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Biomedical subjects

S V Edelman

Publications and source records attributed to S V Edelman.

At least 19 recordsLinked to original sources
PubMed2001

Insulin therapy in type 2 diabetes.

Type 2 diabetes is a common disorder often accompanied by numerous metabolic abnormalities leading to a high risk of cardiovascular morbidity and mortality. Results from the UKPDS have confirmed that intensive glucose control delays the onset and retards the progression of microvascular disease and possibly of macrovascular disease in patients with type 2 diabetes. In the early stages of the disease, insulin resistance plays a major role in the development of hyperglycemia and other metabolic abnormalities, and patients with type 2 diabetes often benefit from measures to improve insulin sensitivity such as weight loss, dietary changes, and exercise. Later, the use of oral insulin secretagogues and insulin sensitizers as monotherapy and in combination helps maintain glycemia for varying periods of time. Ultimately, because of the progressive nature of the disease and the progressive decline in pancreatic beta-cell function, insulin therapy is almost always obligatory to achieve optimal glycemic goals. Not all patients are candidates for aggressive insulin management; therefore, the goals of therapy should be modified, especially in elderly individuals and those with co-morbid conditions. Candidates for intensive management should be motivated, compliant, and educable, without other major medical conditions and physical limitations that would preclude accurate and reliable HGM and insulin administration. In selected patients, combination therapy with insulin and oral antidiabetic medications can be an effective method for normalizing glycemia without the need for rigorous multiple-injection regimens. The patients for whom combination therapy is most commonly successful are those who do not achieve adequate glycemic control using daytime oral agents but who still show some evidence of responsiveness to the medications. Bedtime intermediate-acting or predinner premixed intermediate- and rapid-acting insulin is administered and progressively increased until the FPG concentration is normalized. If combination therapy is not successful, a split-mixed regimen of intermediate- and rapid-acting insulin equally divided between the prebreakfast and pre-dinner periods is advised for oese patients, and more intensive regimens are advised for thin patients. Insulin therapy is invariably associated with weight gain and hypoglycemia. The use of metformin or glitazones in combination with insulin has been demonstrated to have insulin-sparing properties. Also, metformin use may ameliorate weight gain. The use of continuous subcutaneous insulin infusion pumps can be particularly beneficial in treating patients with type 2 diabetes mellitus who do not respond satisfactorily to more conventional treatment strategies. Intraperitoneal insulin delivery systems hold considerable promise in type 2 diabetes because of their more physiologic delivery of insulin and their ability to inhibit hepatic glucose production selectively, with less peripheral insulinemia than with subcutaneous insulin injections. Newer insulin analogues such as the rapidly acting Lispro insulin and the peakless, long-acting glargine insulin are increasingly being used because of their unique physiologic pharmacokinetics. New developments such as inhaled and buccal insulin preparations will also make it easier for many patients to initiate and maintain a proper insulin regimen. Finally, a new generation of gut peptides such as amylin and GLP-1 will add a new dimension to glycemic control through modification of nutrient delivery and other mechanisms; however, the ultimate goal in the management of type 2 diabetes is the primary prevention of the disease. The Diabetes Prevention Program (DPP) sponsored by the National Institutes of Health has currently randomly assigned more than 3000 persons with impaired glucose tolerance and at high risk of developing diabetes into three treatment arms: metformin arm, an intensive lifestyle-modification arm, and a placebo arm. The study will conclude in 2002 after all participants have been followed for 3 to 6 years.

Blood Glucose↗
PubMed2001

Benchmark data from the literature for evaluation of new glucose sensing technologies.

New glucose sensors based on various technologies are being developed to provide information for improved therapy in diabetes. There is a need to establish rational performance standards for these sensors. Frequently sampled, direct blood glucose recordings representative of blood glucose excursions in diabetes are the "gold standard." An extensive literature search revealed a limited number of diabetic and nondiabetic blood glucose recordings suitable for this purpose. Certain blood glucose recordings reflect the diversity of glycemic dynamics and provide sufficient challenge for evaluation of sensor systems. These recordings were converted into an accessible electronic format. An example is given of the use of these benchmark data to estimate aliasing error, or the error due to insufficient sampling frequency, based on a hypothetical sensor system having some properties of conventional "fingerstick" systems. Discrete sampling systems accumulate substantial aliasing error as the sampling period increases.

