A Pathophysiological-based Approach to Diabetes Care
June 14, 2010
Ralph A. DeFronzo
Long before the diagnosis of diabetes, individuals with impaired glucose tolerance have lost over 80% of their beta-cell function (cells made in the pancreas that produce insulin to regulate blood sugar levels) and they are maximally/near-maximally insulin resistant. The Diabetes Prevention Program found a 7.9% prevalence of diabetic retinopathy (damage to the eye’s retina) among individuals with impaired glucose tolerance. These results indicate that beta-cell failure and diabetic complications begin well before the onset of diabetes, as currently defined. The implication is that clinicians must intervene early in the natural history of type 2 diabetes to prevent further worsening of the disease.
Optimal treatment for patients with type 2 diabetes should target all known pathophysiologic defects (all the known changes that accompany the disease of type 2 diabetes). A stepwise therapeutic approach that is based upon reduction of the HbA1c (glucose control) solely, irrespective of the underlying pathophysiology, is unlikely to result in durable metabolic control. The original triumvirate (muscle and liver insulin resistance and beta-cell failure) has now grown to eight players comprising the ominous octet: the fat cell (accelerated lipolysis), gastrointestinal tract (incretin deficiency/resistance), alpha-cell (hyperglucagonemia), kidney (increased glucose reabsorption), and brain (central insulin resistance). Given the multiple metabolic defects in type 2 diabetes, its treatment will require multiple drugs used in combination. A pathophysiological-based approach to diabetes care initiates treatment with lifestyle modification plus combination drug therapy. The antihyperglycemic agents included in the combinatorial therapy are drugs known to: (1) improve insulin sensitivity, (2) preserve beta cell function, (3) suppress inappropriate hyperglucagonemia, (4) limit weight gain, and (5) minimize hypoglycemia. When initiated together, this combinatorial therapeutic approach can simultaneously address the multiple pathogenic abnormalities of type 2 diabetes. In addition, a therapeutic strategy that minimizes hypoglycemia and weight gain allows the clinician to titrate more aggressively to successfully achieve an optimal A1C goal of less than 6% (the standard as recommended by the American Diabetes Association (ADA) is less than 7%).
The number of new treatment modalities will increase in the near future as novel antihyperglycemic agents currently in clinical development come to market. Novel antihyperglycemic agents that improve metabolic control by addressing the multiple underlying pathophysiologic disturbances of type 2 diabetes will help to shift type 2 diabetes treatment from an HbA1c, or glucose-centric approach, to a pathophysiologic-based approach.
Ralph DeFronzo is Professor of Medicine and Chief of the Diabetes Division at the University of Texas Health Science Center and the Audie L. Murphy Memorial VA Hospital in San Antonio, Texas.
For more related articles, click Diabetes Perspectives.