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Biomedical subjects

D Porte

Publications and source records attributed to D Porte.

At least 37 records · Page 2Linked to original sources
PubMed1995

Intraventricular insulin enhances the meal-suppressive efficacy of intraventricular cholecystokinin octapeptide in the baboon.

Chronic intraventricular (IVT) insulin infusion suppresses food intake and body weight in the baboon. It has been hypothesized that one mechanism of this action may be enhancement of the effectiveness of satiety factors that regulate meal size. This hypothesis was supported by prior demonstration of a shift in the meal-suppressive effectiveness of cholecystokinin octapeptide (CCK-8) which was given intravenously. The authors tested the effectiveness of a near threshold dose of CCK-8 (25 ng/kg) given via the lateral ventricles (IVT) prior to a 30-min meal, while baboons were chronically infused with cerebrospinal fluid or insulin (100 microU/day) via the lateral ventricles. IVT CCK-8 infusion resulted in meal size changes of -44 +/- 7% and -75 +/- 9% in the absence and presence of insulin, respectively; this was observed in each of the three animals studied. These results provide further support for the hypothesis that IVT insulin can interact with other, meal-regulatory, peptides.

Animals↗
PubMed1995

The key role of islet dysfunction in type II diabetes mellitus.

Fasting plasma glucose levels are constant from day to day in normal individuals. This constancy is due to a close co-ordination between glucose production by the liver and glucose uptake in peripheral tissues. This review focusses on the key role of the endocrine pancreas alpha- and beta-cells to provide this co-ordination. Non-insulin-dependent diabetes mellitus (NIDDM) is characterized by fasting hyperglycemia. The degree of fasting hyperglycemia, in turn, is correlated with the basal rate of hepatic glucose production. This increased rate of glucose release by the liver results in part from impaired hepatic sensitivity to insulin, but is largely due to reduced insulin secretion and increased glucagon secretion. Though basal immunoreactive insulin and glucagon levels in patients with NIDDM may appear normal when compared to those of healthy individuals, islet function testing at matched glucose levels reveals impairments of basal, steady-state, and stimulated insulin and glucagon secretion due to a reduction in beta-cell secretory capacity and a reduced ability of glucose to suppress glucagon release. The degree of impaired beta-cell responsiveness to glucose is closely related to the degree of fasting hyperglycemia, but in a curvilinear fashion. Thus, islet alpha- and beta-cell function is reduced by more than 50% in NIDDM by the time that clinical fasting hyperglycemia develops (140 mg/dL). The efficiency of glucose uptake by the peripheral tissues is also impaired due to a combination of decreased insulin secretion and defective cellular insulin action.(ABSTRACT TRUNCATED AT 250 WORDS)

Diabetes Mellitus, Type 2↗
PubMed1994

Reliability of error estimates from the minimal model: implications for measurements in physiological studies.

MINMOD provides an estimate of the error in the insulin sensitivity index (SI) and glucose effectiveness at basal insulin (Sg) as the fractional standard deviation (FSD). The validity of the FSD estimate has not been assessed in a large number of human studies, nor has a comparison of the accuracies achievable using the two different intravenous glucose tolerance test (IVGTT) protocols (glucose only and tolbutamide protocol) been performed. To address these two issues, we obtained the FSD value and performed Monte Carlo simulations for 237 IVGTT studies. The FSD underestimated the true error as determined as the coefficient of variation from Monte Carlo simulation (COV-MC) with the ratio of COV-MC to FSD being 3.07 +/- 0.20 (mean +/- SE) for SI using the tolbutamide protocol. Additionally, the mean COV-MC for glucose-only protocol was approximately two to three times that for the tolbutamide protocol for both SI and Sg. We conclude that FSD underestimates the true error in SI and Sg. Additionally, more accurate results are obtained from the tolbutamide protocol than with the glucose-only protocol.

Computer Simulation↗
PubMed1994

Glucokinase gene variations in Japanese-Americans with a family history of NIDDM.