Biosensing Techniques↗
PubMed2000

Multisite evaluation of a new diabetes self-test for glucose and glycated protein (fructosamine).

BACKGROUND: In diabetes management, the true average blood glucose is best obtained using glycated protein tests that give the average blood glucose over a previous time window of either weeks (fructosamine tests) or months (glycated hemoglobin tests). Until now, glycated protein tests have only been available as laboratory tests and have therefore been underutilized in diabetes management. Recently, a fructosamine self-test for use by diabetes patients at home was cleared for marketing by the U.S. Food and Drug Administration (FDA). We have studied the performance of this test in three geographically distinct diabetes clinics to confirm the performance and accuracy of both glucose and fructosamine testing with this device. This new self-testing system has the potential to improve glycemic control dramatically in patients with diabetes, including those patients with type 2 diabetes using oral drug therapy. METHODS: Three geographically different sites (San Diego, CA, Tallahassee, FL, and Minneapolis, MN) were selected for the study. Sixty male and 56 female adult patients, with both type 1 (59) and type 2 (57) diabetes, were selected for participation in the study (total patients = 116). Fingerstick puncture capillary blood glucose was tested using the YSI Model 1500 and the Duet Glucose test. A fingerstick puncture capillary blood test was also tested with the Duet GlucoProtein (fructosamine) test strip in duplicate. For fructosamine comparison, a venipuncture blood sample of ethylene diaminetetraacetic acid (EDTA) plasma was collected and tested using the Roche Unimate laboratory test. RESULTS: The glucose test gave excellent correlation to the reference laboratory method (r = 0.98) and the GlucoProtein test gave a correlation of 0.72 compared to the laboratory method. The bias of both tests compared to the laboratory tests was 10% or less at all concentrations. Error grid analysis of the glucose test showed that 97.5% of test results were in the accurate zone and 2.5% were in the clinically neutral or benign errors zone. Analysis of fructosamine test results using a two-by-two grid yielded sensitivity of 100%, specificity of 92% and accuracy of 94%. CONCLUSIONS: The Duet Glucose Control System is accurate for both measuring glucose and GlucoProtein (fructosamine) using a fingerstick blood sample. This new testing system has the potential to provide useful information to both healthcare specialists in their office and also to patients at home to help them achieve better long-term glucose control and avoid the potential acute and chronic complications of diabetes.

Adolescent↗
PubMed1999

The natural history of type 2 diabetes. Implications for clinical practice.

This article reviews the natural history of type 2 diabetes and emphasizes that the disease is a continuum from impaired glucose tolerance and impaired fasting glucose to frank diabetes. Understanding this natural history aids the clinician in identifying those individuals most at risk for developing type 2 diabetes. Early intervention may significantly limit the severity of the microvascular and macrovascular complications of diabetes. Additionally, this article discusses oral antidiabetic agents and reviews their potential effectiveness at the different stages in the continuum to aid the clinician in developing a treatment strategy.

Diabetes Mellitus, Type 2↗
PubMed1998

Importance of glucose control.

The importance of glycemic control in reducing the microvascular complications of type 1 diabetes has been clearly demonstrated with a long-term prospective, randomized interventional trial. The data are not as strong with regards to type 2 diabetes. The results of several prospective studies and one interventional study, however, all report benefits of improved glycemic indices on reducing microvascular complications. The available literature evaluating the relationship between glycemic control and macrovascular disease in type 1 and type 2 diabetes demonstrates the importance of glucose control. One could make rational scientific arguments or criticize the design and interpretations of any one individual study. Yet collectively the evidence is powerful. Additionally, there have been no negative studies reported. Lowering the glycosylated hemoglobin to less than 2 percentage points above the upper limit of normal should be the first glycemic goal for most patients with diabetes. Obviously, some patients cannot obtain this degree of control for a variety of reasons. Moreover, the intensity of therapy needs to be individualized and tailored to each patient. In addition, intensive glycemic control does not necessarily mean multiple injections or insulin pumps or home glucose monitoring 10 times a day. Intensive glycemic control means that the glycohemoglobin (hemoglobin and A1C and blood glucose values are in a normal or near-normal range, no matter how simple or how complex the treatment regimen. The most controversial issue is with regards to the relationship between hyperinsulinemia and accelerated atherosclerosis. This association is not consistently found in many of the large prospective studies, and certainly there has never been a direct cause-and-effect relationship proven. Most experts in the field recommend that insulin be reserved for patients with type II diabetes when oral therapy cannot achieve near-normal glycemic control. Weight gain and hypoglycemia are adverse effects of sulfonylurea and insulin therapy. These adverse effects are dwarfed, however, by the acute and chronic complications of poorly controlled diabetes. Lastly, estimates on the economic benefits of reducing long-term microvascular and macrovascular complications in populations are staggering. Based on the available literature, all patients with diabetes should be educated and have access to an appropriate individualized treatment regimen with the goal to normalize or near-normalize glycemic control. This should be the standard of care until proven otherwise.

