Showing papers by "Richard N. Bergman published in 1993"

Quantification of the relationship between insulin sensitivity and beta-cell function in human subjects. Evidence for a hyperbolic function.

Abstract: To determine the relationship between insulin sensitivity and β-cell function, we quantified the insulin sensitivity index using the minimal model in 93 relatively young, apparently healthy human subjects of varying degrees of obesity (55 male, 38 female; 18–44 yr of age; body mass index 19.5–52.2 kg/m 2 ) and with fasting glucose levels I was compared with measures of body adiposity and β-cell function. Although lean individuals showed a wide range of S I , body mass index and S I were related in a curvilinear manner ( P I and the β-cell measures was more clearly curvilinear and reciprocal for fasting insulin ( P glucose ; P n = 56; P max ; n = 43; P I and the β-cell measures could not be distinguished from a hyperbola, i.e., S I × β-cell function = constant. This hyperbolic relationship described the data significantly better than a linear function ( P I , a proportionate reciprocal difference occurs in insulin levels and responses in subjects with similar carbohydrate tolerance. We conclude that in human subjects with normal glucose tolerance and varying degrees of obesity, β-cell function varies quantitatively with differences in insulin sensitivity. Because the function governing this relationship is a hyperbola, when insulin sensitivity is high, large changes in insulin sensitivity produce relatively small changes in insulin levels and responses, whereas when insulin sensitivity is low, small changes in insulin sensitivity produce relatively large changes in insulin levels and responses. Percentile plots based on knowledge of this interaction are presented for evaluating β-cell function in populations and over time.

Saturable transport of insulin from plasma into the central nervous system of dogs in vivo. A mechanism for regulated insulin delivery to the brain.

Abstract: By acting in the central nervous system, circulating insulin may regulate food intake and body weight We have previously shown that the kinetics of insulin uptake from plasma into cerebrospinal fluid (CSF) can best be explained by passage through an intermediate compartment To determine if transport kinetics into this compartment were consistent with an insulin receptor-mediated transport process, we subjected overnight fasted, anesthetized dogs to euglycemic intravenous insulin infusions for 90 min over a wide range of plasma insulin levels (69-5,064 microU/ml) (n = 10) Plasma and CSF samples were collected over 8 h for determination of immunoreactive insulin levels, and the kinetics of insulin uptake from plasma into CSF were analyzed using a compartmental model with three components (plasma-->intermediate compartment-->CSF) By sampling frequently during rapid changes of plasma and CSF insulin levels, we were able to precisely estimate three parameters (average standard deviation 14%) characterizing the uptake of insulin from plasma, through the intermediate compartment and into CSF (k1k2); insulin entry into CSF and insulin clearance from the intermediate compartment (k2 + k3); and insulin clearance from CSF (k4) At physiologic plasma insulin levels (80 +/- 74 microU/ml), k1k2 was determined to be 107 x 10(-6) +/- 13 x 10(-6) min-2 With increasing plasma levels, however, k1k2 decreased progressively, being reduced sevenfold at supraphysiologic levels (5,064 microU/ml) The apparent KM of this saturation curve was 742 microU/ml (approximately 5 nM) In contrast, the rate constants for insulin removal from the intermediate compartment and from CSF did not vary with plasma insulin (k2 + k3 = 0011 +/- 00019 min-1 and k4 = 0046 +/- 0021 min-1) We conclude that delivery of plasma insulin into the central nervous system is saturable, and is likely facilitated by an insulin-receptor mediated transport process

Magnesium deficiency produces insulin resistance and increased thromboxane synthesis.

Abstract: Evidence suggests that magnesium deficiency may play an important role in cardiovascular disease. In this study, we evaluated the effects of a magnesium infusion and dietary-induced isolated magnes...

Reduced Sample Number for Calculation of Insulin Sensitivity and Glucose Effectiveness From the Minimal Model: Suitability for Use in Population Studies

Abstract: The FSIGT has been extensively applied to the minimal model of glucose kinetics to obtain noninvasive measures of Sl. The protocol has been modified by the addition of a bolus tolbutamide or insulin injection 20 min after glucose. Although the modified protocol has improved the Sl estimate, the method still requires a relatively large number of samples (n = 30). To reduce the total number of samples, we choose a sample schedule that minimizes the variance of the parameter estimates and the error in reconstructing the plasma insulin profile. With data from 10 subjects (BMI 30 +/- 7 kg/m2; Sl 0.9-10.2 x 10(-4) min-1.microU-1 x ml-1), a schedule consisting of 12 samples (0, 2, 4, 8, 19, 22, 30, 40, 50, 70, 90, and 180 min) was obtained. Estimates of Sl obtained from the reduced sampling schedule were then compared with those obtained with the full sampling schedule. In all 10 individuals, the Sl estimates were almost identical. A second, much larger data base consisting of 118 modified FSIGTs performed in 87 subjects (67 men, 20 women; BMI from 19.6 to 40 kg/m2 for men and 26.7 to 52.5 for women; Sl from 0.35 to 14.1 x 10(-4) min-1 x microU-1 x ml-1) was then used to independently assess the efficacy of the reduced sampling protocol. For this data base, the correlation between Sl, which was calculated from the full versus the reduced sampling schedule, was 0.95. The mean relative deviation was -1.5% (not significantly different from zero), and the SD of the relative deviation was 20.2%.(ABSTRACT TRUNCATED AT 250 WORDS)

