Fredrick L. Dunn

The Role of Blood Osmolality and Volume in Regulating Vasopressin Secretion in the Rat

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 stimulation. We conclude that AVP secretion is regulated principally by blood osmolality but that the responsiveness of this mechanism may be significantly altered by modest changes in blood volume.

The Effect of Improved Diabetic Control on Plasma Lipid and Lipoprotein Levels: A Comparison of Conventional Therapy and Continuous Subcutaneous Insulin Infusion

We studied short-term changes in plasma lipid levels in type I diabetics treated with either a conventional insulin regimen or continuous subcutaneous insulin infusion. Mean plasma glucose dropped from 260 ± 18 to 134 ± 8 mg/dl when conventional treatment was used and from 194 ± 18 to 108 ± 8 mg/dl with CSII. Both forms of therapy were associated with a significant fall in plasma triglyceride levels. However, only CSII treatment produced significant changes in total plasma cholesterol and LDL cholesterol levels. Total cholesterol fell from 195 ± 17 mg/dl to 161 ± 11 mg/dl and LDL cholesterol fell from 129 ± 13 mg/dl to 102 ± 9 mg/dl. We conclude that improved diabetic control by any method is effective in lowering plasma triglyceride levels, but it requires almost perfect metabolic control to affect plasma cholesterol and LDL cholesterol levels. The changes in plasma lipid and lipoprotein achieved with CSII may favorably alter the prediction for the development of premature atherosclerosis in our patients.

The effect of continuous subcutaneous insulin infusion on very-low-density lipoprotein triglyceride metabolism in type I diabetes mellitus.

The effect of continuous subcutaneous insulin infusion (CSII) on very-low-density lipoprotein triglyceride (VLDL-TG) metabolism was studied in seven normolipidemic type I diabetic patients. VLDL-TG transport was determined using 3H-glycerol as an endogenous precursor of VLDL-TG, and the resultant turnover curves were evaluated by multicompartmental analysis. Kinetic studies were performed in the diabetic patients during conventional insulin therapy and again after 3 wk of euglycemia achieved with CSII, and the results were compared with those obtained in 5 age-, weight-, and sex-matched normolipidemic nondiabetic subjects. After 3 wk of CSII, the mean (± SEM) 24-h plasma glucose levels in the diabetic patients decreased from 238 ±15 mg/dl on conventional therapy to 99 ± 11 mg/dl (P < 0.05) on CSII therapy. The total glycosylated hemoglobin levels decreased from 10.2 ± 0.5 to 6.5 ± 0.4%. There was a significant decrease in fasting plasma cholesterol (172 ± 13 mg/dl to 136 ± 4 mg/dl), LDL cholesterol (104 ± 9 mg/dl to 82 ± 4 mg/dl), plasma triglyceride (114 ± 24 mg/dl to 71 ± 9 mg/dl), and VLDL-TG (68 ± 18 mg/dl to 37 ± 5 mg/dl) levels. There was no change in the HDL cholesterol concentration. Results of the kinetic studies in the conventionally treated diabetic patients revealed normal VLDL-TG transport rates and fractional catabolic rates (FCR). CSII caused a marked and significant fall in mean VLDL-TG transport rates (12.2 ± 3.5 to 4.1 ± 0.8 mg/h/kg IW, P < 0.05) to levels below those observed in the nondiabetic subjects (10.2 ± 2.1 mg/h/kg IW, P < 0.05). There was no change in the mean FCR with CSII. These data thus suggest that the mechanism responsible for the observed change in plasma triglyceride levels in normolipidemic type I diabetic patients that occurs with 3 wk of CSII treatment is due to suppression of hepatic VLDL-TG synthesis rather than the result of increased lipoprotein clearance.

Selective modulation of PPARγ activity can lower plasma glucose without typical thiazolidinedione side-effects in patients with Type 2 diabetes

OBJECTIVE INT131 besylate is a potent non-thiazolidinedione selective peroxisome proliferator-activated receptor γ (PPARγ) modulator (SPPARM) designed to improve insulin sensitivity and glucose metabolism while minimizing the side effects of full agonist thiazolidinediones. This study was conducted to determine short-term efficacy and safety of INT131 besylate in patients with Type 2 diabetes mellitus (T2DM). RESEARCH DESIGN AND METHODS This was a 4-week randomized, double-blind, placebo-controlled multi-center study with 1 or 10mg INT131 besylate or placebo daily in subjects with T2DM not receiving pharmacotherapy for their hyperglycemia. The primary efficacy analysis was the comparison of treatment groups with respect to least square mean change from baseline to Week 4 of fasting plasma glucose (FPG). RESULTS Baseline mean (± S.D.) FPG for the study population was 171 ± 42 mg/dl. Change in FPG (± S.E., mg/dl) from baseline after 4 weeks was 8 ± 8 (P=NS) with placebo, -22 ± 8 with 1mg INT131 besylate (P=.0056) and -46 ± 7 with 10mg INT131 besylate (P<.0001). Modeling of available data from the literature of the effect of rosiglitazone under similar study conditions suggested that 1 mg of INT131 besylate had a similar reduction in FPG as expected with 8 mg of rosiglitazone. INT131 besylate was well tolerated, and the 1 mg dose demonstrated no evidence of fluid retention or weight gain. CONCLUSIONS INT131 besylate demonstrated a dose dependent reduction in FPG. The FPG reduction with 1mg INT131 besylate was comparable to the modeled 8 mg dose of rosiglitazone, and did not cause fluid retention or weight gain. These results are consistent with the INT131 SPPARM design.