OBJECTIVE: To determine if sequence variants in the glucokinase (GCK) gene contribute to the high risk of impaired glucose metabolism in Japanese-Americans and whether the gene sequence differs between Japanese-Americans and Caucasians. RESEARCH DESIGN AND METHODS: Forty-seven unrelated Japanese-Americans with one or more first-degree relatives with non-insulin-dependent diabetes mellitus (NIDDM) were selected, irrespective of glucose tolerance status. By World Health Organization criteria, 13 had normal glucose tolerance, 11 had impaired glucose tolerance, and 23 had NIDDM. Variations in the GCK gene were identified by single-strand conformation polymorphism analysis and sequenced using standard techniques. RESULTS: Six variants of the GCK gene were identified in a total of 21 subjects: 1) a G--> A substitution at nucleotide -30 in the beta-cell-specific promoter; 2) an A--> G substitution at nucleotide 244 in the 5'-untranslated region (5'-UTR) of exon 1a; 3) a C--> G substitution at nucleotide 403 in the 5'-UTR of exon 1a; 4) a G--> A variant 13 base pair (bp) 5' to the intron 3 exon 4 junction; 5) a silent substitution in the third base of codon 145 in exon 4; and 6) a C--> T substitution 8 bp 3' to the exon 9 intron 9 junction. None of these variations would be expected to affect the structure of the GCK enzyme. While none of these variants were significantly associated with IGT or NIDDM, a nonsignificant increase in the beta-cell promoter variant was observed in subjects with abnormal glucose tolerance. No uniform sequence differences in the GCK gene were identified between Japanese-American and Caucasian-American subjects. CONCLUSIONS: Mutations affecting the amino acid sequence of GCK do not account for the increased incidence of impaired glucose metabolism in Japanese-Americans, and the gene sequence does not uniformly differ from that in Caucasians.

Adult↗
PubMed1993

Effect of diet-induced obesity and experimental hyperinsulinemia on insulin uptake into CSF of the rat.

We examined the hypothesis that the uptake of plasma insulin into cerebrospinal fluid (CSF) is saturable in two rat models. Dietary obese and control female Osborne Mendel rats received 24-h infusions of vehicle or insulin. CSF insulin levels in cafeteria- and chow-fed rats were comparable at all levels of plasma insulin (4.5 +/- 2.8, 7.6 +/- 2.4, and 23.9 +/- 6.4 microU/ml in cafeteria diet vs. 4.5 +/- 0.9, 6.8 +/- 1.1, and 17.0 +/- 4.0 microU/ml in chow rats). CSF insulin uptake as a percentage of plasma insulin decreased with increased plasma insulin in both groups. A similar relationship was observed in Wistar rats receiving 6-day infusions of vehicle or insulin (plasma insulin = 55 +/- 12 vs. 365 +/- 98 microU/ml; CSF/plasma insulin ratio = 0.022 +/- .007 vs. 0.013 +/- .006, respectively). Hyperinsulinemic Wistar rats did not demonstrate decreased brain capillary insulin binding vs. vehicle-infused controls. The results suggest that a saturable transport process contributes insulin transport into CSF in normal rats and that this process is not altered by moderate diet-induced obesity or hyperinsulinemia per se.

Animals↗
PubMed1993

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

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 +/- 7.4 microU/ml), k1k2 was determined to be 10.7 x 10(-6) +/- 1.3 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 = 0.011 +/- 0.0019 min-1 and k4 = 0.046 +/- 0.021 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.

Animals↗
PubMed1993

Effect of glucocorticoid and growth hormone treatment on proinsulin levels in humans.