Quantitation of measurement error with Optimal Segments: basis for adaptive time course smoothing

Abstract: We introduce a novel technique for estimating measurement error in time courses and other continuous curves. This error estimate is used to reconstruct the original (error-free) curve. The measurement error of the data is initially assumed, and the data are smoothed with "Optimal Segments" such that the smooth curve misses the data points by an average amount consistent with the assumed measurement error. Thus the differences between the smooth curve and the data points (the residuals) are tentatively assumed to represent the measurement error. This assumption is checked by testing the residuals for randomness. If the residuals are nonrandom, it is concluded that they do not resemble measurement error, and a new measurement error is assumed. This process continues reiteratively until a satisfactory (i.e., random) group of residuals is obtained. In this case the corresponding smooth curve is taken to represent the original curve. Monte Carlo simulations of selected typical situations demonstrated that this new method ("OOPSEG") estimates measurement error accurately and consistently in 30- and 15-point time courses (r = 0.91 and 0.78, respectively). Moreover, smooth curves calculated by OOPSEG were shown to accurately recreate (predict) original, error-free curves for a wide range of measurement errors (2-20%). We suggest that the ability to calculate measurement error and reconstruct the error-free shape of data curves has wide applicability in data analysis and experimental design.

Insulin sensitivity, insulin secretion and glucose effectiveness in diabetic and non-diabetic cirrhotic patients

Abstract: In cirrhotic patients with normal fasting glucose levels both insulin insensitivity and a blunted early insulin response to oral glucose are important determinants of the degree of intolerance to oral glucose. It is not known whether the ability of hyperglycaemia per se to enhance glucose disposal (glucose effectiveness) is also impaired. It is also unclear whether overt diabetes is due to: (1) more marked insulin insensitivity; (2) impaired insulin secretion; (3) reduced glucose effectiveness; or (4) a combination of these mechanisms. We used the "minimal model" to analyse the results of a 3-h intravenous glucose tolerance test to assess glucose effectiveness, insulin sensitivity and insulin responses in 12 non-diabetic cirrhotic patients, 8 diabetic cirrhotic patients and 10 normal control subjects. Fasting blood glucose levels were 4.8 +/- 0.2, 7.5 +/- 0.6 and 4.7 +/- 0.1 mmol/l, respectively. Fasting insulin and C-peptide levels were higher in both cirrhotic patient groups compared with control subjects. The glucose clearance between 6 and 19 min after i.v. glucose was lower in both cirrhotic groups (non-diabetic, 1.56 +/- 0.14, diabetic, 0.76 +/- 0.06, control subjects, 2.49 +/- 0.16 min-1%, both p < 0.001 vs control subjects). Serum insulin peaked at 3 and 23 min in the non-diabetic cirrhotic patients and control subjects; both peaks were higher in the non-diabetic cirrhotic patients and showed a delayed return to basal levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Dynamics of Hepatic and Peripheral Insulin Effects Suggest Common Rate-Limiting Step In Vivo

Abstract: This study compares the dynamics and sensitivity of hepatic and peripheral insulin action in conscious dogs. Glucose turnover was measured simultaneously by HOT GINF tracer methodology and by hepatic AV differences. SRIF was infused during euglycemic clamps to suppress endogenous insulin and glucagon secretion. Basal plasma glucagon levels were recreated by intraportal replacement (2 ng · min −1 · kg −1 ), and insulin was infused intraportally at 0, 3, 6, 10, or 20 pmol · min −1 · kg −1 for 3 h. Steady-state HGO and NHGO were suppressed by insulin with EC 50 s of 164 and 95 pM, respectively. As expected, these were lower than the EC 50 for R d stimulation (516 pM), demonstrating greater hepatic than peripheral insulin sensitivity. In contrast to sensitivity, dynamics for suppression of HGO and NHGO and for stimulation of R d by insulin were indistinguishable: half-times averaged 43 ± 5, 42 ± 9, and 45 ± 5 min, respectively ( P > 0.77). For all three variables, the half-time of insulin effect was independent of insulin dose ( P > 0.26). The striking similarity of the time courses for suppression of glucose production and stimulation of glucose uptake suggests that both effects are secondary manifestations of a single, rate-limiting phenomenon. We hypothesize this single gateway to Insulin action is transendothelial insulin transport, which we previously have shown to be rate limiting for insulin9s effect on glucose uptake in vivo.

