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D T Finegood

Publications and source records attributed to D T Finegood.

68 records · Page 4Linked to original sources
PubMed1990

A modified protocol for estimation of insulin sensitivity with the minimal model of glucose kinetics in patients with insulin-dependent diabetes.

An exogenous insulin administration-modified, frequently sampled iv glucose tolerance test (FSIGT) for application in insulin-dependent diabetic patients (IDDM) to allow for estimation of insulin sensitivity (SI) and glucose effectiveness (SG) with Bergman's minimal model of glucose kinetics was investigated. An insulin infusion protocol (either 4 or 8 mU/min.kg from 20-25 min) was compared to the standard tolbutamide-modified (300 mg at 20 min) FSIGT in normal control subjects. SI and SG were not different for the insulin infusion- and tolbutamide-modified protocols [SI, 2.8 +/- 0.4, 3.6 +/- 0.6, and 2.5 +/- 0.5 X 10(4) min1/(microU/mL), respectively]. SI and SG were quantified in insulin-requiring newly diagnosed IDDM and in noninsulin-requiring IDDM in clinical remission with the exogenous insulin administration protocol. Both SI and SG were reduced in newly diagnosed IDDM compared to normal controls (by 64% and 40%, respectively). SI was normalized in IDDM in clinical remission despite a continued poor insulin secretory response to both glucose and tolbutamide. Although SI was normal in patients in clinical remission, SG remained reduced (by 65%) compared to that in normal controls. In conclusion, our results demonstrate that modification of the FSIGT with the exogenous administration of insulin allows for estimation of insulin sensitivity and glucose effectiveness in IDDM patients. Comparison to the standard protocol in normal subjects suggests that this results in valid measurements of insulin sensitivity and glucose effectiveness. Results of the application of this protocol in IDDM were consistent with previous observations that insulin sensitivity is reduced in poorly controlled IDDM and normalized in well controlled patients. Glucose effectiveness was found to be reduced in all IDDM subjects regardless of the degree of control.

Adolescent↗
PubMed1990

Androgen response to endogenous insulin secretion during the frequently sampled intravenous glucose tolerance test in normal and hyperandrogenic women.

Women with ovarian hyperandrogenism frequently have insulin resistance, whose underlying mechanism remains to be determined. In the present study we have investigated the relationship between insulin sensitivity and the acute effect of endogenous insulin secretion on circulating androgen levels. Insulin sensitivity, glucose-mediated insulin release, and glucose/insulin-stimulated androgen responses were determined during a frequently sampled iv glucose tolerance test in a group of 19 women with clinical evidence of polycystic ovary syndrome (PCOS) and 9 age- and weight-matched controls. Insulin (I), glucose, androstenedione, testosterone (T), free T, and dehydroepiandrosterone (DHEA) levels were measured before and during the 3 h following iv administration of glucose (300 mg/kg). Intravenous tolbutamide (300-500 mg) was injected 20 min after the glucose injection. Insulin sensitivity (SI) was calculated by application of the minimal model of glucose kinetics. Fasting androstenedione, T, free T, and I concentrations were significantly higher in the women with PCOS than in controls (P less than 0.02). In PCOS subjects, fasting I was correlated with both T (r = 0.51; P less than 0.05) and DHEA (r = 0.706; P less than 0.01). SI was significantly lower in PCOS subjects [SI, 68.35 +/- 8.34 min-1/(nmol/mL] than in control subjects (SI, 133.36 +/- 21.7 min-1/(nmol/mL)]. A significant decline in DHEA levels was observed in control subjects 3 h after glucose administration (from 28.4 +/- 3.0; final, 16.2 +/- 2.4; P less than 0.02). PCOS women with normal insulin sensitivity [SI, greater than 75.0 min-1/(nmol/mL)] showed a similar fall in DHEA (from 20.3 +/- 2.5 to 12.8 +/- 1.8 nmol/L; P less than 0.02). No significant change occurred in insulin-resistant PCOS subjects [SI, less than 75.0 min-1/(nmol/mL)]. Other androgen levels showed a modest nonsignificant decline during the study in PCOS and control groups. These findings confirm the weight-independent insulin resistance of some hyperandrogenic women. The failure of glucose-stimulated endogenous insulin secretion to significantly depress DHEA levels in insulin-resistant women with PCOS may account in part for their androgen excess.

