A B S T R A C T A sensitive and specific radioimmunoassay for plasma arginine vasopressin (AVP) has been used to study the effects of blood osmolality and volume in regulating AVP secretion in unanesthetized rats. Under basal conditions, plasma AVP and osmolality were relatively constant, averaging 2.3+0.9 (SD) pg/ml and 294±+1.4 mosmol/kg, respectively. Fluid restriction, which increased osmolality and decreased volume, resulted in a progressive rise in plasma AVP to about 10 times basal levels after 96 h. A 2-3-fold increase in plasma AVP occurred as early as 12 h, when osmolality and volume had each changed by less than 2%. Intraperitoneal injections of hypertonic saline, which had no effect on blood volume, also produced a rise in plasma AVP that was linearly correlated with the rise in osmolality (r > 0.9) and quantitatively similar to that found during fluid restriction (plasma AVP increased 2-4-fold with each 1% increase in osmolality). Intraperitoneal injection of polyethylene glycol, which decreased blood volume without altering osmolality, also increased plasma AVP but this response followed an exponential pattern and did not become significant until volume had decreased by 8% or more. At these levels of hypovolemia, the osmoregulatory system continued to function but showed a lower threshold and increase sensitivity to osmotic stimula-A 'preliminary report of this work was published in abstract form in Clin. Res. 21: 329. 1973.

Insulin therapy with implantable pumps is effective and safe for periods up to 1.7 yr with a decreased risk of severe hypoglycemia than with intensive subcutaneous insulin therapy.

Patients with insulin-dependent diabetes mellitus (IDDM) have proatherogenic disturbances in cholesteryl ester transfer (GET) despite intensive subcutaneous insulin therapy (ISC). Since CET is activated by insulin-sensitive lipoprotein lipase (LPL), which normally increases postprandially, we queried whether iatrogenic hyperinsulinism from ISC stimulated LPL and CET by studying well-controlled IDDM patients after ISC and then 6 months after lowering systemic insulin levels by intraperitoneal (IP) insulin delivery. Although glycemic control (HbA,c IDDM, 6.9±1.7%; control, 4.5% to 8%) was excellent during ISC, CET was accelerated (P<.001) and both systemic insulin levels and LPL specific activity were increased (P< .05). Following IP, basal systemic insulin levels declined by more than one half (ISC, 8.22±6.5 versus IP, 2.77±2.4 ^iU/mL; mean±SD; P<.025), and both LPL and CET activities returned to normal. Plasma triglyceride, cholesterol, high-density lipoprotein-2 (HDL 2 ) cholesterol, HDL, cholesterol, cholesteryl ester transfer protein mass, and glyce-A ssiduous diabetic management can reduce the /\ prevalence of the renal and retinal microvascu-.Z \-lar and neuropathic complications of insulindependent diabetes mellitus (IDDM) 12 but not the premature morbidity and mortality attributable to cardiovascular disease. The failure of rigorous glycemic control achieved with multiple daily injections of insulin to slow the development of diabetic macrovascular disease has led to the suspicion that the hyperinsulinemia that inevitably results from insulin therapy might actually promote atherogenesis. C 1994 American Heart Association, Inc.mic control (HbA,c, 6.3±0.8%) were unchanged and remained normal. These findings indicate that ISC is associated with high levels of basal CET and LPL. These alterations both appear to be closely linked to iatrogenic hyperinsulinemia resulting from ISC. The fact that they are both reversed when systemic insulin levels are reduced by IP suggests that insulin, acting through LPL, influences the nature of the interaction of the lipoproteins engaged in CET. Since accelerated CET is believed to result in the enrichment of certain subpopulations of apolipoprotein B-containing lipoproteins with cholesteryl ester, an alteration presumed to enhance their atherogenicity, its correction by IP therapy suggests that this more physiological mode of insulin delivery may reduce cardiovascular risk in IDDM. (Arterioscler Thromb. 1994;14:1933-1939

OBJECTIVEINT131 besylate is a potent, nonthiazolidinedione, selective peroxisome proliferatoractivated receptor g (PPARg) modulator (SPPARM) designed to improve glucose metabolism while minimizing the side effects of full PPARg agonists. This placebocontrolled study compared the efficacy and side effects of INT131 besylate versus 45 mg pioglitazone HCl in subjects with type 2 diabetes (T2D). RESEARCH DESIGN AND METHODSThis was a 24-week randomized, double-blind, placebo-and active-controlled study of 0.5-3.0 mg INT131 versus 45 mg pioglitazone or placebo daily in 367 subjects with T2D on sulfonylurea or sulfonylurea plus metformin. The primary efficacy analysis was the comparison of change from baseline to week 24 in hemoglobin A 1c (HbA 1c ) across treatment groups. Fluid status was assessed with a prospective scoring system for lower-extremity pitting edema. RESULTSINT131 had a steep dose response for efficacy as measured by changes in HbA 1c . After 24 weeks' treatment, the 0.5-mg dose demonstrated minimal efficacy (HbA 1c 20.3 6 0.12%) and the 2-mg dose demonstrated near-maximal efficacy (HbA 1c 21.1 6 0.12%), which was not statistically different from the efficacy of 45 mg pioglitazone (HbA 1c 20.9 6 0.12%; P < 0.01 for noninferiority). With the 1-mg dose, INT131 provided significant improvements in glycemic control (HbA 1c 0.8 6 0.12; P < 0.001 vs. placebo) but with less edema, weight gain, and hemodilution than observed with 45 mg pioglitazone. CONCLUSIONSINT131 demonstrated dose-dependent reductions in HbA 1c , equivalent to 45 mg pioglitazone, but with less fluid accumulation and weight gain, consistent with its SPPARM design.Insulin resistance is a key etiologic factor in type 2 diabetes (T2D). Peroxisome proliferator-activated receptor (PPAR)g activation is associated with significant improvement in insulin resistance, hyperglycemia, endothelial function, and markers of inflammation (1,2). However, clinical use of thiazolidinediones (TZDs) has been limited by their side effect profile, namely, fluid retention, congestive

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