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T A Buchanan

Publications and source records attributed to T A Buchanan.

At least 73 records · Page 4Linked to original sources
PubMed1992

Whole body insulin sensitivity in Osborne-Mendel and S 5B/Pl rats eating a low- or high-fat diet.

To determine whether whole body insulin sensitivity differs between a rat strain that does not (S 5B/Pl) and a strain that does [Osborne-Mendel (OM)] become obese when eating a high-fat diet, we performed euglycemic clamp studies in animals from each strain during low- and high-fat feeding. Clamps were performed after 2 days ("initial clamp") and 9 days ("final clamp") on each diet. Plasma glucose and insulin levels during the final 60 min of initial and final clamps were similar in S 5B/Pl and OM rats regardless of diet. Insulin sensitivity, measured as the glucose clearance rate during the final 60 min of the clamp, averaged 35 +/- 3 ml.kg-1.min-1 in S 5B/Pl rats after 2 days on a low-fat diet. This did not change significantly during an additional 7 days on the low-fat diet. The high-fat diet was associated with a 13% reduction in insulin sensitivity after 2 days and a 30% reduction after 9 days in S 5B/Pl rats. OM rats exhibited similar patterns of insulin sensitivity during low- and high-fat diets, albeit at lower insulin sensitivity overall (P < 0.0005 vs. S 5B/Pl). Mean glucose clearance after 2 days on the low-fat diet was 27 +/- 2 mg.kg-1.min-1 and did not change significantly during seven more days of low-fat feeding. The high-fat diet was associated with a 19% reduction in glucose clearance after 2 days and a 38% reduction after 9 days in OM rats. The magnitude of reduction in insulin sensitivity during high-fat diets did not differ significantly between strains.(ABSTRACT TRUNCATED AT 250 WORDS)

Analysis of Variance↗
PubMed1992

Enhanced glucose tolerance in spontaneously hypertensive rats. Pancreatic beta-cell hyperfunction with normal insulin sensitivity.

We used intravenous glucose tolerance tests in vivo and 3-O-methylglucose transport into skeletal muscle in vitro to assess glucose tolerance, pancreatic beta-cell function, and insulin action in 9- to 11-wk-old spontaneously hypertensive rats (SHR) and age-matched normotensive Wistar Kyoto rats (WKY). Body weight was slightly higher in the WKY (P less than 0.001), while blood pressure was elevated in the SHR (P less than 0.001). Insulin responses to intravenous glucose after 4 or 12 h of fasting in SHR were 2-3 times the responses of WKY rats (P less than 0.001). The greater insulin responses in SHR were associated with accelerated glucose disappearance P less than 0.001 vs. WKY rats). A direct correlation (r = 0.49, P less than 0.05) between the peak plasma insulin responses to glucose and Kg values in SHR suggested that the exaggerated insulin responses contributed to the accelerated glucose disappearance in that group. 3-O-methylglucose transport rates into epitrochlearis muscles in vitro did not differ significantly between SHR and WKY groups in the absence of insulin (P less than 0.2) or in the presence of insulin at physiological (600 pM, P greater than 0.4) or pharmacological (120,000 pM, P greater than 0.9) concentrations. Thus, compared with WKY rats, SHR had exaggerated insulin responses to glucose, similar insulin-mediated glucose transport into skeletal muscle, and enhanced glucose tolerance. Our findings indicate that young, hypertensive SHR have hyperfunction of pancreatic beta-cells that is unrelated to insulin resistance. The resultant nutrient-stimulated hyperinsulinemia could play a role in the development or maintenance of elevated blood pressure in SHR.

3-O-Methylglucose↗
PubMed1991

Hypothermia is critical for survival during prolonged insulin-induced hypoglycemia in rats.

