Managing Diabetes and Hyperglycemia in the Hospital Setting. Boris Draznin

glucose 100–125 mg/dL (impaired glucose tolerance)

       OR

      2-h plasma glucose in the 75-g oral glucose tolerance test 140–199 mg/dL

       OR

      HbA1c 5.7–6.4%

      *For all three tests, risk is continuous, extending below the lower limit of the range and becoming disproportionately greater at higher ends of the range.

      Classification

      The goal of classifying a patient with a particular type of diabetes in the hospital setting should be to provide useful information about the pathogenesis, natural history, genetics, and phenotype of their disease to optimize safe and appropriate treatments, monitoring, education, patient expectations, and quality of life. Additionally, proper classification of hospitalized patients with hyperglycemia assists in appropriate transitions of aftercare.

      Recent classifications have broadly distinguished the types of diabetes into two groups—autoimmune (T1D) and nonautoimmune (T2D)—with all other types being classified in an “other” category. The other category includes monogenic, gestational, pancreatic, steroid-induced, HIV-associated, hepatitis C–associated, polycystic ovarian syndrome–related, and endocrinopathy-associated (acromegaly and Cushing’s syndrome) diabetes. This general schema is useful despite considerable overlap in classic phenotypic presentation in each major class and will guide the knowledgeable health-care provider to make prudent decisions on whom to consider for more specific assignment. In addition to sophisticated testing, it is highly useful to obtain accurate and detailed histories of presentation and family history to advise further evaluation.

      Type 1 Diabetes

      T1D accounts for ~5–10% of diabetes and is the result of cellular-mediated autoimmune destruction of the pancreatic β-cells,¹³ resulting in moderate to severe insulin deficiency. It classically but not invariably manifests with acute and severe symptoms of hyperglycemia, dehydration, and ketoacidosis. Although the presence of autoantibodies assists in identifying autoimmune versus nonautoimmune diabetes, these antibodies usually but not always disappear over a variable amount of time. The most common antibody in the adult population is glutamic acid decarboxylase 65 (GAD65).¹⁴ Other antibodies that are quickly becoming commercially available include antibodies to tyrosine phosphatase IA-2 and zinc transporter 8 (ZnT8). Traditional islet cell antibodies (ICA) generally are not used because of the assay’s subjectivity. Insulin autoantibodies rarely are seen in adults (although they cross-react with antibodies from exogenous insulin). T1D has strong human leukocyte antigen (HLA) associations, which may be either predisposing or protective in most cases.

      Although severe insulin deficiency and the tendency to ketosis and acute onset of symptoms are the hallmarks of T1D, the time of progression to absolute insulin deficiency is variable. Particularly in adults with newly diagnosed T1D, residual endogenous insulin secretion may still be present decades after the diagnosis¹⁵ and appears to be protective to the complications of the disease.¹⁶ This is significant to the health-care provider in the hospital setting because the measurement of c-peptide, while helpful in some circumstances, does not necessarily differentiate T1D from T2D as previously thought and may be misleading. Because a number of factors significantly influence the accurate measurement of c-peptide (antecedent hyperglycemia leading to glucotoxicity, nonstandardization of c-peptide measurement and assay), it generally is not recommended as a helpful test to classify the inpatient with hyperglycemia and may be misleading.

      Age and BMI do not invariably discriminate T1D and T2D. Although most commonly presenting in childhood and adolescence, T1D can manifest at any decade of life and with extended life spans in the T1D population combined with the increased frequency of T2D in the young adult obese population, age is no longer a reliable discriminatory factor in the classification between T1D and T2D. Similarly, recent data show that the BMI breakdown for the T1D population is now identical to that of the general population, a shift thought to be related to more intensive insulin regimens and secondary weight gain in the T1D population.¹⁷

      Patients with T1D may have personal or family histories of one or more autoimmune disorders. These include Graves’ disease, Hashimoto’s thyroiditis, Addison’s disease, celiac disease, myasthenia gravis, vitiligo, and pernicious anemia. Other historical features may be helpful, such as family history of associated endocrinopathies, or features at initial disease presentation, but these facts may not be available to the treating health-care provider in the hospital setting.

      Classic T1D is now appreciated to include factors of β-cell dysfunction as well as β-cell loss and the understanding of the mechanisms that trigger these processes is still incomplete but rapidly expanding.

      One of the most confusing controversies in the nomenclature of T1D classification is latent autoimmune diabetes of adults (LADA). Originally described in patients over the age of 30 years, who were GAD65 antibody positive,¹⁸ but who did not require insulin treatment in the first 6 months after diagnosis, these patients eventually required insulin for survival similarly to what was seen in individuals with complete insulin deficiency. LADA also has been called “slowly progressive insulin dependent diabetes,” “latent T1D,” “antibody-positive, noninsulin-dependent diabetes,” and “type 1.5 diabetes.” Not all adults who develop autoimmune diabetes have LADA, however, progression to complete β-cell deficiency and even ketosis can be rapid in some adults or may be provoked suddenly by acute illness, infection, hyperthyroidism, or other stress.

      It is estimated that between 2 and 12% of all diabetes in adults is LADA. In the United Kingdom Prospective Diabetes Study (UKPDS), ~10% of adults presumed to have T2D at diagnosis had evidence of positive GAD or ICA¹⁹ and most of these progressed to require insulin within 6 years. These patients should be sought for accurate diagnosis because they require vigilance as to the timing of beginning insulin and optimal therapies to preserve β-cell function. Some authors consider all adult-diagnosed patients with diabetes who are antibody positive to have LADA or type 1.5 diabetes. We suggest it may be useful to differentiate the classical nonobese (noninsulin-resistant) adult with positive diabetes autoantibodies and not requiring insulin 6 months after diagnosis as LADA,¹⁸ and those adults who are antibody positive but exhibit classic insulin resistance with phenotypic features of metabolic syndrome as type 1.5 diabetes. This differentiation may inform more effective and specific treatment strategies based on pathogenesis. Despite widespread use of these diabetes classifications in the literature, neither LADA nor type 1.5 diabetes is included in the current ADA classification scheme.⁵

      For the typical LADA patient, basal-bolus insulin therapy has been shown to retard the progression to more profound β-cell failure.²⁰ The obese, antibody-positive patients classified as having type 1.5 diabetes may respond to all of the T2D agents, although these individuals will likely progress to profound insulin deficiency more rapidly than if they were antibody negative.²¹ Patients with LADA and type 1.5 diabetes generally will require insulin in the hospital setting.

      Another group of adult autoantibody-positive patients is seen more frequently in the early 21st century with a phenotype rarely seen 30 years ago and variously called “double diabetes” or “hybrid diabetes,” but to keep the nomenclature consistent, we call this “type 3 diabetes.” This class refers to adults who developed classic T1D autoimmune diabetes as children but because of all of the genetic and environmental issues that have resulted in the current obesity epidemic, as they reach adolescence and adulthood, these individuals also become obese and develop features of the metabolic syndrome.²² Although they may appear to be the same, the factor differentiating these patients from those with type 1.5 diabetes is the history of being diagnosed initially with classic childhood diabetes and having relatively rapid β-cell failure as opposed to the more recently diagnosed adults with autoimmune diabetes who tend to have less profound β-cell destruction and slower development of insulin deficiency.

      Admittedly, there is no consensus on these various T1D subcategories as yet, but classifying patients as LADA (diagnosed as an adult, normal body weight, normal insulin resistance, gradually deficient in endogenous insulin, and antibody positive), type 1.5 (diagnosed as an adult, obese, insulin resistant, and antibody