Biomedical subjects

R N Bergman

Publications and source records attributed to R N Bergman.

At least 145 records · Page 8Linked to original sources

PubMed1988

Defects in beta-cell function and insulin sensitivity in normoglycemic streptozocin-treated baboons: a model of preclinical insulin-dependent diabetes.

During the preclinical period of human insulin-dependent diabetes, both impaired pancreatic beta-cell function and increased insulin resistance are found, although normoglycemia is preserved. To better understand the changes in beta-cell function and insulin sensitivity that occur in preclinical insulin-dependent diabetes, we performed a panel of in vivo beta-cell function tests and measured insulin sensitivity in adolescent male baboons both in normal health and after a small dose of streptozocin which did not induce hyperglycemia. Nine animals were studied before (stage 1) and 1 week after receiving a low dose of streptozocin (stage 2). There was no change in fasting plasma glucose or insulin. The mean glucose disposal rate (Kg) remained within the normal range, but dropped from 2.0 +/- 0.2% +/- SE) to 1.2 +/- 0.1%/min (P less than 0.01), the acute insulin response to arginine (AIR(arg)) fell from 67.7 +/- 19.4 microU/mL (485.8 +/- 139.2 pmol/L) to 32.8 +/- 7.2 microU/mL (235.3 +/- 51.7 pmol/L; P less than 0.05), and the acute insulin response to glucose (AIR(gluc)) fell from 881 +/- 243 microU/mL.10 min (6321 +/- 1744 pmol/L.10 min) to 334 +/- 82 microU/mL.10 min (2396 +/- 588 pmol/L.10 min; P less than 0.01). The most dramatic change, however, was in the ability of hyperglycemia to potentiate AIR(arg) (expressed as the slope of potentiation). This was reduced by 94% from 1.8 +/- 0.5 to 0.1 +/- 0.1 (P less than 0.01), with almost no overlap in values between stages 1 and 2. Insulin sensitivity was also lower 1 week after streptozocin treatment. When the animals were restudied 8 weeks after streptozocin treatment (stage 3) most measures of beta-cell function were not significantly different from those in stage 1. The fasting plasma glucose level was 85.4 +/- 4.3 mg/dL (4.7 +/- 0.2 mmol/L), Kg was 1.8 +/- 0.3%/min, fasting plasma insulin was 35.9 +/- 8.5 microU/mL (257.6 +/- 61.0 pmol/L), AIR(arg) was 67.0 +/- 15.4 microU/mL (480.7 +/- 110.5 pmol/L), and AIR(gluc) was 615.3 +/- 265.3 microU/mL.10 min (4413 +/- 1901 pmol/L.10 min), and tissue insulin sensitivity was 2.7 +/- 0.4 x 10(4) min/microU.mL. These values show extensive overlap with those of stage 1, from which they are not significantly different. The slope of glucose potentiation, however, remained low in all animals at stage 3.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗

PubMed1988

Insulin resistance and beta-cell dysfunction in aging: the importance of dietary carbohydrate.