Differences in physical growth of Aymara and Quechua children living at high altitude in Peru

Abstract: Physical growth of Amerindian children living in two Aymara and three Quechua peasant communities in the Andean highlands of southern Peru (altitude 3,810-3,840 m) was studied, taking into account differences in the microclimate, agronomic situation, and sociodemographic variables. Anthropometric measurements were taken in 395 children aged under 14 years of age in a sample of 151 families in these communities, who were surveyed for sociodemographic variables as well. Data on the land system were available for 77 families. In comparison with reference populations from the United States (NCHS) and The Netherlands, stature, weight, head circumference, and midupper arm circumference (but not weight for stature) in the sample children were reduced. Growth retardation increased after the age of 1 year. Stature and weight in the present sample were very similar compared with previously published data on growth of rural Aymara children living near Lake Titicaca in Bolivia. Head circumference, midupper arm circumference, and weight for stature were significantly larger in Aymara children compared with Quechua children. Land was significantly more fragmented in Aymara compared with Quechua families, but amount of land owned was not different. Perinatal and infant mortality was elevated in Aymara vs. Quechua communities. Most families in Aymara communities used protected drinking water. One Quechua community had a severe microclimate, grim economic outlook, and weak social cohesion. Children in this community showed significant reductions in weight and midupper arm circumference compared with their peers in the other communities. We conclude that (presumably nutritionally mediated) intervillage and Aymara-Quechua differences in childhood physical growth existed in this rural high-altitude population in Peru and were associated with microclimate and the village economy, sociodemographic factors, and differences in the land system.

On Insulin Action in Vivo: The Single Gateway Hypothesis

Abstract: It has become increasingly clear that insulin resistance plays an important role in the pathogenesis of chronic diseases of Westernized societies. Compelling evidence exists not only that insulin resistance is a risk factor for diabetes mellitus (1,2) but this metabolic characteristic is also associated with hypertension and atherosclerosis (3,4). In addition, there is evidence from the Pima Indians (5) and from high-risk offspring of two NIDDM parents (6) that insulin resistance is an inherited trait. Given that there must be one or more specific underlying mechanistic defects which are responsible for insulin resistance, and given its potential importance in the pathogenesis of chronic disease, it is incumbent upon us to continue to try to identify the cellular or molecular defects which underlie this condition.

Effects of Epinephrine on Insulin Secretion and Action in Humans: Interaction With Aging

Abstract: This study was designed to define the effects on glucose metabolism of small increases of plasma EPI, comparable to increases observed during physiological sympathoadrenal activation. This study was also designed to determine the effects of EPI on glucose metabolism in older adults, in whom changes in adrenergic responsiveness of several tissues were described. Tolbutamide-boosted IVGTTs were performed during intravenous infusions of saline (control) or EPI at 2.7, 5.5, and 10.9 mmol/min to achieve physiological levels of EPI in 7 young subjects (19-26 yr of age) and 7 old subjects (62-75 yr of age), all with a normal screening OGTT. IVGTT results were analyzed to determine the AIR and with the minimal model method of Bergman to determine SI and SG. A significant fall was observed in AIR, SI, and SG for all subjects, even with the lowest dose of EPI, which resulted in only a two- to threefold increase in plasma EPI. Older subjects had a delayed recovery from hyperglycemia during the EPI infusions, although we detected no significant differences between the young and old subjects in the ability of EPI to alter either acute phase insulin secretion or insulin action. In contrast, the impairment of SG by EPI appeared to be greater in the elderly. We conclude that small increases of plasma EPI can significantly affect determinants of glucose tolerance in both young and old people.

Thoracic Duct Lymph: Relative Contribution From Splanchnic and Muscle Tissue

Abstract: We have shown previously that thoracic duct lymph insulin dynamics are well correlated with tracer-determined whole-body glucose uptake and have suggested that thoracic duct lymph insulin is representative of insulin concentration in muscle interstitial fluid. However, thoracic duct lymph is comprised of interstitial fluid from all sub-thoracic tissue beds. To investigate the relative contribution of muscle interstitial fluid to total thoracic duct lymph flow, the distribution and elimination of [14C]inulin was investigated in eight experiments with conscious dogs. Both plasma and thoracic duct lymph were measured, and a three-compartment model that was hypothesized to consist of plasma, splanchnic interstitial fluid, and muscle interstitial fluid was identified. Identifications were performed with either a bolus protocol ( n = 4) or an infusion protocol ( n = 4), and the predicted [14C]inulin dynamics in the splanchnic and muscle interstitial fluid compartments were compared with measured values in thoracic duct lymph. Neither compartment predicted the thoracic duct [14C]inulin dynamics; however, a model based on a percentage contribution from each tissue bed fit the thoracic data well. The relative contribution of splanchnic interstitial fluid to the total thoracic duct lymph flow averaged 78 ± 5% for the bolus protocol and 54 ± 5% for the infusion protocol. Thus, we conclude that in the conscious animal, ∼25–50% of thoracic duct lymph originates from muscle interstitial fluid.