Hypothermia is a well-known concomitant of hypoglycemia in mammals. We tested the hypothesis that this hypothermia is an important adaptive response to hypoglycemia in 11 normal Sprague-Dawley rats. Twelve-hour fasted, conscious animals received primed, continuous insulin infusions for up to 8 hours. Plasma glucose was clamped between 30 and 40 mg/dL and core body temperature was monitored continuously during the insulin infusions. Five of the animals were maintained in a room temperature environment (22 to 24 degrees C) during the hypoglycemia; all became hypothermic (mean +/- SE nadir core temperature, 31 +/- 0.5 degrees C). Spontaneous activity was reduced in these animals, but they remained conscious and responsive to external stimuli. All five returned to normal behavior after euglycemia was restored at the end of the insulin infusions. In the remaining six animals, hypothermia was prevented during hypoglycemia by warming of the air in their cages (mean of hourly core temperatures, 37 +/- 0.1 degrees C). None of these animals survived more than 7 hours. The severity of the hypoglycemia was no greater in the euthermic than in the hypothermic group, as judged by the mean of individual nadir plasma glucose levels (25 +/- 1 v 24 +/- 1 mg/dl, respectively) and by the mean number of glucose values per animal that were less than 30 mg/dL (2 +/- 1 v 7 +/- 1). Plasma osmolality did not change significantly in either group during the period of hypoglycemia, suggesting that dehydration was not the cause of death in the euthermic animals.(ABSTRACT TRUNCATED AT 250 WORDS)

3-Hydroxybutyric Acid↗
PubMed1991

Glucose tolerance and insulin action in rats with renovascular hypertension.

To test whether hypertension can cause hyperinsulinemia or insulin resistance, we performed intravenous glucose tolerance tests at 1 month and euglycemic clamps at 3 months after induction of two-kidney, one clip renovascular hypertension in rats. At 1 month, systolic pressure was higher in 21 clipped than in 12 control animals (161 +/- 5 mm Hg, range 134-187 mm Hg versus 119 +/- 3 mm Hg, range 108-146 mm Hg; p less than 0.001). Glucose tolerance, assessed as the glucose fractional disappearance rate between 3 and 11 minutes after the glucose injection, was similar in the clipped and sham groups (0.059 +/- 0.002 versus 0.056 +/- 0.002 min-1, respectively; p greater than 0.4). The total area under the insulin curve during glucose tolerance tests was also similar in the clipped and sham groups (926 +/- 95 versus 869 +/- 126 microunits/ml x min; p greater than 0.4). There was no significant relation between systolic blood pressure and insulin area during glucose tolerance tests in the clipped group, but there was a positive rectilinear relation in the control group (r = 0.66; p = 0.01). Fourteen animals had euglycemic clamps 2 months after glucose tolerance tests. At that time, systolic pressure (direct femoral measurement) was higher in the seven clipped animals (189 +/- 13 mm Hg versus 122 +/- 5 mm Hg in controls; p less than 0.001). Insulin infusions of 1 and 4 milliunits/min/kg body wt effected similar plasma insulin levels in the two groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Serum lipids within 36 mo of delivery in women with recent gestational diabetes.

We prospectively evaluated fasting serum total cholesterol (chol), low- and high-density lipoprotein cholesterol (LDL-chol and HDL-chol), and triglycerides (TGs) in a large cohort of Hispanic women during the first 36 mo after pregnancies complicated by gestational diabetes mellitus (GDM). In 1340 women studied 6-12 wk postpartum (PP-GDM group), chol and LDL-chol were similar to levels in 43 postpartum control subjects without prior GDM. Compared with control subjects (2.01 +/- 1.24 mM), TG was elevated in the PP-GDM women with diabetes mellitus (DM) (2.86 +/- 2.21 mM, P less than 10(-5)) and impaired glucose tolerance (IGT) (2.64 +/- 1.68 mM, P = 0.02) but not in those with normal glucose tolerance (2.00 +/- 1.21 mM). HDL-chol was decreased in PP-GDM women with DM compared with those with normal glucose tolerance. A subgroup of 157 women with prior GDM returned for at least one annual follow-up test on nonhormonal contraception (FU-GDM: n = 60 at 3-11 mo after delivery, n = 78 at 12-23 mo, and n = 39 at 24-35 mo). The cumulative prevalence of DM by 36 mo was 40%. Chol or LDL-chol levels did not significantly change during the 1-yr intervals in the FU-GDM group and were similar to a control group of 36 women without prior GDM. TG was elevated and HDL-chol was decreased in the FU-GDM women with DM at 3-11 mo but not thereafter. Overall, the prevalence of moderate- and high-risk LDL-chol in the FU-GDM group was not different from that of control subjects. These findings suggest that lipid abnormalities are uncommon during the first 36 mo after delivery in women with recent GDM. The abnormalities found consisted of increased TG and decreased HDL-chol in subjects who had developed DM during the study period.

