. Several terms have been introduced to describe this population. The term latent autoimmune diabetes of adults (LADA) as originally described represents perhaps as many as 1020% of adult-onset patients with diabetes. Typical patients are 35 years old or older, nonobese, and present without ketoacidosis and weight loss.4 Many of these people may maintain good control for several years with sulfonylureas before becoming "insulin dependent."4 Since the antibodies known for type 1 diabetes are present in this group, the assumption is that the autoimmune process can proceed quite slowly over many years.5
The terminology for this population is extremely confusing. Besides LADA, these patients (with some variations) have also been said to have "slowly progressive IDDM," "latent type 1 diabetes," "youth-onset diabetes of maturity," "progressive insulin-dependent diabetes mellitus," and "type 1.5 diabetes."6 To be consistent with the new nomenclature,1 I prefer type 1.5 diabetes.
The implications of the identification of this population are tremendous. First, the need for insulin in the short term can almost be guaranteed. For example, in the United Kingdom Prospective Diabetes Study (UKPDS), the presence of GADA or ICA predicted insulin therapy at 6 years in 84% and 94% of the patients, respectively.7 With neither antibody, only 14% of the UKPDS subjects required insulin therapy 6 years after the diagnosis of the diabetes.7 Even more important, insulin therapy appears to slow -cell destruction in both animal and human trials. One trial in patients with type 1.5 diabetes showed not only that -cell function does improve, but also that the ICA status may revert from positive to negative.8
The use of exogenous insulin therapy to alter the autoimmune response is part of the rationale for a large multicenter study, the Diabetes Prevention Trial of Type 1 Diabetes, in which insulin is administered to individuals with preclinical type 1 diabetes. Although we are still waiting publication of the UKPDS patients randomized to insulin therapy, I suspect we will learn that they did better in terms of -cell function, HbA1c, and perhaps complications from their diabetes.
Fortunately, the measurements of these immune markers are finally becoming available for clinical use outside of the research arena. Certainly, there are problems with standardization of assays. Many are concerned that at this time we do not yet understand the implication of the absence or presence of these antibodies, and, therefore, we should not measure them, at least until more data are available.
I disagree. The presence of these markers strongly suggests an autoimmune process, the probability of a lack of long-term efficacy of sulfonylureas, and the lack of insulin resistance and thus indicates that there is no need to waste time with metformin or a thiazolidinedione. Furthermore, insulin likely retards the autoimmune destruction of the -cells.
Finally, what about adults who present with diabetes, are catabolic with ketonuria and weight loss, but when started on insulin seem to have only a slowly progressive loss of insulin secretion? Many of these patients may be maintained on extremely low doses of insulin for years.
This "honeymoon" (a term originally used to describe a similar situation in newly diagnosed children with type 1 diabetes) should not be mistaken as a signal to try an oral agent. On the other hand, these patients do not have type 1.5 diabetes, as described above. I tend to think of these people as having "type 1.25 diabetes." The closer to the numeral 1, the quicker the destruction of the -cells.
This is all getting quite confusing. Maybe we should just call this condition "type-1-and-change diabetes."
1National Diabetes Data Group: Classification and diagnosis of diabetes mellitus and other categories of glucose intolerance. Diabetes 28:1039-57, 1979.
2World Health Organization: Diabetes Mellitus: Report of a WHO Study Group. Geneva, World Health Org., 1985 (Tech. Rep. Ser., no. 727).
3The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus: Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care 20:1183-97, 1997.
4Zimmet PZ: The pathogenesis and prevention of diabetes in adults: genes, autoimmunity, and demography. Diabetes Care 18:1050-64, 1995.
5Tarn AC, Thomas JM, Dean BM, Ingram D, Scheartz G, Bottazzo GF: Predicting insulin-dependent diabetes. Lancet i:845-50, 1988.
6Juneja R, Palmer JP: Type 1 1/2 diabetes: myth or reality. Autoimmunity 29:65-83, 1999.
7Turner R, Stratton I, Horton V, Manley S, Zimmet P, Mackay IR, Shattock M, Bottazzo GF, Holman R: UKPDS 25: autoantibodies to islet-cell cytoplasm and glutamic acid decarboxylase for prediction of insulin requirement in type 2 diabetes. Lancet 350:1288-93, 1997.
8Kobayashi T, Nakanishi K, Murase T, Kosaka K: Small doses of subcutaneous insulin as a strategy for preventing slowly progressive beta-cell failure in islet cell antibody-positive patients with clinical features of NIDDM. Diabetes 45:622-26, 1997.
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