Aging is associated with a progressive decrease in glucose tolerance. This decrease is associated with insulin resistance and beta-cell dysfunction. This study was performed to evaluate the possible role of dietary factors in the glucose intolerance of aging. Two groups of men were studied: one young (Y; n = 8; age range, 18-36 yr) and one elderly (E; n = 10; age range, 65-82 yr). Frequently sampled iv glucose tolerance tests were performed in random order: 1) during ad libitum home dietary conditions; 2) after a 3- to 5-day regimen of very high (85%) carbohydrate intake; and 3) after a 3- to 5-day regimen of low (30%) carbohydrate intake (Y only). From the frequently sampled iv glucose tolerance test data, we calculated the glucose disappearance rate (Kg) and metabolic parameters according to the minimal model method, including the insulin sensitivity index (S1) and the first and second phase beta-cell responsivity to glucose (phi 1 and phi 2). The elderly men, while eating an ad libitum diet, were less tolerant to glucose than the young [mean Kg: E = 1.5 +/- 0.2% (+/- SE) min-1; Y = 2.3 +/- 0.3% min-1; P less than 0.025], had relative insulin resistance (mean Si: Y = 6.1 +/- 1.1; E = 2.4 +/- 0.7 min-1 10(-4)/(microU/mL) [0.85 +/- 0.15 vs. 0.33 +/- 0.10 min-1 10(-4)/(pmol/L)]; P less than 0.01), and lesser second phase beta-cell responsiveness to glucose (mean phi 2: Y = 18.5 +/- 3.6; E = 8.7 +/- 2.7 (microU/mL).min-2/(mg/dL) [2390 +/- 465 vs. 1120 +/- 349 (pmol/L).min-2/(mmol/L)]; P less than 0.05). A maximum improvement in Kg and S1 occurred at 41% carbohydrate feeding in the young men, whereas in the elderly men there was a significant increase in both of these parameters while eating the very high (85%) carbohydrate diet. Thus, the difference in glucose tolerance between groups was corrected by the very high carbohydrate diet (mean Kg: Y = 2.2 +/- 0.2%; E = 2.0 +/- 0.3%/min; P greater than 0.05), as was the age-related difference in insulin sensitivity (mean S1: Y = 5.6 +/- 1.2; E = 4.4 +/- 1.3 min-1 10(-4)/(microU/mL) [0.78 +/- 0.17 vs. 0.61 +/- 0.18 min-1 10(-4)/(pmol/L)]; P greater than 0.5).(ABSTRACT TRUNCATED AT 400 WORDS)

Adolescent↗

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↗

PubMed1988

Modeling in nutrition and metabolism.

Fundamentals of modeling of in vivo nutritional and metabolic systems are discussed. Emphasis is placed upon the potential usefulness of models, and the relationship between utility and model complexity. With the glucose regulating system used as a metaphoric example, the balance between available data and model simplification is drawn, with the goal of obtaining a representation of optimal complexity. From such an optimization procedure, it is argued that the maximum usefulness of models can be obtained with respect to the testing of specific physiological hypotheses, and the estimation of unmeasurable parameters or variables. The view is expressed that only with careful modeling procedures, in which principles of optimal complexity are applied, will the impact of models of nutritional systems be significant.

Adrenocorticotropic Hormone↗

PubMed1987

Fructose effect to suppress hepatic glycogen degradation.

The effect of fructose on glycogen degradation was examined by measuring the flux of 14C from prelabeled glycogen in perfused rat livers. During 2-h refeeding of 24-h-fasted rats, newly synthesized hepatic glycogen was labeled by intraperitoneal injection of [U-14C] galactose (0.1 mg and 0.02 microCi/g of body weight). The livers of refed rats were then perfused in a nonrecirculating fashion for an initial 30 min with glucose alone (10 mM) for the following 60 min with glucose (10 mM) without (n = 5) or with fructose (1, 2, or 10 mM; n = 5 for each). When livers were exposed to fructose, release of label into the perfusate immediately declined and remained markedly suppressed through the end of perfusion (p less than 0.05). The suppression was dose-dependent; at steady state (50-70 min), label release was suppressed 45, 64, and 72% by 1, 2, and 10 mM fructose, respectively (p less than 0.0001). Suppression was not accompanied by significant changes in the activities of glycogen synthase or phosphorylase assessed in vitro. These results suggest the existence of allosteric inhibition of phosphorylase in the presence of fructose. Fructose 1-phosphate (Fru-1-P) accumulated in proportion to fructose (0.11 +/- 0.01 without fructose, 0.86 +/- 0.03, 1.81 +/- 0.18, and 8.23 +/- 0.60 mumol/g of liver with 1, 2, and 10 mM fructose, respectively; p less than 0.0001). Maximum inhibition of label release was 82%; the Fru-1-P concentration for half inhibition was 0.57 mumol/g of liver, well within the concentration of Fru-1-P attained during refeeding. We conclude that fructose enhances net glycogen accumulation in liver by suppressing glycogenolysis and that the suppression is presumably caused by allosteric inhibition of phosphorylase by Fru-1-P.

Animals↗

PubMed1987

Insulin sensitivity in the intact organism.