Arteriosclerosis↗
PubMed1998

The Veterans Affairs Implantable Insulin Pump Study: effect on cardiovascular risk factors.

OBJECTIVE: To determine whether implantable insulin pump (IIP) and multiple-dose insulin (MDI) therapy have different effects on cardiovascular risk factors in insulin-requiring patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: A randomized clinical trial was conducted at seven Veterans Affairs medical centers in 121 male patients with type 2 diabetes between the ages of 40 and 69 years receiving at least one injection of insulin per day and with HbA1c, levels of > or =8% at baseline. Weights, blood pressures, insulin use, and glucose monitoring data were obtained at each visit. Lipid levels were obtained at 0, 4, 8, and 12 months, and free and total insulin levels were obtained at 0, 6, and 12 months. All medications being taken were recorded at each visit. RESULTS: No difference in absolute blood pressure, neither systolic nor diastolic, was seen between patients receiving MDI or IIP therapy, but significantly more MDI patients required anti-hypertensive medications. When blood pressure was modeled against weight and time, IIP therapy was significantly better than MDI therapy for systolic blood pressure in patients with BMI <33 and for diastolic blood pressure in patients with BMI >34 kg/m2. Total cholesterol levels decreased in the overall sample, but IIP patients exhibited significantly higher levels than MDI patients. Triglyceride levels increased over time for both groups, with IIP patients having significantly higher levels than patients in the MDI group. BMI was a significant predictor of, and inversely proportional to, HDL cholesterol level. No difference in lipid-lowering drug therapy was seen between the two groups. Free insulin and insulin antibodies tended to decrease in the IIP group as compared with the MDI group. C-peptide levels decreased in both groups. CONCLUSIONS: IIP therapy in insulin-requiring patients with type 2 diabetes has advantages over MDI therapy in decreasing the requirement for antihypertensive therapy and for decreasing total and free insulin and insulin antibodies. Both therapies reduce total cholesterol and C-peptide levels.

Adult↗
PubMed1998

Type II diabetes mellitus.

Type II diabetes is a common disorder whose prevalence is increasing in the United States and throughout the world. Type II diabetes is also associated with several other metabolic abnormalities such as central obesity, hypertension, and dyslipidemia, which contributes to the very high rate of cardiovascular morbidity and mortality. The main pathologic defects in diabetes consist of excessive hepatic glucose production, peripheral insulin resistance, and defective beta-cell secretory function. The duration and severity of the hyperglycemia dictate the microvascular complications, no matter what the etiology of the glucose intolerance, and the goals of therapy should be similar to those of insulin-dependent type I diabetic patients. Initiation of nonpharmacologic therapy should be started as soon as the diagnosis is made. Pharmacologic agents should be initiated if the glycemic goals are not met with a 3-month trial of diet and exercise. The cornerstone of therapy consists of a regular exercise routine along with a diet consisting of 40% to 50% complex carbohydrates, 10% to 20% protein, and monounsaturated fats such as canola oil and olive oil. If nonpharmacologic therapy does not achieve adequate glycemic control, initiation of an oral antidiabetic agent is warranted. In addition to the sulfonylureas, which work by stimulating insulin secretion, we now have metformin, which inhibits excessive hepatic glucose production; acarbose, which delays the absorption of carbohydrates in the gut; and troglitazone, which reduces insulin, resistance primarily in skeletal muscle. The selection of an initial oral antidiabetic agent depends on patient characteristics such as the presence of obesity and dyslipidemia, the duration of diabetes, and other concomitant conditions. Combination therapy with two or three of the different classes of oral antidiabetic agents is effective and has been used throughout the world. When maximum doses of oral antidiabetic agents do not adequately control glycemia, insulin therapy is necessary. In selected patients, combination therapy consisting of bedtime intermediate-acting insulin in addition to daytime oral antidiabetic agent(s) can be an effective method to normalize glucose control without the need for rigorous insulin regimens. When combination therapy fails, a split-mixed regimen using premixed 70/30 insulin prebreakfast and predinner can be very effective in obese subjects. In thin insulin-requiring subjects with type II diabetes, more intensive regimens may be required. In general, the risk of severe hypoglycemia is quite low in patients with type II diabetes, and the main adverse effect of insulin therapy is weight gain. Prevention and aggressive treatment of glucose intolerance and the other adverse metabolic conditions associated with type II diabetes will not only have a positive effect on the quality of life but also provide long-term cost savings.

