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 positive), or type 3 (diagnosed as a child, obese, insulin deficient, and resistant) may be useful if this classification results in a more clear appreciation of the pathogenesis and institution of optimal treatments
A minority of T1D occurs without evidence of autoimmunity as in the cause of the insulin deficiency, which nonetheless can be profound and develop rapidly. This is referred to as idiopathic diabetes, previously called “type 1b diabetes.” Included in the category of idiopathic diabetes is “fulminant type 1 diabetes,”23 most commonly described in Asian patients24 and usually presenting after a viral infection or during pregnancy. Onset is acute, usually with DKA despite HbA1c levels that are near normal because of the rapid onset of the hyperglycemia. Of special relevance to treating health-care providers in the emergency room and hospital, death from DKA may occur within 24 h if insulin therapy is not initiated immediately upon presentation.23
Type 2 Diabetes
T2D accounts for the majority of diabetes in the world, accounting for ~90% of all cases. Uncontrolled hyperglycemia in T2D often goes undiagnosed for many years because of the absence of symptoms or presence of vague symptoms. In the hospitalized setting, DKA can occur, but it is almost always associated with stress of another illness, such as infection or ischemia. Undiagnosed diabetes is particularly common in patients admitted for myocardial infarction.25 An inpatient admission can be an important opportunity for diagnosis and initiation of treatment in such high-risk individuals. Even patients with previously well-controlled T2D usually will require discontinuation of prior diabetes oral agents and noninsulin injectable therapies during hospitalizations and treatment with IV or subcutaneous insulin therapies to optimally and safely control hyperglycemia.
Individuals with T2D are resistant to insulin and have relative, as opposed to absolute, insulin deficiency. Over time, they can become profoundly insulin deficient. Depending on the individual and the situation, insulin and c-peptide levels may be high, normal, or low. Autoimmune destruction of the β-cells does not occur, and patients are antibody negative. The risk of developing T2D increases with age, obesity, sedentary lifestyle, and positive family history. It occurs more frequently in women with previous gestational diabetes and polycystic ovarian syndrome; postmenopause, it is seen in individuals with dyslipidemia and hypertension; and it is seen in many ethnic groups (African American, Native American, Hispanic, Pacific Islander, and Asian American). Approximately 85% of individuals with T2D are obese or overweight, and those who are not obese often have an increased percentage of body fat distributed in the abdominal region. The obesity definition is ethnicity-related. For example, although Caucasians are considered obese with a BMI >30 kg/m2, the World Health Organization defines obesity <30 kg/m2 for most Asians and the recent ADA standards changed the BMI cut point for screening overweight Asian Americans for T2D to 23 kg/m2, from the previous 25 kg/m2.5
Multiple genetic mutations have been associated with T2D but in clinical practice it is not possible to identify a specific genetic