Insulin resistance is a classic characteristic of type II diabetes. Precise quantification of insulin sensitivity in vivo is essential for elucidation of the pathogenesis of observed glucose intolerance. The euglycaemic glucose clamp of Andres and colleagues assesses insulin action by disrupting the negative feedback relationship of glucose and insulin. Insulin is infused, but euglycaemia is maintained by exogenous glucose infusion (GINF). At steady state, GINF (M) represents total insulin action, i.e. suppression of hepatic glucose output (HGO) plus acceleration of peripheral uptake (Rd). Coupled with the isotope dilution techniques of Steele et al, these hepatic and peripheral effects can be partitioned, although this approach may underestimate HGO and Rd. Modifications of the Steele method may be required for more reliable quantification of glucose turnover. The dose-response relationship between insulin and Rd also provides a measure of sensitivity from the glucose clamp: the ED50 (and Rdmax), analogous to the Km and Vmax of Michaelis-Menten analysis. However, extensive labour requirements, cost and difficulties in ED50 estimation limit its widespread use. Glucose clearance (Rd/G) has also been used to assess insulin sensitivity in subjects of differing glycaemia, but because it fails to rise in proportion to glucose it is an inappropriate measure. Hence, we have introduced the insulin sensitivity index SIP(clamp), defined as the action of insulin to increase glucose clearance (delta Rd/(G delta I], which is independent of prevailing glycaemia and insulinaemia. Lastly, we proposed the minimal model method, which determines insulin sensitivity (SI) from analysis of the simple intravenous glucose tolerance test (IVGTT). By adding tolbutamide injection after glucose, the resultant model-based SI is equivalent to SIP(clamp). Furthermore, minimal model analysis will also yield SG, the parameter of insulin-independent glucose disappearance. We conclude that assessment of insulin sensitivity, whilst important, must be considered in the context of its relation to pancreatic function and insulin-dependent glucose disappearance. Only a clear understanding of the complex interrelation of these factors will lead to elucidation of the mechanisms underlying glucose intolerance.

Constriction↗

PubMed1987

Patterns of glycogen turnover in liver characterized by computer modeling.

We used a computer model of liver glycogen turnover to reexamine the data of Devos and Hers, who reported the time course of accumulation in and loss from glycogen of label originating in [1-14C]galactose injected at different times after the start of refeeding of 40-h fasted mice or rats. In the present study computer representation of individual glycogen molecules was utilized to account for growth and degradation of glycogen according to specific hypothetical patterns. Using this model we could predict the accumulation and localization within glycogen of labeled glucose residues and compare the predictions with the previously published data. We considered three specific hypotheses of glycogen accumulation during refeeding: 1) simultaneous, 2) sequential, and 3) accelerating growth. Hypothetical patterns of glycogen degradation were 1) ordered and 2) random degradation. The pattern of glycogen synthesis consistent with experimental data was a steadily increasing number of growing glycogen molecules, whereas during degradation glycogen molecules are exposed to degrading enzymes randomly, rather than in a specific reverse order of synthesis. These patterns predict the existence of a specific mechanism for the steadily increasing "seeding" of new glycogen molecules during synthesis.

Computer Simulation↗

PubMed1987

Modified protocols improve insulin sensitivity estimation using the minimal model.

We attempted to improve the precision of the estimation of insulin sensitivity (S1) from the minimal model technique by modifying insulin dynamics during a frequently sampled intravenous glucose tolerance test (FSIGT). Tolbutamide and somatostatin (SRIF) were used to change the insulin dynamics without directly affecting insulin sensitivity. Injection of tolbutamide (100 mg) at t = 20 min provoked an immediate secondary peak in insulin response, resulting in a greater integrated incremental insulin than the standard FSIGT. SRIF, injected at t = -1 min, delayed insulin secretion in proportion to the dose without any change in magnitude. Computer simulation was used to assess the precision of S1 estimation. Insulin dynamics from both standard and modified protocols were adjusted in magnitude, with the shape unchanged and analyzed to determine the effect of the magnitude of insulin response. Fractional standard deviation was reduced from 73% with the standard insulin profile to 23% with tolbutamide and 18% with the highest dose of SRIF. In addition, the fractional standard deviation of S1 estimates decreased exponentially with increasing magnitude of insulin response. Modified FSIGTs require a smaller insulin response than the standard protocol to achieve the same precision.

Animals↗

PubMed1987

Equivalence of the insulin sensitivity index in man derived by the minimal model method and the euglycemic glucose clamp.

