Insulin and oral hypoglycemic agents should not be used in combination in the treatment of type 2 diabetes.

C URRENT TREATMENT paradigms for type 2 diabetes mellitus usually relegate insulin to the position of a last option, for patients in whom monotherapy or combination therapy with oral agents has failed. When insulin is used in this scheme, the common practice is to add it to the oral agent regimen rather than use it by itself. However, this treatment approach does not recognize the natural course of type 2 diabetes and the importance of tight glycemic control. Very often, less than optimal glycemic control is the consequence of maintaining oral agents in the management of type 2 diabetes. The etiology of type 2 diabetes involves both peripheral resistance to insulin and defective -cell function. When the cells fail to maintain an adequate insulin supply in the face of insulin resistance, hyperglycemia and then the development of type 2 diabetes occur. Data from the UKPDS suggest that -cell function is already reduced by about 50% at the time of diagnosis. This defect in insulin secretion appears to worsen during the course of the disease, and is believed to be responsible for the observation that control of type 2 diabetes deteriorates with time. In the UKPDS, treatment interventions were successful at first in meeting target glycemic control; however, the proportion of patients who continued to maintain their target control declined over the duration of the study. About 50% of patients were able to sustain their control at 3 years but only about 25% were able to do so at 9 years. -Cell function was assessed in UKPDS patients not treated with insulin, and it appeared to deteriorate at a constant rate over the study period. The mechanism responsible for -cell failure is not certain, but some of the factors associated with insulin resistance have been implicated. Chronic hyperglycemia as well as increased free fatty acids may promote both insulin resistance and -cell dysfunction. These effects are referred to as glucotoxicity and lipotoxicity, respectively. They may prevent cells from secreting insulin adequately by affecting the expression of transcription factors critical to -cell function and formation. They may also induce a type of death in the cells called apoptosis. In addition, the adverse effects of hyperglycemia on the functioning of the glucose transport system in peripheral tissues lead to tissue resistance to insulin. Thus, insulin resistance and secretion are closely intertwined. Each problem can magnify the other, thereby creating a self-perpetuating cycle of worsening hyperglycemia. To some extent, this cycle can be broken simply by aggressively treating the hyperglycemia with insulin monotherapy. Insulin monotherapy refers to the use of insulin alone in various combinations of insulin and insulin analogues of varying duration of action. In patients newly diagnosed with type 2 diabetes, this therapy may improve longterm glycemic control. Ilkova et al treated patients newly diagnosed with type 2 diabetes for 2 weeks with an insulin pump regimen that provided near normal glycemic control. Following discontinuation of the insulin, most patients were able to maintain adequate glycemic control for at least 6 months without insulin or oral agent therapy. Likewise, in a study by Kayashima et al, intensive early treatment with insulin regimens that achieved tight glycemic control in patients with type 2 diabetes relatively early in their disease course resulted in good glycemic control that persisted in most without their needing pharmacologic therapy. Strict glycemic control appears to result in the improvement of -cell function and insulin action—the 2 key activities affected by glucotoxicity. Thus, the reduction in glucotoxicity probably explains the maintenance of the good glycemic control reached with aggressive insulin monotherapy even after the treatment has been withdrawn. Others have shown that, in patients with type 2 diabetes for whom treatment with oral agents had failed, strict glycemic control with insulin monotherapy may improve insulin action and secretion. However, in these patients, a strong correlation has been reported between baseline fasting C-peptide level and the improvement in -cell function that occurred following insulin therapy: the higher the level, the better the response. In accordance with this is the observation in the study of Kayashima et al that patients who were able to remain off therapy had a mean duration of diabetes of 3.9 years whereas those who needed oral agent therapy had a mean diabetes duration of 7.6 years. Thus, aggressive insulin monotherapy in patients with type 2 diabetes may be more likely to have a durable effect if it is used early in the course of the disease. Used early on, it could preserve endogenous insulin secretion and possibly prevent or delay the decline of -cell function and irreversible changes, such as -cell apoptosis, that have been associated with hyperglycemia. These From the Departments of Medicine, Maricopa Medical Center, Phoenix, Ariz (Dr Westphal), and Mayo Clinic Scottsdale, Scottsdale, Ariz (Dr Palumbo). The authors have no relevant financial interest in this article.