The effect of diabetic control on very low-density lipoprotein―triglyceride metabolism in patients with type II diabetes mellitus and marked hypertriglyceridemia

We examined the effect of diabetic control on very low-density lipoprotein-triglyceride (VLDL-TG) metabolism in six patients with type II (noninsulin-dependent) diabetes mellitus and marked hypertriglyceridemia. VLDL-TG transport was determined using 3H-glycerol as an endogenous precursor of VLDL-TG, and the resultant kinetic data were evaluated by multicompartmental analysis. Studies were performed in the hypertriglyceridemic diabetic subjects during poor diabetic control and again after 3 months of diabetic treatment, and the results were compared to studies in nondiabetic normolipidemic subjects and nondiabetic subjects with familial forms of hypertriglyceridemia. In the poorly controlled diabetics, mean VLDL-TG synthesis was threefold higher than in the normolipidemic subjects, and the mean fractional catabolic rate (FCR) of VLDL-TG was only one-third of the normals. With diabetic treatment, plasma triglyceride levels fell by more than 50%, but remained fourfold higher than the normals. This was associated with a decrease in mean VLDL-TG synthesis to a level similar to that observed in the genetic hyperlipidemic subjects, but still 2.6-fold higher than the normals. In addition, the mean FCR rose after diabetic control to a level slightly above that of the genetic hyperlipidemic subjects, but remained less than one-half of the normal value. However, the response of VLDL-TG kinetics to diabetic treatment was not uniform. In four subjects, control of hyperglycemia ameliorated the hypertriglyceridemia primarily by decreasing VLDL-TG overproduction. In the other two subjects, diabetic treatment had a greater effect on the FCR than an overproduction of VLDL-TG. Thus, in this select group of diabetic, hypertriglyceridemic subjects, poor diabetic control contributed to both VLDL-TG overproduction and low FCRs. Failure of diabetic treatment to restore VLDL-TG kinetic parameters to normal suggests that the hypertriglyceridemia was due not only to diabetes mellitus but also to an additional abnormality affecting lipoprotein metabolism.(ABSTRACT TRUNCATED AT 250 WORDS)

Can a Selective PPARγ Modulator Improve Glycemic Control in Patients With Type 2 Diabetes With Fewer Side Effects Compared With Pioglitazone

OBJECTIVE INT131 besylate is a potent, nonthiazolidinedione, selective peroxisome proliferator–activated receptor γ (PPARγ) modulator (SPPARM) designed to improve glucose metabolism while minimizing the side effects of full PPARγ agonists. This placebo-controlled 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 METHODS This 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 A1c (HbA1c) across treatment groups. Fluid status was assessed with a prospective scoring system for lower-extremity pitting edema. RESULTS INT131 had a steep dose response for efficacy as measured by changes in HbA1c. After 24 weeks’ treatment, the 0.5-mg dose demonstrated minimal efficacy (HbA1c −0.3 ± 0.12%) and the 2-mg dose demonstrated near-maximal efficacy (HbA1c −1.1 ± 0.12%), which was not statistically different from the efficacy of 45 mg pioglitazone (HbA1c −0.9 ± 0.12%; P < 0.01 for noninferiority). With the 1-mg dose, INT131 provided significant improvements in glycemic control (HbA1c 0.8 ± 0.12; P < 0.001 vs. placebo) but with less edema, weight gain, and hemodilution than observed with 45 mg pioglitazone. CONCLUSIONS INT131 demonstrated dose-dependent reductions in HbA1c, equivalent to 45 mg pioglitazone, but with less fluid accumulation and weight gain, consistent with its SPPARM design.