Studies were done to determine whether the minimal model approach and the glucose clamp measure equivalent indices of insulin action. Euglycemic glucose clamps (glucose, G: 85 mg/dl) were performed at two rates of insulin (I) infusion (15 and 40 mU/min per m2) in 10 subjects (body mass index, BMI, from 21 to 41 kg/m2). Insulin sensitivity index (SI) from clamps varied from 0.15 to 3.15 (mean: 1.87 +/- 0.36 X 10(-2) dl/[min per m2] per microU/ml), and declined linearly with increasing adiposity (versus BMI: r = -0.97; P less than 0.001). SI from modeling the modified frequently sampled intravenous tolerance test varied from 0.66 to 7.34 X 10(-4) min-1 per microU/ml, and was strongly correlated with SIP(clamp) (r = 0.89; P less than 0.001). SI and SIP(clamp) were similar (0.046 +/- 0.008 vs. 0.037 +/- 0.007 dl/min per microU/ml, P greater than 0.35); the relation had a slope not different from unity (1.05 P greater than 0.70) and passed through the origin (P greater than 0.40). However, on a period basis, SI exceeded SIP(clamp) slightly, due to inhibition of hepatic glucose output during the FSIGT, not included in SIP(clamp). These methods are equivalent for assessment of overall insulin sensitivity in normal and insulin-resistant nondiabetic subjects.

Adult↗

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

Calculated pattern of intraportal insulin appearance without independent assessment of C-peptide kinetics.

Prehepatic beta-cell insulin release can be calculated with C-peptide measurements, but this requires independent determination of kinetics of C-peptide disappearance from plasma. We introduce an approach by which a prehepatic insulin release pattern is calculated from plasma insulin and C-peptide, without separate C-peptide kinetic analysis. Human insulin and C-peptide were infused intraportally into conscious dogs (n = 11) at equimolar rates; endogenous insulin and C-peptide release were suppressed with somatostatin (0.8 micrograms . kg-1 . min-1). Insulin and C-peptide were infused at basal and equimolar rates (range 19-72 pmol/min in dogs), and the infusions were slowly increased, in stepwise fashion, to a maximum at 60 min (range 152-613 pmol/min) and subsequently renormalized at either 85 (n = 6) or 195 (n = 5) min. Plasma insulin and C-peptide measurements were described simultaneously by a composite model of insulin and C-peptide plasma kinetics, with the molar intraportal appearance rate due to the infusion R(t) as an unknown input for both insulin and C-peptide catabolism. The model assumes one-compartment disappearance kinetics for both peptides. Fitting the model to the measured insulin and C-peptide data, we were able to compute the insulin-appearance pattern accurately for every experiment; calculated and actual secretion rates were highly correlated (r = .93-.97) and had very similar temporal patterns. Also calculated were the fractional disappearance rates for human insulin (t1/2 = 6.9 min) and C-peptide (t1/2 = 14 min) in the dog, as well as the C-peptide distribution volume (12.3 +/- 0.5% body wt).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1987

Beta-cell function and insulin sensitivity in nondiabetic HLA-identical siblings of insulin-dependent diabetics.

Insulin secretion and insulin sensitivity were compared in 12 HLA-identical siblings of insulin-dependent diabetics and nondiabetic controls. Only the maximum acute insulin response to intravenous arginine was lower in the siblings than in the matched controls (P less than .05); other measures of insulin secretion, including the acute insulin response to glucose or arginine, the second-phase insulin response to glucose, and the slope of glucose potentiation, were not significantly different. Insulin sensitivity, derived from an intravenous glucose tolerance test with a minimal-modeling technique, was lower in the siblings (P less than .01). In a large group of nondiabetic controls of various adiposity, insulin secretion and insulin sensitivity were inversely related. In view of the difference in insulin sensitivity between siblings and matched controls, a direct comparison of beta-cell function tests may be inappropriate, and the measures of insulin secretion were compared with those of nondiabetics when adjusted for differences in insulin sensitivity. This analysis revealed that all measures of insulin secretion were significantly lower in the siblings. We conclude that HLA-identical siblings of insulin-dependent diabetics show evidence of both insulin resistance and impaired beta-cell function and that analysis of beta-cell function in relation to insulin sensitivity shows a greater frequency of beta-cell secretory abnormalities than previously appreciated.