Blood Glucose↗
PubMed1996

Acute effects of intraperitoneal versus subcutaneous insulin delivery on glucose homeostasis in patients with NIDDM. Veterans Affairs Implantable Insulin Pump Study Group.

OBJECTIVE: The objective of this study is to compare the effect of intraperitoneal versus subcutaneous insulin injection on hepatic glucose production (HGP) and systemic glucose utilization (Rd) in patients with NIDDM. RESEARCH DESIGN AND METHODS: Eight male volunteers with NIDDM, each of whom had a programmable-rate, implantable insulin pump, were given an injection of insulin (0.15 units/kg body wt) by intraperitoneal or subcutaneous injection on separate days in randomized order. Plasma glucose was kept constant for 5 h using the glucose clamp technique, and HGP and Rd were measured using isotope dilution. RESULTS: Intraperitoneal insulin injection resulted in higher and earlier peak systemic insulin concentrations (1,469 +/- 245 vs. 454 +/- 48 pmol/l, P < 0.01). Glucose Rd doubled within 1 h after intraperitoneal injection and was greater than that attained with subcutaneous injection (3.91 +/- 0.27 vs. 2.60 +/- 0.19 mg.kg-1.min-1, P < 0.01). Intraperitoneal and subcutaneous injections suppressed HGP and plasma free fatty acid to a similar extent during the first 3 h, effects tht persisted through 5 h after subcutaneous insulin injection but waned 3-4 h after intraperitoneal injection. CONCLUSIONS: In patients with NIDDM, intraperitoneal insulin injection achieves more rapid and greater peak values for stimulation of glucose Rd than subcutaneous insulin injection. With regard to HGP and lipolysis, intraperitoneal and subcutaneous injections achieve similar initial suppression but this is maintained for a more limited duration with intraperitoneal as compared with subcutaneous injection. These differences in insulin action seem directly related to the rapidity of insulin absorption with intraperitoneal injection.

Blood Glucose↗
PubMed1992

Effects of epinephrine on insulin-mediated glucose uptake in whole body and leg muscle in humans: role of blood flow.

In vivo insulin-mediated glucose uptake (IMGU) occurs chiefly in skeletal muscle, where it is determined by the product of arteriovenous glucose difference (delta AVG) and blood flow (BF) rate into muscle. Epinephrine (Epi) reduces the rate of IMGU in whole body. To examine whether this is due to a reduction in delta AVG across or BF into skeletal muscle we constructed insulin dose-response curves for whole body IMGU and leg muscle IMGU- using euglycemic clamp ((+)[3-3H]glucose infusion) and leg balance techniques during insulin infusions ranging from 10 to 1,200 mU.m-2.min-1. We studied six subjects [wt 70 +/- 2 (SE) kg] during an Epi infusion at a single rate of 0.002 mg.kg-1.min-1 and six subjects (70 +/- 3 kg) during a saline infusion alone. Maximum whole body glucose uptake (WBGU) was similar during Epi and saline infusions [71.4 vs. 73.6 mmol.kg-1.min-1, P = not significant (NS)]. Compared with saline, maximum delta AVG was decreased during Epi infusion (1.04 vs. 1.31 mM, P less than 0.01). Compared with saline alone maximum leg BF was increased (5.3 vs. 4.3 dl/min, P less than 0.01) during Epi infusion. Thus maximum leg glucose uptake (LGU) was similar (696 vs. 821 pmol.leg-1.min-1, P = NS) during infusion of Epi and saline, respectively. Half-maximal effective dose for insulin's effect to stimulate WBGU, delta AVG, BF, and LGU was increased two- to threefold during Epi vs. saline infusions (P less than 0.01 for all values).(ABSTRACT TRUNCATED AT 250 WORDS)

Blood Circulation↗
PubMed1992

Impaired insulin-mediated skeletal muscle blood flow in patients with NIDDM.