Adult↗
PubMed1989

Insulin sensitivity and glucose effectiveness in long-term islet-autotransplanted dogs.

Parameters determining glucose tolerance were quantified with Bergman's minimal-model method applied to frequently sampled intravenous glucose tolerance tests in five normal and five islet-autotransplanted mongrel dogs 8-10 mo posttransplantation. Despite normal fasting glucose and insulin levels, glucose tolerance was reduced in the islet-transplanted dogs (1.5 +/- 0.4 vs. 4.2 +/- 0.4%/min in normal controls, P less than .002). The reduction in glucose tolerance was due to a reduced insulin response to glucose injection (4 +/- 1 vs. 32 +/- 5 microU/ml, P less than .001) and reduced glucose effectiveness (1.7 +/- 0.5 vs. 5.3 +/- 0.6 x 10(2) min-1, P less than .005) but not to a reduction in insulin sensitivity (8.4 +/- 0.6 vs. 7.8 +/- 0.7 x 10(4) min-1.microU-1.ml-1, P greater than .5). Our results suggest that reduced insulin secretory response as a result of islet transplantation may result in a defect in glucose's ability to promote its own disposal but not necessarily in a defect in insulin sensitivity.

Animals↗
PubMed1988

Modeling error and apparent isotope discrimination confound estimation of endogenous glucose production during euglycemic glucose clamps.

We previously demonstrated that conventional tracer methods applied to euglycemic-hyperinsulinemic glucose clamps result in substantially negative estimates for the rate of endogenous glucose production, particularly during the first half of 180-min clamps. We also showed that addition of tracer to the exogenous glucose infusate resulted in nonnegative endogenous glucose production (Ra) estimates. In this study, we investigated the underlying cause of negative estimates of Ra from conventional clamp/tracer methods and the reason for the difference in estimates when tracer is added to the exogenous glucose infusate. We performed euglycemic-hyperinsulinemic (300-microU/ml) clamps in normal dogs without (cold GINF protocol, n = 6) or with (hot GINF protocol, n = 6) tracer (D-[3-3H]glucose) added to the exogenous glucose infusate. In the hot GINF protocol, sufficient tracer was added to the exogenous glucose infusate such that arterial plasma specific activity (SAa) did not change from basal through the clamp period (P greater than .05). In the cold GINF studies, plasma SAa fell 81 +/- 2% from the basal level by the 3rd h of clamping. We observed a significant, transient, positive venous-arterial difference in specific activity (SAv-SAa difference) during the cold GINF studies. The SAv-SAa difference reached a peak of 27 +/- 6% at 30 min and diminished to a plateau of 7 +/- 1% between 70 and 180 min. We also observed a positive but constant SAv-SAa difference (4.6 +/- 0.2% between 10 and 180 min) during the hot GINF studies. The observations of a difference between hot and cold GINF endogenous Ra estimates and a positive but transient SAv-SAa difference during the cold GINF studies are consistent with the interpretation that a portion of the underestimation of Ra is due to insufficient mixing of endogenous and exogenous glucose for the one-compartment, fixed-pool volume model to be applicable. Alternatively, our results suggest that the one-compartment, fixed-pool volume model of glucose kinetics is insufficient to account for the complex dynamics of labeled and unlabeled glucose during euglycemic-hyperinsulinemic clamps. Improved mixing through addition of tracer to the exogenous glucose infusate or improved modeling by allowing for a variable-pool volume appears to improve the accuracy of the tracer methods; however, these approaches remain to be validated. The constant positive SAv-SAa difference observed during the hot GINF studies is consistent with the interpretation that an additional contributor to underestimation of endogenous Ra is apparent isotope discrimination.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1987

Recombinant deoxyribonucleic acid-derived 22K- and 20K-human growth hormone generate equivalent diabetogenic effects during chronic infusion in dogs.