Adult↗

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↗

PubMed1986

Synergism of glucose and fructose in net glycogen synthesis in perfused rat livers.

Synergism of glucose and fructose in net glycogen synthesis was studied in perfused livers from 24-h fasted rats. With either glucose or fructose alone, net glycogen deposition did not occur (p greater than 0.10 for each), whereas the addition of both together resulted in significant glycogen accumulation (net glycogen accumulation was 0.21 +/- 0.03 mumol of glucose/g of liver/min at 2 mM fructose and 30 mM glucose, p less than 0.001). To better understand this synergism, intermediary substrate levels were compared at steady state with various glucose levels in the absence and in the presence of 2 mM fructose. Independent of fructose, hepatic glucose and glucose 6-phosphate increased proportionally when glucose level in the medium was raised (r = 0.86, p less than 0.001). Unlike glucose 6-phosphate, UDP-glucose did not consistently increase with glucose (p greater than 0.10); in fact, there was a small decrease at a very high glucose level (30 mM), a result consistent with the well-established activation of glycogen synthase by glucose. With elevated glucose, the level of glucose 6-phosphate was strongly correlated with glycogen content (r = 0.71, p less than 0.01, slope = 32). Adding fructose increased the "efficiency" of glucose 6-phosphate to glycogen conversion: the effect of a given increment in glucose 6-phosphate upon glycogen accumulation was increased 2.6-fold (r = 0.73, p less than 0.01, slope = 86). A kinetic modeling approach was used to investigate the mechanisms by which fructose synergized glycogen accumulation when glucose was elevated. Based on steady-state hepatic substrate levels, net hepatic glucose output, and net glycogen synthesis rate, the model estimated the rate constants of major enzymes and individual fluxes in the glycogen metabolic pathway. Modeling analysis is consistent with the following scenario: glycogen synthase is activated by glucose, whereas glucose-6-phosphatase was inhibited. In addition, the model supports the hypothesis that fructose synergizes net glycogen accumulation due to suppression of phosphorylase. Overall, our analysis suggests that glucose enhances the metabolic flux to glycogen by inducing a build up of glucose 6-phosphate via combined effects of mass action and glucose-6-phosphatase inhibition and activating glycogen synthase and that fructose enhances glycogen accumulation by retaining glycogen via phosphorylase inhibition.

Animals↗

PubMed1986

Pathophysiology of malnutrition in the adult cancer patient.

A number of common metastatic cancers are associated with marked weight loss at the time of diagnosis. Cancer patients with weight loss at the time of diagnosis have decreased mean survival compared to similar cancer patients without weight loss. Provision of excess calories alone does not appear to change median survival in patients with advanced cancer and many patients either maintain body weight or lose weight while receiving calories which would be predicted to result in weight gain. The authors recently have extended their studies to head and neck cancer patients without detectable metastatic disease in order to detect systemic metabolic effects of a localized tumor. These patients failed to gain weight despite the administration of apparently adequate calories by continuous enteral alimentation. Abnormalities of carbohydrate metabolism with secondary effects on fat and protein metabolism have been identified in several populations of patients with common cancers. These abnormalities offer potential points of intervention which may enhance nutritional therapy as rehabilitation and as a potential biological modifier of the response of specific cancers to chemotherapy, radiation therapy, or surgery.

Adult↗

PubMed1986

MINMOD: a computer program to calculate insulin sensitivity and pancreatic responsivity from the frequently sampled intravenous glucose tolerance test.

Insulin sensitivity and pancreatic responsivity are the two main factors controlling glucose tolerance. We have proposed a method for measuring these two factors, using computer analysis of a frequently-sampled intravenous glucose tolerance test (FSIGT). This 'minimal modelling approach' fits two mathematical models with FSIGT glucose and insulin data: one of glucose disappearance and one of insulin kinetics. MINMOD is the computer program which identifies the model parameters for each individual. A nonlinear least squares estimation technique is used, employing a gradient-type of estimation algorithm, and the first derivatives (not known analytically) are computed according to the 'sensitivity approach'. The program yields the parameter estimates and the precision of their estimation. From the model parameters, it is possible to extract four indices: SG, the ability of glucose per se to enhance its own disappearance at basal insulin, SI, the tissue insulin sensitivity index, phi 1, first phase pancreatic responsivity, and phi 2, second phase pancreatic responsivity. These four characteristic parameters have been shown to represent an integrated metabolic portrait of a single individual.