Treatment with glucocorticoids is associated with a disproportionate elevation in the PI/IRI ratio. To determine whether growth hormone--another agent capable of producing insulin resistance and changing B-cell function--also alters the PI/IRI ratio and whether growth hormone and glucocorticoids have a synergistic effect on PI and IRI levels, we examined these variables in four groups of young healthy subjects (n = 8/group) after 7 days of treatment with placebo, prednisone (0.8 mg.kg-1 x day-1), rhGH (0.1 mg.kg-1 x day-1), and the combination of prednisone and rhGH. Fasting plasma glucose levels increased significantly above those of the control group in subjects receiving prednisone or prednisone and rhGH but not in subjects receiving rhGH alone. The basal concentration of IRI increased in response to prednisone, rhGH, and the combination of prednisone and rhGH. However, this increase in IRI was largely due to an increase in PI, so that the PI/IRI ratio increased from 14.7 +/- 2.4% in control subjects to 33.9 +/- 5.3% in subjects on prednisone (P < 0.005), 40.9 +/- 4.3% in individuals receiving rhGH (P < 0.001 vs. control subjects), and 58.1 +/- 9.2% in subjects receiving both prednisone and rhGH (P < 0.001 vs. control subjects). We suggest that this change in PI/IRI with glucocorticoid and growth hormone treatment may be due to an alteration in B-cell synthesis or release of PI. This change in the PI/IRI ratio is not dependent on fasting hyperglycemia but may contribute to the hyperglycemia often observed with these agents. Furthermore, these data show that IRI is not a reliable indicator of true insulin levels or insulin sensitivity in either growth hormone- or glucocorticoid-treated subjects.

Adult↗
PubMed1992

Isolation and characterization of LexA mutant repressors with enhanced DNA binding affinity.

The LexA repressor from Escherichia coli is a sequence-specific DNA binding protein that shows no pronounced sequence homology with any of the known structural motifs involved in DNA binding. Since little is known about how this protein interacts with DNA, we have selected and characterized a great number of intragenic, second-site mutations which restored at least partially the activity of LexA mutant repressors deficient in DNA binding. In 47 cases, the suppressor effect of these mutations was due to an Ind- phenotype leading presumably to a stabilization of the mutant protein. With one exception, these second-site mutations are all found in a small cluster (amino acid residues 80 to 85) including the LexA cleavage site between amino acid residues 84 and 85 and include both already known Ind- mutations as well as new variants like GN80, GS80, VL82 and AV84. The remaining 26 independently isolated second-site suppressor mutations all mapped within the amino-terminal DNA binding domain of LexA, at positions 22 (situated in the turn between helix 1 and helix 2) and positions 57, 59, 62, 71 and 73. These latter amino acid residues are all found beyond helix 3, in a region where we have previously identified a cluster of LexA (Def) mutant repressors. In several cases the parental LexA (Def) mutation has been removed by subcloning or site-directed mutagenesis. With one exception, these LexA variants show tighter in vivo repression than the LexA wild-type repressor. The most strongly improved variant (LexA EK71, i.e. Glu71----Lys) that shows an about threefold increased repression rate in vivo, was purified and its binding to a short consensus operator DNA fragment studied using a modified nitrocellulose filter binding assay. As expected from the in vivo data, LexA EK71 interacts more tightly with both operator and (more dramatically) with non-operator DNA. A determination of the equilibrium association constants of LexA EK71 and LexA wild-type as a function of monovalent salt concentration suggests that LexA EK71 might form an additional ionic interaction with operator DNA as compared to the LexA wild-type repressor. A comparison of the binding of LexA to a non-operator DNA fragment further shows that LexA interacts with the consensus operator very selectively with a specificity factor of Ks/Kns of 1.4 x 10(6) under near-physiological salt conditions.

Amino Acid Sequence↗
PubMed1992

Short-term hyperglycemia and hyperinsulinemia improve insulin action but do not alter glucose action in normal humans.