Patients with non-insulin-dependent diabetes mellitus (NIDDM) exhibit decreased rates of skeletal muscle insulin-mediated glucose uptake (IMGU). Because IMGU is equal to the product of the arteriovenous glucose difference (AVG delta) across and blood flow (F) into muscle (IMGU = AVG delta x F), reduced tissue permeability (AVG delta) and/or glucose and insulin delivery (F) can potentially lead to decreased IMGU. The components of skeletal muscle IMGU were studied in six obese NIDDM subjects (103 +/- 9 kg) and compared with those previously determined in six lean (weight 68 +/- 3 kg), and six obese (94 +/- 3 kg) with normal glucose tolerance. The insulin dose-response curves for whole body and leg muscle IMGU were constructed using the combined euglycemic clamp and leg balance techniques during sequential insulin infusions (range of serum insulin 130-80,000 pmol/L). In lean, obese, and NIDDM subjects, whole body IMGU, femoral AVG delta, and leg IMGU increased in a dose-dependent fashion over the range of insulin with an ED50 of 400-500 pmol/L in lean, 1000-1200 pmol/L in obese, and 4000-7000 pmol/L in NIDDM subjects (P less than 0.01 lean vs. obese and NIDDM). In lean and obese subjects, maximally effective insulin concentrations increased leg blood flow approximately 2-fold from basal with an ED50 of 266 pmol/L and 957 pmol/L, respectively (P less than 0.01 lean vs. obese). In contrast, leg F did not increase from the basal value in NIDDM subjects (2.7 +/- 0.1 vs. 3.5 +/- 0.5 dl/min, NS).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1992

Advances in treatment of type II diabetes mellitus in the elderly.

Elderly diabetic patients are prone to the acute and subacute consequences of hyperglycemia, which can adversely affect health, well being, and quality of life. Every elderly patient with diabetes should be offered an individualized treatment plan, consisting of education, dietary counseling, and an exercise program. If fasting and postprandial glucose levels do not stay consistently in the desired range, then an oral hypoglycemic agent should be instituted at the lowest possible dose. When the oral hypoglycemic agent fails, it may be possible to achieve good glycemic control with the addition of insulin. Recent developments in insulin administration can optimize glycemic benefits and reduce potential adverse effects.

Aged↗
PubMed1991

Reduced capacity and affinity of skeletal muscle for insulin-mediated glucose uptake in noninsulin-dependent diabetic subjects. Effects of insulin therapy.

We have estimated the capacity and affinity of insulin-mediated glucose uptake (IMGU) in whole body and in leg muscle of obese non-insulin-dependent diabetics (NIDDM, n = 6) with severe hyperglycemia, glycohemoglobin (GHb 14.4 +/- 1.2%), lean controls (ln, n = 7) and obese nondiabetic controls (ob, n = 7). Mean +/- SEM weight (kg) was 67 +/- 2 (ln), 100 +/- 7 (ob), and 114 +/- 11 (NIDDM), P = NS between obese groups. NIDDM were also studied after 3 wk of intensive insulin therapy, GHb post therapy was 10.1 +/- 0.9, P less than 0.01 vs. pretherapy. Insulin (120 mu/m2 per min) was infused and the arterial blood glucose (G) sequentially maintained at approximately 4, 7, 12, and 21 mmol/liter utilizing the G clamp technique. Leg glucose uptake (LGU) was calculated as the product of the femoral arteriovenous glucose difference (FAVGd) and leg blood flow measured by thermodilution. Compared to ln, ob and NIDDM had significantly lower rates of whole body IMGU and LGU at all G levels. Compared to ob, the NIDDM exhibited approximately 50% and approximately 40% lower rates of whole body IMGU over the first two G levels (P less than 0.02) but did not differ at the highest G, P = NS. LGU was 83% lower in NIDDM vs. ob, P less than 0.05 at the first G level only. After insulin therapy NIDDM were indistinguishable from ob with respect to whole body IMGU or LGU at all G levels. A significant correlation was noted between the percent GHb and the EG50 (G at which 1/2 maximal FAVGd occurs) r = 0.73, P less than 0.05. Thus, (a) insulin resistance in NIDDM and obese subjects are characterized by similar decreases in capacity for skeletal muscle IMGU, but differs in that poorly controlled NIDDM display a decrease in affinity for skeletal muscle IMGU, and (b) this affinity defect is related to the degree of antecedent glycemic control and is reversible with insulin therapy, suggesting that it is an acquired defect.

