Is Insulin the Only Treatment for Obese NIDDM Patients Poorly Controlled By Oral Hypoglycemic Agents?b

Antonio E. Pontiroli

Istituto Scientifico San Raffaele and Università degli Studi Milano, Italy 20132

In their paper on 1-yr insulin treatment of obese and nonobese NIDDM patients poorly controlled by oral hypoglycemic agents, Yki-Jarvinen et al. (1) have shown that nonobese patients display a constant improvement of metabolic control, while obese patients, after an initial improvement have a deterioration of glucose metabolism and a greater gain in body weight than nonobese patients, suggesting that this deterioration is linked to a disproportionate increase in insulin requirement, due to a greater insulin resistance; they conclude that weight gain in obese patients is harmful, as it is associated with increases in blood pressure and low density lipoprotein cholesterol. Previous studies had indicated that insulin treatment improves glucose metabolism for a limited period of time and that insulin induces a higher increase in body weight and in blood pressure in obese than in nonobese patients (2).

The issue raised by Yki-Jarvinen et al. is of great importance; in fact, the frequency of insulin-treated NIDDM patients is exceptionally high, as half of all insulin-treated patients (IDDM plus NIDDM) were originally diagnosed as NIDDM (3). This has led to the general assumption that the majority of NIDDM patients are eventually treated with insulin. However, the few available studies on the role of body weight in NIDDM do not support this assumption; the pathogenesis of NIDDM is different in obese and in nonobese NIDDM, being mainly caused in the former by increased insulin resistance, and in the latter by decreased insulin release (4, 5). Insulin requirement is more frequent in nonobese than in obese patients, and is due, in nonobese patients, to a further reduction of insulin release, but this does not seem to apply to obese patients (2, 6). In addition, insulin treatment is irreversible in nonobese patients (2). In contrast, progression to insulin is avoidable in obese patients by education (7), and insulin-treated obese patients can be transferred back to oral agents when body weight is reduced (2). Hyperglycemia is a risk factor for micro- and macroangiopathy in NIDDM (8); however, one should consider the value of insulin treatment in the prevention of diabetic complications; similar to that reported for IDDM in the DCCT study (9), intensive insulin regimens delayed the appearance and progression of microangiopathy in lean NIDDM patients (10); in contrast, cardiovascular mortality was increased, not decreased, in obese patients treated with intensive insulin regimens (11). This raises the issue of improving glucose metabolism while avoiding insulin resistance, especially in obese patients. Insulin together with triglycerides induces insulin resistance and releases endothelin-1, a potent vasoconstrictor peptide (12), and this is only one of the possible reasons why hyperinsulinemia and insulin resistance per se represent a major risk factor for ischemic heart disease in diabetic (13) and in nondiabetic individuals (14). Therefore, while combined treatment (oral agents plus insulin) or insulin alone appear adequate for nonobese NIDDM patients poorly controlled with oral agents, it does not seem justified to treat obese NIDDM patients with high doses of insulin simply to compensate hyperglycemia; reduction of body weight should be obtained whenever possible. Alternatively, the use of acarbose (15), metformin (16), and benfluorex (17) has been shown to improve the effect of insulin and to allow reduction of insulin doses. For the massively obese patients, gastric by-pass has been shown to be a long-standing solution to NIDDM and to hypertension (18).

Footnotes

Address correspondence to: Antonio E. Pontiroli, M.D., Istituto Scientifico San Raffaele and Università degli Studi, Via Olgettina 60, 20132 Milano, Italy.

Received February 24, 1998.

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