Computer Simulation↗

PubMed1986

Oscillations enhance the efficiency and stability of glucose disposal.

Oscillations in plasma concentrations of glucose and insulin as well as the rates of glucose disposal by liver and periphery have been observed in dogs during states of net glucose anabolism. To examine whether the existence of oscillations is important for efficient disposal of nutrients, we compared constant glucose infusion (with plasma glucose and insulin oscillations) to experiments in which glucose oscillations were suppressed using the glucose clamp. Mean glucose levels attained were the same for the two protocols (142 +/- 2 for constant glucose infusion at 10.8 +/- 0.4 mg X kg-1 X min-1, 144 +/- 1 mg/dl for clamps, P = 0.35). Despite matched mean glucose, integrated plasma insulin was 36.3 +/- 3.2 mU X ml-1 X 600 min in controls but higher in clamps (53.8 +/- 9.1 mU X ml-1 X 600 min, P = 0.017). Despite 48% higher insulin, total glucose disposed during the 10-h clamps was not greater than during constant glucose infusion (clamps, 162.1 +/- 10.7 g/600 min; infusions, 154.4 +/- 7.5 g/600 min; P = 0.19). These studies demonstrate that the presence of coordinated oscillations in glucose and insulin, during glucose infusion, are associated with more efficient disposal of glucose than when oscillations are suppressed. The results suggest that oscillations may play an important role in the efficient disposal of administered nutrient and may be an important component of normal glucose tolerance.

Animals↗

PubMed1986

Putative hypothalamic glucoreceptors play no essential role in the response to moderate hypoglycemia.

The response to insulin-induced hypoglycemia includes increased plasma levels of glucagon, epinephrine, norepinephrine, cortisol, and growth hormone. This integrated response is thought to be mediated via sympathetic afferent pathways emanating from the ventromedial hypothalamus. However, the precise loci of the receptors that sense glucopenia are not known. In this study, we investigated the importance of putative forebrain glucoreceptors to the systemic response to hypoglycemia. Three protocols were performed. Protocol 1: the systemic response was observed in conscious dogs to hypoglycemia induced by infusion of insulin at a high rate (150 mU/min). Protocol 2: the effect of concomitant bilateral, intracarotid glucose infusion on the response to intravenous insulin was examined. Intracarotid glucose infusion rates were chosen to yield central euglycemia in the face of systemic hypoglycemia. Protocol 3: as a control for protocol 2, glucose was infused at low rates into the systemic circulation, yielding hypoglycemia in both central and systemic blood. When insulin was infused at 150 mU/min, without glucose replacement (protocol 1; N = 6), plasma insulin increased from 14 +/- 3 to 335 +/- 35 microU/ml at 60 min (P less than 0.001). Glucose fell from basal (104 +/- 3 mg/dl) to 38 +/- 3 mg/dl (P less than 0.001). Significant increases were observed in epinephrine (basal, B: 63 +/- 8; steady state, SS: 1762 +/- 582 pg/ml; P less than 0.007), norepinephrine (B: 209 +/- 33, SS: 650 +/- 133 pg/ml; P less than 0.01), and glucagon (B: 256 +/- 35, SS: 467 +/- 35 pg/ml; P less than 0.03). In addition, endogenous glucose production (Ra) increased from 72 +/- 4 to 108 +/- 9 mg/min (P less than 0.02) despite frank hyperinsulinemia. Infusion glucose into the carotid arteries at 204 +/- 10 mg/min (protocol 2; N = 7) during a 4-h systemic insulin infusion was sufficient to prevent jugular hypoglycemia [jugular glucose, Gj, B: 100 +/- 3, SS (90-160 min): 101 +/- 3 mg/dl; P greater than 0.70], but not peripheral hypoglycemia (Gp, B: 102 +/- 2, SS: 55 +/- 3 mg/dl; P less than 0.001). Despite carotid glucose replacement, counterregulatory responses were still observed in epinephrine (B: 98 +/- 14, SS: 466 +/- 127 pg/ml; P less than 0.04) and norepinephrine (B: 213 +/- 19, SS: 474 +/- 133 pg/ml; P less than 0.05).(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