Chronic administration of human GH (mol wt, 22,000; 22K-hGH) is known to generate insulin resistance in dogs. However, recent hypotheses claim that diabetogenicity may be attributable to smaller weight contaminants or fragments not found in purified lower weight hGH (mol wt, 20,000; 20K-hGH) also secreted by the pituitary. In this study, we examined the effects of chronic (12-day) low dose (0.02 mg/kg X day) infusion of recombinant DNA-derived methionyl 22K- and 20K-hGH on glucose tolerance in conscious dogs. Minimal model analysis of the frequently sampled iv glucose tolerance tests quantified insulin sensitivity and glucose effectiveness, the ability of glucose per se to normalize its own concentration. Infusion of 22K-hGH, raising plasma hGH levels to 3.8 +/- 0.6 ng/ml, resulted in an elevation in fasting glucose levels after 2 days of infusion (104 +/- 1 vs. pre-hGH 97 +/- 2 mg/dl; P less than 0.01), but the effect was transient. No change was noted during 20K-hGH treatment (P greater than 0.2). Mildly elevated fasting insulin levels were observed in both 22K- and 20K-hGH-treated dogs (P less than 0.04 and 0.03, respectively). However, despite maintenance of adequate glucose tolerance during both infusions (P greater than 0.07), marked insulin resistance was apparent; insulin sensitivity dropped from 9.7 +/- 2.4 and 11.2 +/- 2.1 X 10(-4) min-1/(microU/ml) in 22K- and 20K-hGH-treated dogs, to 2.5 and 2.8 X 10(-4) min-1/(microU/ml), a drop of 75% (P less than 0.01 and 0.001). Insulin resistance persisted throughout the infusion period, slowly returning to pre-hGH treatment levels in 22K-hGH-treated dogs during recovery. Insulin resistance persisted 3 days after cessation of 20K-hGH treatment (day 15), but returned to pre-hGH levels by day 25. Integrated glucose-stimulated insulin release was enhanced after 2 days of 22K- or 20K-hGH treatment (P less than 0.03 and less than 0.05), but the effect was transient. Maintenance of normal glucose tolerance in the face of severe insulin resistance and only transiently elevated insulin response was possible because glucose effectiveness remained unchanged. In conclusion, despite minimal effects of low dose hGH infusion on glucose tolerance and fasting glucose and insulin levels, 22K- and 20K-hGH are equipotent in generating severe insulin resistance and potentiating glucose-stimulated insulin release.

Animals↗
PubMed1987

Estimation of endogenous glucose production during hyperinsulinemic-euglycemic glucose clamps. Comparison of unlabeled and labeled exogenous glucose infusates.

Tracer methodology has been applied extensively to the estimation of endogenous glucose production (Ra) during euglycemic glucose clamps. The accuracy of this approach has been questioned due to the observation of significantly negative estimates for Ra when insulin levels are high. We performed hyperinsulinemic (300 microU/ml)-euglycemic glucose clamps for 180 min in normal dogs and compared the standard approach, an unlabeled exogenous glucose infusate (cold GINF protocol, n = 12), to a new approach in which a tracer (D-[3-3H]glucose) was added to the exogenous glucose used for clamping (hot GINF protocol, n = 10). Plasma glucose, insulin and glucagon concentrations, and glucose infusion rates were similar for the two protocols. Plasma glucose specific activity was 20 +/- 1% of basal (at 120-180 min) in the cold GINF studies, and 44 +/- 3 to 187 +/- 5% of basal in the hot GINF studies. With the one-compartment, fixed pool volume model of Steele, Ra for the cold GINF studies was -2.4 +/- 0.7 mg X min-1 X kg-1 at 25 min and remained significantly negative until 110 min (P less than .05). For the hot GINF studies, Ra was never significantly less than zero (P greater than .05) and was greater than in the cold GINF studies at 20-90 min (P less than .05). There was substantially less between-(78%) and within- (40%) experiment variation for the hot GINF studies compared with the cold GINF studies. An alternate approach (regression method) to the application of the one-compartment model, which allows for a variable and estimable effective distribution volume, yielded Ra estimates that were suppressed 60-100% from basal. In conclusion, the one-compartment, fixed pool volume model of glucose kinetics is inadequate for the estimation of Ra during euglycemic glucose clamps. Two new strategies for estimating Ra from the one-compartment model, the hot GINF protocol and the regression method calculation, yielded more accurate and physiologically plausible estimates of Ra than currently used methodology.