Screening for Microalbuminuria: A comparison of single sample methods of collection and techniques of albumin analysis

OBJECTIVE To evaluate single-sample urine collections to determine their ability to screen patients for the presence of microalbuminuria. Microalbuminuria in patients with type I diabetes predicts the development of diabetic renal disease. RESEARCH DESIGN AND METHODS Cross-sectional analysis of single-sample urine collection techniques (first morning void, random upright void) and methods of albumin analysis (RIA, reagent tablet) were compared with conventional 24-h urine collections (RIA). The study included 94 patients (45 males, 49 females; mean serum creatinine 88 μM) with type I diabetes, selected from a screened population of 301 patients from the University Hospital Subspecialty Clinics. RESULTS A 24-hour urine collection RIA analysis for albumin revealed 36 normal patients (< 30 mg), 27 with microalbuminuria (30–300 mg), and 31 with albuminuria (> 300 mg). Random upright urine samples were more sensitive (RIA 89%, tablets 78%) for the detection of microalbuminuria than first morning void specimens (RIA 70%, tablets 60%). Specificity was > 80% with both random and first morning voids. CONCLUSIONS Screening for microalbuminuria can be performed in the clinic by random upright single-sample urine collections. When reagent tablets were used, these results are available immediately. Patients who screen positive should be confirmed by 24-h or other timed urine collections.

Plasma Lipid and Lipoprotein Disorders in IDDM

Abnormal lipoprotein metabolism contributes to the increased risk of premature atherosclerosis in people with insulin-dependent (type I) diabetes. Although hypertriglyceridemia is common in those with untreated IDDM, treatment with conventional insulin therapy usually restores fasting lipoprotein profiles to nondiabetic levels. Intensive insulin therapy improves glycemie control and lipoprotein concentrations, but does not ameliorate the changes in lipoprotein composition described in people with IDDM. Some of these persistent changes in lipoprotein composition have been attributed to peripheral hyperinsulinemia associated with s.c. insulin therapy. The recent availability of implantable insulin-infusion pumps for treatment of IDDM has allowed the study of the effect of i.p. insulin delivery on lipoprotein metabolism, i.p. insulin therapy is capable of maintaining near normal plasma glucose levels while reducing the peripheral hyperinsulinemia. Although results have been contradictory, studies of i.p. insulin therapy may eventually help to determine whether some of the observed changes in lipoprotein metabolism and composition in people with IDDM are due to the peripheral hyperinsulinemia associated with s.c. insulin therapy.

Long-Term Therapy of IDDM With an Implantable Insulin Pump

OBJECTIVE To examine the long-term benefits and risks of treatment of IDDM with an implantable programmable insulin pump. RESEARCH DESIGN AND METHODS Seventy-six patients with IDDM were studied at nine clinical centers. After 3–4 months of intensive subcutaneous therapy, the Infusaid Model 1000 pump was implanted, and insulin was delivered either intraperitoneally or intravenously for an average of 39.6 ± 10 months (251 patient-years). Data was collected for glycemic control, lipid levels, weight gain, insulin requirements, adverse events, and quality of life. Sixty-three patients were also followed for 8.5 ± 6.3 months (45 patient-years) after pump therapy was discontinued. RESULTS Mean quarterly HbA1c fell with subcutaneous intensive therapy and remained stable on implantable pump therapy between 6.9 and 7.5%. Severe hypoglycemia was relatively rare, with only 4 episodes/100 patient-years of implantable pump therapy. This rate was significantly less than with subcutaneous intensive therapy before implantable pump initiation (33 episodes/100 patient-years) or after discontinuation of implantable pump therapy (36/100 patient-years) (P < 0.003). Weight did not increase significantly in the 1st year of therapy, but increased by 2.0 ± 4.3 kg after 3 years of therapy. There were no significant differences in metabolic control or adverse events between intraperitoneal and intravenous insulin therapy except for minor differences in lipid levels and the more frequent development of catheter obstruction with intravenous delivery. Most pump slow-downs and catheter occlusions were corrected noninvasively. Quality of life, as measured by the Diabetes Control and Complications Trial instrument, showed high satisfaction and improved impact scores. CONCLUSIONS Long-term implantable pump therapy maintained HbA1c in a range similar to intensive subcutaneous therapy, but with fewer episodes of severe hypoglycemia. Although pump and catheter occlusions remain a limitation, patient satisfaction with implantable pump therapy remains high.

Catheter Survival During Long-Term Insulin Therapy With an Implanted Programmable Pump

OBJECTIVE To survey catheter complications and to analyze catheter survival during long-term intraperitoneal and intravenous insulin therapy with an implanted programmable pump with a sideport. RESEARCH DESIGN AND METHODS Catheter occlusions were documented by measuring dynamic catheter resistance. Catheter migrations or breaks were demonstrated by × ray. When flushing the catheter with buffer solution through the sideport failed to clear the occlusion, catheters were replaced or laparoscopy was performed for the excision of fibrous tissue growth. Broken or migrated catheters were replaced. RESULTS Occlusions were the most common catheter complications, and the majority of them (79% intraperitoneal and 84% intravenous) were cleared by flushing the catheter. Survival at 3 years was significantly higher for intraperitoneal catheters compared with intravenous catheters (60% intraperitoneal and 22% intravenous). CONCLUSIONS Nonsurgical management of catheter occlusions contributed to extend catheter lifetime. Intraperitoneal catheters have a lower morbidity and a higher survival than intravenous catheters.