and after 2 wk of hydroflumethiazide (HFT) administration in a daily dose of 75 mg. Insulin ... diabetics before (â¢) and after (O) 2 wk hydroflumethiazide therapy.
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nsulin Action in Insulin-Dependent Diabetics After Short-Term Thiazide Therapy O. SCHMITZ, MD, K. HERMANSEN, MD, O. HOTHER NIELSEN, MD, C. K. CHRISTENSEN, MD, J. ARNFRED, MD, H. E. HANSEN, MD, C. E. MOGENSEN, MD, H. 0RSKOV, MD, AND H. BECK-NIELSEN, MD
The influence of short-term thiazide treatment on peripheral tissue and liver sensitivity to insulin in insulin-dependent diabetes mellitus was determined by the euglycemic insulin clamp technique. A sequential three-step hyperinsulinemic clamp was performed in six insulin-dependent diabetics before and after 2 wk of hydroflumethiazide (HFT) administration in a daily dose of 75 mg. Insulin was infused at rates of 0.5, 2.0, and 4.0 mU • kg"1 • min" 1 , and each dose was given for at least 120 min. Glucose uptake during the last 30 min of each step was almost identical in the two situations (2.7 ± 0.6 vs. 2.4 ± 0.5 mg kg - 1 min"1, 9.6 ± 0.9 vs. 9.7 ± 1.2 mg • kg"1 • min"1, and 12.0 ± 1.3 vs. 12.6 ± 1.5 mg • kg" 1 min"1)* Serum insulin levels were also similar, and blood glucose was kept at 100 ± 3, 99 ± 4, and 97 ± 3 mg/dl before thiazides and at 93 ± 6, 93 ± 6, and 94 ± 6 mg/dl after thiazides. Another five insulin-dependent diabetics were infused with tritiated glucose followed by insulin infusion at two rates: 0.45 and 1.0 mU • kg" 1 • min" 1 . Basal glucose output was comparable before and after thiazides (3.63 ± 0.24 vs. 2.97 ± 0.26 mg • kg" 1 • min" 1 ), as was the liver response to increasing insulin concentrations. The metabolic state as assessed by HbA lc and fasting blood glucose did not differ in the two experiments. In conclusion, short-term HFT therapy has no impact on either insulinmediated glucose uptake or sensitivity of the liver to insulin. Thus, probably no adverse effects on the metabolic state will be encountered in diabetics with minimal endogenous insulin during treatment with thiazides. DIABETES CARE 1986; 9:631-36. 1
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he occurrence of impaired glucose tolerance or diabetes mellitus after treatment with thiazide diuretics is well recognized.1"6 The mechanisms by which thiazides influence glucose homeostasis, however, are not fully understood. Studies have suggested effects on the endocrine pancreas7"9 as well as on tissue sensitivity to insulin.1011 Because thiazides may be chosen in controlling the fluid retention and/or the hypertension often associated with diabetic nephropathy, a potential thiazideinduced insulin resistance may interfere with optimization of the glycemic and metabolic state in insulin-dependent diabetics. Therefore, it is important to obtain better insight into the pathogenesis of thiazide-induced glucose intolerance. Our study was consequently undertaken to evaluate the influence of thiazide diuretics on insulin action in peripheral tissues as well as in liver. Insulin-mediated glucose uptake and suppression of glucose production were assessed with the
insulin clamp technique12 before and after 2 wk of hydroflumethiazide (HFT) therapy. SUBJECTS AND METHODS
Subjects. Eleven male C peptide-negative insulin-dependent diabetics (plasma C peptide g
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P > .10), and basal blood glucose level (average of last glucose determinations before insulin infusion) did not differ either (134 ± 20 vs. 162 ± 2 1 mg/dl). The higher steady-state serum insulin during step 1 after thiazides resulted in 48% lower glucose production at this step than without thiazide treatment (0.78 ± 0.14 vs. 1.39 ± 0.23 mg • kg" 1 • min" 1 ; P = .06), i.e., the opposite trend of what would be found if thiazides had any deteriorating effect on glucose metabolism. During infusion of insulin in a dose of 1.0 mU • kg"1 • min" 1 , the glucose production was almost totally suppressed (