Tissue glucose uptake occurs by insulin-dependent and insulin-independent mechanisms. To evaluate the effect of mild hyperglycemia and hyperinsulinemia on the parameters responsible for glucose disposal, glucose (1.17 mmol/min) or saline was infused into six healthy male subjects (age 25-38 yr, body mass index 22.1-26.3 kg/m2) for 24 h. Thereafter, while the infusion continued, indexes of insulin sensitivity (SI), glucose effectiveness at basal insulin (SG), basal insulin effect (BIE = SI x basal insulin), and glucose effectiveness at zero insulin (GEZI = SG - BIE) were measured using Bergman's minimal model of insulin action. GEZI provides a measure of the efficiency of glucose to accelerate its own disposal independent of insulin. Twenty-four hours of glucose infusion increased the basal plasma glucose (5.1 +/- 0.1 to 6.4 +/- 0.2 mM, P = 0.001) and insulin (79 +/- 8 to 174 +/- 31 pM, P less than 0.05) levels. Hyperglycemia was also associated with an increase in the insulin response, predominantly in the second-phase component (138 +/- 31 to 258 +/- 66 pM, P less than 0.05). SI (4.8 +/- 1.0 to 8.2 +/- 1.6 x 10(-5) min-1.pM-1, P less than 0.05) and SG (1.7 +/- 0.1 to 2.5 +/- 0.3 x 10(-2) min-1, P less than 0.05) both increased after glucose infusion. The increase in SG was entirely due to the combined increase in basal insulin and insulin sensitivity (BIE 0.4 +/- 0.1 to 1.2 +/- 0.1 x 10(-2) min-1, P = 0.001) since GEZI did not change at all (1.3 +/- 0.1 vs. 1.3 +/- 0.3 x 10(-2) min-1, P = not significant). From these data we conclude that, in normal subjects, the mild hyperglycemia and hyperinsulinemia occurring during a prolonged glucose infusion improves glucose disposal in the basal state by increasing insulin secretion and insulin sensitivity but does not enhance glucose effectiveness independent of insulin. Both of these changes thus tend to minimize the development of hyperglycemia.

Adult↗
PubMed1992

Intraventricular CCK-8 reduces single meal size in the baboon by interaction with type-A CCK receptors.

Intraventricular cholecystokinin COOH-terminal octapeptide (CCK-8) decreases meal size in the meal-trained baboon. In the present study, we tested whether this action is mediated by CCK-A receptors, CCK-B receptors, or both. Intraventricular administration of the selective CCK-A receptor agonist A71623 at 1 and 10 nmol/kg suppressed 30-min meal size 69 +/- 22% and 75 +/- 7%, respectively. Additionally, intraventricular A71623 was equipotent to CCK-8 at 1 nmol/kg (% suppression of meal by CCK = 59 +/- 17). However, intraventricular administration of the CCK-B receptor agonist A63387 at 10 nmol/kg had no effect on 30-min meal size (% suppression = 18 +/- 29). Intravenous administration of 10 nmol/kg A71623 did not result in an alteration of meal size, but prandial plasma insulin and glucose responses were delayed and blunted. Basal plasma insulin levels doubled after intravenous administration of A71623. Both behavioral and metabolic responses to A71623 in the baboon are virtually identical to those we have previously observed after CCK-8 treatment. Thus we conclude that the predominant receptor population with which intraventricular CCK-8 interacts are type-A CCK receptors that are accessible to the ventricular system of the baboon.

Animals↗
PubMed1992

Effect of insulin resistance and hyperglycemia on proinsulin release in a primate model of diabetes mellitus.

An elevated plasma proinsulin (PI) to immunoreactive insulin (IRI) ratio occurs in relatives of patients with insulin-dependent diabetes mellitus and in subjects with non-insulin-dependent diabetes mellitus. To determine whether this alteration is the result of B-cell dysfunction and/or insulin resistance, we infused nicotinic acid for 3 weeks to produce insulin resistance in five adolescent male baboons before and after the administration of streptozocin (200 mg/kg). We measured basal PI and IRI levels and the acute incremental PI (APIR) and IRI (AIRIR) responses to iv arginine. The quantity of IRI comprised of PI was calculated in the basal state (PI/IRI) and following arginine injection (APIR/AIRIR). Streptozocin administration did not change the fasting plasma glucose (FPG) compared to that in the normal animals (4.7 +/- 0.3 vs. 4.3 +/- 0.2 mM) but raised the PI/IRI (16.4 +/- 3.4 vs. 5.9 +/- 1.7%) and APIR/AIRIR (7.1 +/- 1.0 vs. 2.8 +/- 1.0%) due to a concurrent reduction in IRI and increase in PI concentrations. The induction of experimental insulin resistance with nicotinic acid in the normal animals had no effect on the FPG (4.4 +/- 0.2 mM) but in the streptozocin treated animals, fasting hyperglycemia (8.3 +/- 1.7 mM) developed. Neither the basal PI/IRI (10.2 +/- 2.2%) or the APIR/AIRIR (2.3 +/- 0.6%) increased in the insulin-resistant streptozocin animals thus being no different to that of normal control animals before or during experimental insulin resistance. We conclude that disproportionate proinsulinemia is a manifestation of B-cell damage from streptozocin which is not exacerbated by insulin resistance or hyperglycemia.