Animals↗
PubMed1984

Extrapancreatic effect of somatostatin infusion to increase glucose clearance.

Constant intraportal insulin, coupled with variable intraportal glucagon, was used in the attempt to reestablish basal metabolic conditions in dogs during somatostatin (SRIF) infusion (0.8 micrograms X min-1 X kg-1). SRIF alone lowered glucose (G), insulin (I), and glucagon (GN) (G: 90 +/- 5 to 69 +/- 1 mg/dl; I: 18 +/- 4 to 4 +/- 1 microU/ml; GN: 257 +/- 52 to 168 +/- 40 pg/ml; P less than 0.05 or better). Hormone replacement. Hypoglycemia persisted (G at steady state, SS, 60-150 min): 12 +/- 3 mg/dl below basal; P = 0.006) despite intraportal insulin replacement (200 microU X min-1 X kg-1; insulin at basal: 14 +/- 1; at SS: 14 +/- 2 microU/ml; P greater than 0.9) and glucagon overreplacement (basal: 341 +/- 42; SS: 486 +/- 80 pg/ml; P less than 0.05). Glucose clearance was increased 65% above basal (P less than 0.0001). Insulin underreplacement. With a lower intraportal insulin infusion rate (50 microU X min-1 X kg-1), insulin fell from basal (10 +/- 2 microU/ml) to 4 +/- 1 microU/ml during steady state (P = 0.03). Glucose and glucose clearance were normalized to basal values (G: 85 +/- 3 mg/dl, P = 0.3; clearance: 5.7 +/- 0.5 ml X min-1 X kg-1; P = 0.2) with full glucagon replacement (basal: 281 +/- 120; SS: 264 +/- 80 pg/ml; P greater than 0.9). Thus, during constant SRIF infusion, normoglycemia was reattained when insulin was underreplaced via the portal vein. The failure to reattain euglycemia with normoinsulinemia was due to a SRIF-induced increase in extrahepatic glucose clearance. Insulin replacement and growth hormone (GH) infusion. GH (15 ng X min-1 X kg-1) partially reversed the hypoglycemia during SRIF, with full insulin replacement. The SRIF-induced increase in glucose clearance may be partially mediated by a decrease in GH.

Animals↗
PubMed1984

The insulin sensitivity index. Correlation in dogs between values determined from the intravenous glucose tolerance test and the euglycemic glucose clamp.

We previously proposed the insulin sensitivity index, Sl, as an absolute measure of whole body tissue sensitivity to insulin. Sl is defined, in the physiologic range of insulin action, as the effect of insulin to augment glucose's ability to reduce its own plasma level. This parameter can be determined from the frequently sampled intravenous glucose tolerance test (IVGTT) by using a digital computer to find the coefficients of a minimal mathematical model of glucose kinetics. In the present study we compared, in normal dogs, Sl determined from the IVGTT to an analogous parameter [Sl(clamp)] calculated from the euglycemic glucose clamp (EGC). Fifteen pairs of experiments (1 IVGTT and 1 EGC) were performed on 12 animals. IVGTTs: After glucose injection (0.3 g/kg), frequent blood samples were taken over the subsequent 3 h. KG ranged from 1.7 to 4.7%/min, and integrated insulin from 0.4 to 5.9 (mU/ml) min for 0-60 min. Sl varied over a nine-fold range from 1.0 to 9.1 X 10(-4) (min-1)/(microU/ml), with a mean of 4.3 +/- 0.7 X 10(-4). Fractional glucose disappearance rate independent of insulin (p1) was 4.3 +/- 0.5%/min. EGCs: Low-rate insulin infusion (8 mU/min from 1 to 150 min) elevated plasma insulin (INS) from 15 +/- 4 to 43 +/- 10 microU/ml. Glucose was infused (GINF) at 119 +/- 20 mg/min to maintain euglycemia. Moderate insulin infusion (40 mU/min: 151-300 min) further elevated plasma insulin (to 176 +/- 37 microU/ml) and the requisite glucose infusion (to 372 +/- 36 mg/min).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1983

