Clinical Briefs

By Louis Kuritzky, MD

Short-term Intensive Insulin Therapy in Newly Diagnosed DM2

The best initial treatment for the newly diagnosed type 2 diabetic (DM2) remains a matter of debate. Although there is consensus that DM2 is characterized by both insulin secretory and insulin responsivity defects, and that hyperglycemia may contribute to both (so-called "glucotoxicity"), it is unclear whether intensive early treatment, with a goal of prompt eradication of glucotoxicity, results in any long-term benefits. Since insulin is capable of providing the most rapid, consistent, and substantial declines in glucose, it was a logical choice for studying this issue.

Newly diagnosed DM2 patients (n = 16) were instructed in appropriate use of short-acting insulin before each meal (5 u regular, starting dose), and intermediate acting insulin at bedtime (10-15 u NPH at HS, starting dose). Insulin doses were increased 2-5 u per dose on a daily basis until postprandial and fasting goals were achieved. Clinic visits occurred twice weekly during the first 2-3 weeks until goals were achieved. After 3 weeks insulin was discontinued, and patients were seen monthly (with phone contact every 2 weeks) for one year.

At 1 year, 7 of the subjects were able to maintain glucose control on diet alone, the remaining subjects requiring oral hypoglycemic agents (n = 8) or insulin (n = 1) to maintain control. The subjects who were characterized as requiring less insulin to achieve goals (0.37 u/kg/d vs 0.73 u/kg/d), and attaining a lower fasting glucose (5.9 vs 7.7 mmol/L) during the 3 week intensive insulin program were shown to be able to best sustain control with diet alone.

These data support the concept that brisk resolution of glucose toxicity provides some potentially sustained restoration of beta-cell function and/or insulin responsivity.

Ryan EA, et al. Diabetes Care. 2004; 27:1028-1032.

Endothelial Dysfunction and Risk of Type 2 Diabetes Mellitus

The primary cause of mortality in type 2 diabetes (DM2) is cardiovascular disease (CVD). Indeed, our most recent national guidelines have recognized that at the point of diagnosis, a person with DM2 has a similar or greater risk of subsequent coronary heart disease (CHD) end point as a person who has already suffered a myocardial infarction. The prominent CVD risk seen in DM2 has been variously, but somewhat unconvincingly ascribed to such risk factors as insulin resistance and hyperinsulinemia. In an effort to better elucidate the pathophysiologic underpinnings of DM2-related CVD, Meigs and colleagues studied plasma biomarkers of endothelial dysfunction in ostensibly healthy women at the time of enrollment into the Nurses Health Study (n = 32,826) in 1989-1990. Biomarkers measured included E-selectin, intercellular adhesion molecule 1 (ICAM-1), and vascular cell adhesion molecule 1.

By the year 2000, 737 women had developed DM2. Baseline biomarkers in these women, when compared to an equal number of controls, showed that E-selectin, ICAM-1, and VCAM-1 each were predictive of future DM2 development. Even after adjustment for BMI, family history, diet, alcohol, and activity level, the likelihood of developing DM2 was increased more than 5-fold in the highest baseline quintile of E-selectin, and approximately 4-fold for the top quintile of ICAM-1.

Endothelial dysfunction presages DM2, and helps explain the disproportionate burden of CVD in this population.

Meigs JB, et al. JAMA. 2004;291: 1978-1986.

Treatment of Parkinson’s Disease with Pergolide and Relation to Restrictive Valvular Heart Disease

Even medications that are generally considered safe and effective may cause adverse effects that are sufficiently uncommon that they escape adequate identification. Although valvular heart disease (VHD) has been described as potentially associated with pergolide treatment, initial estimates suggested a very low frequency (one in 20,000). To provide a better estimate of the VHD risk with pergolide treatment, 78 pergolide-treated Parkinson’s disease patients were compared with a population of Parkinsonian subjects who had not received an ergot-derived dopamine agonist. All subjects underwent transthoracic echocardiography. The echocardiographic measurement used to define restrictive VHD was "tenting distance and area."

Even when restricting analysis to only those with major suspicion of VHD on echocardiography, almost 20% of pergolide-treated patients manifest some degree of disease. Frequency of VHD correlated both with dose-intensity, and cumulative dose of pergolide.

This frequency of heretofore little-recognized valvulopathy associated with pergolide should stimulate clinicians to investigate for VHD in appropriately symptomatic individuals. Indeed, a case can be made for consideration of routine echocardiography in recipients of pergolide. The frequency of VHD detected in this study is similar to the valvulopathy rate seen amongst women who utilized appetite suppressants such as dexfenfluramine (Redux).

Van Camp G, et al. Lancet. 2004;363:1179-1183.