Animals↗
PubMed1991

Mechanisms for hyperglycemia in type II diabetes mellitus: therapeutic implications for sulfonylurea treatment--an update.

Non-insulin-dependent diabetes mellitus (NIDDM) is characterized by fasting hyperglycemia associated with defects in the pancreatic islet, the liver, and the peripheral tissues, which together comprise a feedback loop responsible for maintenance of glucose homeostasis. This review focuses on the key role of the endocrine pancreas alpha and beta cells to coordinate glucose output from the liver with glucose utilization. The basal rate of hepatic glucose utilization. The basal rate of hepatic glucose production is elevated in subjects with NIDDM, and this is positively correlated with the degree of fasting hyperglycemia. This increased rate of glucose release by the liver results from impaired hepatic sensitivity to insulin, reduced insulin secretion, and increased glucagon secretion. Though basal immunoreactive insulin levels in patients with NIDDM may appear normal when compared with healthy individuals, islet function testing at matched glucose levels reveals impairments of basal, steady-state, and stimulated insulin secretion due to a reduction in beta-cell secretory capacity and a reduced ability of glucose to suppress glucagon. The degree of impaired beta-cell responsiveness to glucose is closely related to the degree of fasting hyperglycemia but in a curvilinear fashion. The efficiency of glucose uptake by the peripheral tissues is also impaired due to a combination of decreased insulin secretion and defective cellular insulin action. This impairment becomes more important to the hyperglycemia as the islet alpha- and beta-cell function declines. Therapeutic interventions, to be effective, must reduce hepatic glucose production either by improving islet dysfunction and raising plasma insulin levels, or improving the effectiveness of insulin on the liver. Both result in a decline in the fasting glucose levels regardless of the cause of hyperglycemia. We conclude that NIDDM is characterized by a steady-state re-regulation of plasma glucose concentration at an elevated level in which islet dysfunction plays a necessary role. Treatment should be based on this physiologic understanding.

Diabetes Mellitus, Type 2↗
PubMed1991

Glucose stimulates and potentiates islet amyloid polypeptide secretion by the B-cell.

Islet amyloid polypeptide (IAPP) has been shown to be actively secreted by the pancreatic B-cell along with insulin. To determine whether the modulation of B-cell IAPP secretion is similar to that of insulin, we assessed IAPP release in response to glucose at 4 different concentrations (1.67, 5.5, 8.8 and 16.7 mM) and to non-glucose secretagogues at different glucose concentrations in a neonatal rat islet monolayer culture preparation. Glucose alone stimulated IAPP and insulin secretion in a dose dependent fashion with maximal release for both peptides occurring at 8.8 mM. B-cell secretion of IAPP in response to arginine, isobutylmethylxanthine or both together was potentiated by increasing glucose concentrations from 1.67 to 16.7 mM. This same pattern of glucose potentiation was observed for insulin secretion. The data indicate that the pattern of peptide responses of cultured neonatal B-cells to glucose is similar for both IAPP and insulin release. Furthermore, the data suggest that glucose is capable of potentiating B-cell secretion of both IAPP and insulin.

1-Methyl-3-isobutylxanthine↗
PubMed1991

Evidence for entry of plasma insulin into cerebrospinal fluid through an intermediate compartment in dogs. Quantitative aspects and implications for transport.