Optimal segments: a method for smoothing tracer data to calculate metabolic fluxes.

Metabolic fluxes (Ra and Rd) are calculated in the nonsteady state using Steele's equations. These calculations require estimates of the values and rates of change of glucose and specific activity at discrete sampling times. Data smoothing minimizes the effect of measurement error that confounds the Ra and Rd calculations. We compared three smoothing methods: a) moving average, b) polynomial fitting, and c) optimal segments, a new technique that utilizes optimization methods. Experimental designs were simulated: 1) constant infusion of glucagon in depancreatized dogs, and 2) glucose oscillations generated by constant high-level glucose infusion. Measurement error was added to raw data. After smoothing, fluxes were calculated and compared to the "actual" Ra and Rd. Ra calculated from unsmoothed noisy data were in error by an average 39%. Error was reduced by smoothing to: 23%, moving average; 18%, polynomial fitting; 15%, optimal segments. Optimal segments was best for calculating Ra (P less than 0.01) and was better than or equal to other methods for Rd. Distortion in flux patterns was greatest for polynomial fitting (P less than 0.01) and least for optimal segments (P less than 0.001). Optimal segments is the method of choice for smoothing tracer data; it improves calculations of Ra and Rd with minimal distortion.

Animals↗
PubMed1982

A minimal-model-based glucose clamp yielding insulin sensitivity independent of glycemia.

A new technique is introduced for automatic control of the blood sugar ("glucose clamp") at basal (euglycemic) or elevated (hyperglycemic) levels during variable insulin infusion. A minimal mathematical model of glucose kinetics is implemented on a laboratory minicomputer during clamp experiments. From the measured time course of plasma glucose concentration, the computer estimates the fractional disappearance rate of glucose (X) and calculates the rate of exogenous infusion required to match the desired concentration (M). Eight clamp experiments were performed on three conscious dogs. Euglycemic (N = 4): insulin was infused at 8, 40, and 150 microU/min for sequential 2.5-h periods )I, II, and III); hyperglycemic (N = 4): following the establishment of 140 mg/dl hyperglycemia (period I), insulin was infused at 30 and 120 mU/min for 2.5 h each (periods II and III). Plasma insulin levels [range: 21 +/- 9 (basal) to 1729 +/- 209 microunits/ml] were matched in comparable periods in the two types of experiments [P greater than 0.8 (I); P greater than 0.5 (II), P greater than 0.2 (III)]. Glucose was successfully clamped for all periods at euglycemia (99.6 +/- 0.7% of desired value) and hyperglycemia (100.0 +/- 1.1% desired 140-mg/dl value). Glucose infusion rates necessary to achieve stable glycemia were greater at elevated than basal glucose (P less than 0.001) despite comparable insulinemia during the three insulin infusion periods. Thus, the glucose infusion rate versus insulin level (M/I) was glycemia-dependent, and therefore not a direct measure of insulin sensitivity. In contrast, the insulin-induced increases in fractional glucose disappearance (delta X), also provided by our clamp technique during experiments, were highly correlated within insulin (r = 0.08 to r = 0.99, P less than 0.01) and independent of glycemia (P greater than 0.7). The ratio delta X/delta I (increase in glucose fractional disappearance rate/incremental insulin level) was a measure of insulin sensitivity independent of glycemia, and could successfully differentiate insulin-resistant from normal animals (P less than 0.001; delta X/delta I in three animals: 6.9 X 10(-4), 5.5 X 10(-4), and 1.4 X 10(-4) min-1 microunits/ml). Thus, this model-dependent glucose clamp technique provides a direct measurement of insulin sensitivity independent of glycemia.

