OBJECTIVE -To investigate the metabolic effects of metformin, as compared with placebo, in type 2 diabetic patients intensively treated with insulin.RESEARCH DESIGN AND METHODS -Metformin improves glycemic control in poorly controlled type 2 diabetic patients. Its effect in type 2 diabetic patients who are intensively treated with insulin has not been studied. A total of 390 patients whose type 2 diabetes was controlled with insulin therapy completed a randomized controlled double-blind trial with a planned interim analysis after 16 weeks of treatment.The subjects were selected from three outpatient clinics in regional hospitals and were randomly assigned to either the placebo or metformin group, in addition to insulin therapy. Intensive glucose monitoring with immediate insulin adjustments according to strict guidelines was conducted. Indexes of glycemic control, insulin requirements, body weight, blood pressure, plasma lipids, hypoglycemic events, and other adverse events were measured.RESULTS -Of the 390 subjects, 37 dropped out (12 in the placebo and 25 in the metformin group). Of those who completed 16 weeks of treatment, metformin use, as compared with placebo, was associated with improved glycemic control (mean daily glucose at 16 weeks 7.8 vs. 8.8 mmol/l, P ϭ 0.006; mean GHb 6.9 vs. 7.6%, P Ͻ 0.0001); reduced insulin requirements (63.8 vs. 71.3 IU, P Ͻ 0.0001); reduced weight gain (Ϫ0.4 vs. ϩ1.2 kg, P Ͻ 0.01); and decreased plasma LDL cholesterol (Ϫ0.21 vs. Ϫ0.02 mmol/l, P Ͻ 0.01). Risk of hypoglycemia was similar in both groups.CONCLUSIONS -In type 2 diabetic patients who are intensively treated with insulin, the combination of insulin and metformin results in superior glycemic control compared with insulin therapy alone, while insulin requirements and weight gain are less.

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The relationship between norepinephrine (NE) and prostaglandins in the regulation of systemic blood pressure during pregnancy was examined in conscious rabbits. The arterial prostaglandin E2 (PGE2) concentration was higher in pregnant than in nonpregnant rabbits. Resting blood pressure was slightly lower in the gravid animals. The pressor response to incremental doses of intravenous NE was blunted in the pregnant rabbits. Meclofenamate, a cyclooxygenase inhibitor, failed to alter the resting blood pressure in either group of animals, although it reduced PGE2 levels more than 60% in the pregnant rabbits. The pressor response to NE was significantly increased only in the pregnant rabbits when the NE infusion was repeated following meclofenamate. Pregnant rabbits could also be differentiated from nonpregnant by their higher peripheral blood levels of NE and their uniform hypotensive response to alpha-adrenergic blockade. These observations define an altered responsiveness to both endogenous and exogenous NE in pregnant rabbits that appears to be related to an increase in vasodilator prostaglandins.

We assessed the effect of insulin and atrial natriuretic peptide (ANP) on renal sodium handling in eight patients with sickle cell disease (SCD), who are characterized by loss of vasa recta and long loops of Henle, and matched control subjects. During insulin infusion (50 mU. kg(-1). h(-1)), fractional sodium excretion decreased by 0.44 +/- 0.72% (P = 0.13) in patients with SCD and by 0. 57 +/- 0.34% (P = 0.002) in control subjects, whereas fractional distal sodium reabsorption increased by 4.1 +/- 1.5% (P < 0.001) and 3.0 +/- 1.5% (P < 0.001), respectively. Low-dose (0.3 pmol. kg(-1). h(-1)) ANP infusion did not affect renal sodium handling in patients with SCD but increased fractional sodium excretion by 0.34 +/- 0.22% (P = 0.003) in control subjects. High-dose (2 microg/min) ANP increased natriuresis to a similar extent in both groups. Insulin's antinatriuretic effects predominated over the natriuretic effects of low-dose, but not high-dose, ANP. These data suggest that insulin's antinatriuretic effect is localized at a distal tubular site other than the long loops of Henle and that the long loops are involved in the natriuretic effect of low-dose ANP, possibly mediated by changes in medullary blood flow.