To study the route by which plasma insulin enters cerebrospinal fluid (CSF), the kinetics of uptake from plasma into cisternal CSF of both insulin and [14C]inulin were analyzed during intravenous infusion in anesthetized dogs. Four different mathematical models were used: three based on a two-compartment system (transport directly across the blood-CSF barrier by nonsaturable, saturable, or a combination of both mechanisms) and a fourth based on three compartments (uptake via an intermediate compartment). The kinetics of CSF uptake of [14C]inulin infused according to an "impulse" protocol were accurately accounted for only by the nonsaturable two-compartment model (determination coefficient [R2] = 0.879 +/- 0.044; mean +/- SEM; n = 5), consistent with uptake via diffusion across the blood-CSF barrier. When the same infusion protocol and model were used to analyze the kinetics of insulin uptake, the data fit (R2 = 0.671 +/- 0.037; n = 10) was significantly worse than that obtained with [14C]inulin (P = 0.02). Addition of a saturable component of uptake to the two-compartment model improved this fit, but was clearly inadequate for a subset of insulin infusion studies. In contrast, the three-compartment model accurately accounted for CSF insulin uptake in each study, regardless of infusion protocol (impulse infusion R2 = 0.947 +/- 0.026; n = 10; P less than 0.0001 vs. each two-compartment model; sustained infusion R2 = 0.981 +/- 0.003; n = 5). Thus, a model in which insulin passes through an intermediate compartment en route from plasma to CSF, as a part of a specialized transport system for the delivery of insulin to the brain, best accounts for the dynamics of this uptake process. This intermediate compartment could reside within the blood-CSF barrier or it may represent brain interstitial fluid, if CNS insulin uptake occurs preferentially across the blood-brain barrier.

Animals↗
PubMed1991

Central insulin administration reduces neuropeptide Y mRNA expression in the arcuate nucleus of food-deprived lean (Fa/Fa) but not obese (fa/fa) Zucker rats.

By acting in the brain, insulin suppresses food intake, whereas neuropeptide Y (NPY) has the opposite effect. Since fasting increases NPY gene expression in the hypothalamic arcuate nucleus (ARC) and also lowers circulating insulin levels, we hypothesized that the anorexiant effect of insulin could result from insulin inhibition of NPY gene transcription in the ARC. Therefore, we determined whether the administration of insulin (200 mU per 12 hrs) into the 3rd cerebral ventricle of lean (Fa/Fa) female Zucker rats (n = 5) during 48 hrs of food deprivation reduces the expression of preproNPY mRNA in the ARC compared to vehicle-treated controls (n = 5). Coronal sections of rat brain were hybridized with an oligonucleotide probe complementary to preproNPY mRNA and apposed to x-ray film. Hybridization was quantified in both the ARC and the hippocampal dentate gyrus by computerized image analysis of the resulting autoradiographs. Central insulin significantly reduced the area of hybridization in the ARC (0.235 +/- 0.017 mm2; mean +/- SE) compared to vehicle-treated controls (0.331 +/- 0.037 mm2; p less than 0.05), but was without effect in the hippocampus. Thus, insulin reduced the expression of mRNA for NPY specifically in the ARC. Since the genetically obese (fa/fa) Zucker rat is insensitive to the anorexiant effect of insulin and over-expresses NPY in the ARC, we next tested the hypothesis that insulin does not suppress NPY mRNA expression in the ARC of these rats. Consistent with this hypothesis, central insulin administration to obese Zucker rats during 48 hrs of food deprivation (n = 6) did not lower hybridization area in the ARC compared to vehicle alone (n = 4) (0.286 +/- 0.036 vs. 0.248 +/- 0.019 mm2; p greater than 0.05). We conclude that insulin suppresses the expression of mRNA for NPY in the ARC of fasted lean but not obese Zucker rats. Regulation of hypothalamic NPY gene expression by insulin may account for its anorexiant effect, and a defect in this action may contribute to certain forms of obesity.

Animals↗