Animals↗
PubMed1980

Quantitative estimation of beta cell sensitivity to glucose in the intact organism: a minimal model of insulin kinetics in the dog.

We propose an approach to quantifying the sensitivity of B cells to glucose in the intact organism, whereby we interpret the complex dynamic plasma insulin response to glucose injection in terms of a minimal mathematical model of posthepatic insulin delivery and insulin clearance. The best model for this purpose was chosen by comparing the ability of a series of proposed models to account precisely for plasma insulin dynamics. Intravenous glucose tolerance tests (IVGTT) (300 mg/kg) were performed on conscious dogs, and blood was sampled frequently until the basal steady state was reestablished. Glucose injection produced variable plasma insulin responses, which were characterized by an early peak (76 microU/ml above basal), a plateau with occasional additional peaks, and by an abrupt return of plasma insulin to basal by 37 min. A set of eight models was examined; one emerged as superior, in that it was able to account for insulin dynamics with the smallest number of physiologically meaningful parameters (N = 4). The chosen (minimal) model assumes that (1) clearance of insulin is of the first order, (2) the initial peak represents a bolus of insulin loaded into the plasma after the glucose injection, and (3) the rate of the secondary rise in insulin is determined by the concentration of glucose in plasma above a specific threshold value. The sensitivity of first phase insulin delivery to glucose (phi 1; 1.28 +/- 0.15 microU/ml per min per mg/dl), the sensitivity of the secondary phase to glucose concentration [phi 2; 0.038 +/- 0.005 (microU/mg) . min-2], and the threshold for glucose stimulation of second phase secretion (h; 125 +/- 8 mg/100 ml) were all precisely estimated from the dynamic insulin responses. These three parameters of insulin kinetics (phi 1, phi 2, and h) can be calculated from a single IVGTT, and they characterize the insulin responsiveness of a single individual. Estimating these characteristic parameters of insulin kinetics from IVGTT data has potential for quantitating the individual factors contributing to glucose-stimulated insulin secretion in intact animal models, and it may be applicable to man.

Animals↗
PubMedDate not supplied

OPSEG: a general routine for smoothing and interpolating discrete biological data.

The optimal segments technique is a new approach to smoothing and interpolating between small numbers of discrete biological data. This method balances the degree of smoothness against the expected error of the observed data. The OPSEG computer program searches for the set of smoothed data points which will match the overall difference between the smoothed and observed data to an a priori estimate of the measurement error. The smoothed curve is described as a series of linked individual line segments. This approach is useful for the analysis of biological signals such as plasma measurements of hormone and metabolite concentration and has been applied to the development of assay standard curves.

Biometry↗
PubMedDate not supplied

Assessing insulin sensitivity in the cat: evaluation of the hyperinsulinemic euglycemic clamp and the minimal model analysis.

Current methods of assessing glucose tolerance in the cat are inadequate for quantifying insulin sensitivity. The hyperinsulinemic euglycemic clamp (EGC) and the minimal model analysis (MMA) of the frequently sampled intravenous glucose tolerance test (FSIGT) have been used in other species to assess the effects of insulin on glucose homeostasis. Each of these procedures was performed on healthy cats, two weeks apart, to generate indices of insulin sensitivity - M/I (amount of glucose metabolised per unit of plasma insulin concentration) from the EGC and S(I) (insulin sensitivity) from the MMA. Close and significant correlation between M/I and S(I) in individual cats was found (r=0.91, P=0.032). Use of these research methods may further our understanding of feline diabetes mellitus and other endocrinopathies.

Animals↗