Biological Transport↗
PubMed1991

Mechanism of insulin resistance in insulin-dependent diabetes mellitus: a major role for reduced skeletal muscle blood flow.

To define the kinetic mechanisms of insulin resistance (IR) in insulin-dependent diabetes (IDDM), we studied seven control (C) and five IDDM (glycohemoglobin, 14 +/- 2+) men matched for age (36 +/- 2 vs. 37 +/- 3 yr), lean body mass (59 +/- 2 vs. 58 +/- 3 kg), and leg volume (mean +/- SEM, 10.4 +/- 0.3 vs. 9.8 +/- 0.5 L). Maximal capacity (Vmax) and affinity (Km) for glucose uptake in whole body (WBGU) and leg skeletal muscle (LGU) were measured during a 120 mU/m2.min insulin infusion, and blood glucose was clamped at about 4, 7, 12, and 21 mmol/L. LGU = femoral arterio-venous glucose difference (FAVGD) X leg blood flow (LBF). Compared to C, IDDMs had about 35% lower rates of WBGU at all glucose levels (P less than 0.01). The FAVGD (millimoles per L) in C vs. IDDM was 1.23 +/- 0.05 vs. 1.06 +/- 0.09, 2.44 +/- 0.11 vs. 2.24 +/- 0.16, 2.91 +/- 0.18 vs. 2.91 +/- 0.30, and 3.27 +/- 0.12 vs. 3.35 +/- 0.4 (P = NS at each glucose). LBF (decaliters per min) was reduced in IDDM vs. C [2.8 +/- 0.5 vs. 4.3 +/- 0.4 (P less than 0.05), 3.1 +/- 0.4 vs. 5.1 +/- 0.7 (P less than 0.05), 2.7 +/- 0.2 vs. 6.3 +/- 0.8 (P less than 0.01), and 3.1 +/- 0.7 vs. 6.5 +/- 0.8 (P less than 0.01) at each glucose level]. Kinetic analysis revealed that 1) the Vmax for WBGU and LGU were reduced in IDDM vs. C (P less than 0.05), and 2) the Vmax for skeletal muscle glucose extraction (FAVGD) was identical in C and IDDM (3.6 mmol/L). The Km values for WBGU, LGU, and glucose extraction were not different in C and IDDM (approximately 6 mmol/L). Thus, in IDDM 1) decreased glucose uptake is due to reduced skeletal muscle glucose uptake; 2) muscle glucose extraction is normal, but blood flow is reduced; and thus, 3) in IDDM, IR is due to reduced glucose and insulin delivery (blood flow) to skeletal muscle. This represents a novel mechanism for in vivo IR.

Adult↗
PubMed1990

Use of a variable tracer infusion method to determine glucose turnover in humans.

The single-compartment pool fraction model, when used with the hyperinsulinemic glucose clamp technique to measure rates of glucose turnover, sometimes underestimates true rates of glucose appearance (Ra) resulting in negative values for hepatic glucose output (HGO). We focused our attention on isotope discrimination and model error as possible explanations for this underestimation. We found no difference in [3-3H] glucose specific activity in samples obtained simultaneously from the femoral artery and vein (2,400 +/- 455 vs. 2,454 +/- 522 dpm/mg) in 6 men during a hyperinsulinemic euglycemic clamp study where insulin was infused at 40 mU.m-2.min-1 for 3 h; therefore, isotope discrimination did not occur. We compared the ability of a constant (0.6 microCi/min) vs. variable tracer infusion method (tracer added to the glucose infusate) to measure non-steady-state Ra during hyperinsulinemic clamp studies. Plasma specific activity fell during the constant tracer infusion studies but did not change from base line during the variable tracer infusion studies. By maintaining a constant plasma specific activity the variable tracer infusion method eliminates uncertainty about changes in glucose pool size. This overcame modeling error and more accurately measures non-steady-state Ra (P less than 0.001 by analysis of variance vs. constant infusion method). In conclusion, underestimation of Ra determined isotopically during hyperinsulinemic clamp studies is largely due to modeling error that can be overcome by use of the variable tracer infusion method. This method allows more accurate determination of Ra and HGO under non-steady-state conditions.

Blood Glucose↗