Adult↗
PubMed1990

Insulin sensitivity and B-cell responsiveness to glucose during late pregnancy in lean and moderately obese women with normal glucose tolerance or mild gestational diabetes.

We used the minimal model technique to obtain concurrent measurements of whole-body insulin sensitivity and pancreatic B-cell responsiveness to glucose during the third trimester of pregnancy. Insulin sensitivity in normal pregnant women (n = 8) was reduced to only one third that of a group of nonpregnant women (n = 7) of similar age and relative weight. This marked insulin resistance was compensated by reciprocal enhancement of the first and second-phase insulin responses to intravenous glucose, which were increased threefold as compared with the nonpregnant women. Women with gestational diabetes mellitus (n = 16) had mean insulin sensitivity that was similar to that of the normal pregnant group, which indicates that insulin action was appropriate for the late phase of pregnancy in the gestational diabetic group. By contrast, the mean first-phase insulin response was significantly reduced in women with gestational diabetes mellitus, as compared with that of normal pregnant women (p less than 0.001). However, approximately one fifth of the group with gestational diabetes mellitus had first-phase responses that did not fall below the 95% confidence interval for the mean in normal pregnant women. The mean second-phase response was also lower in the group with gestational diabetes, although the difference was of borderline statistical significance (p less than 0.09). Our findings reveal the quantitative nature of the reciprocal changes in insulin sensitivity and B-cell function that normally accompany late pregnancy. They further indicate that during the third trimester, mild gestational diabetes is characterized by an impairment of pancreatic B-cell function rather than an exaggeration of the normal insulin resistance of late pregnancy.

Adult↗
PubMed1990

Accelerated starvation in late pregnancy: a comparison between obese women with and without gestational diabetes mellitus.

We compared the glucose, insulin, free fatty acid, and 3-hydroxybutyrate responses to a briefly extended overnight fast during the third trimester of pregnancy between two groups: obese women with normal glucose tolerance (n = 10) and age- and weight-matched women with gestational diabetes mellitus (n = 10). After a 12-hour overnight fast, plasma glucose (95 +/- 4 vs. 78 +/- 2 mg/dl; p less than 0.01), insulin (32 +/- 5 vs. 17 +/- 2 microU/ml; p less than 0.02), and free fatty acid (860 +/- 63 vs. 639 +/- 79 mmol/L; p less than 0.05) levels were higher in the patients with gestational diabetes mellitus. 3-Hydroxybutyrate levels were similar in the two groups at that time (0.23 +/- 0.04 vs. 0.18 +/- 0.03 mmol/L; p greater than 0.3). When the fast was extended to 18 hours by having the patients skip breakfast, glucose levels fell more rapidly in the group with gestational diabetes mellitus but remained elevated compared with the nondiabetic women. Insulin levels declined at a similar rate in the two groups. Free fatty acid levels did not increase significantly in the group with gestational diabetes mellitus during the extended fast. In contrast, free fatty acid levels increased by 44% in the normal pregnant women, reaching the level observed in the group with gestational diabetes mellitus after 18 hours. 3-Hydroxybutyrate levels remained virtually identical in the two groups throughout the brief fast. Thus, compared with that of normal pregnant women, the response of obese women with gestational diabetes mellitus to brief caloric deprivation during late pregnancy was characterized by a greater fall in plasma glucose values without a greater propensity to ketosis. Our findings may have important implications for the dietary management of obese patients with gestational diabetes mellitus.

Adult↗
PubMed1990

Gestational diabetes mellitus: the prevalence of glucose intolerance and diabetes mellitus in the first two months post partum.

To determine the prevalence of abnormal carbohydrate metabolism in the early postpartum period in women with gestational diabetes mellitus, we performed 2-hour oral glucose tolerance tests between 5 and 8 weeks post partum in 246 women with recent gestational diabetes mellitus. Patients were stratified into three study groups based on their fasting serum glucose level during pregnancy: (1) group A1: all fasting serum glucose levels during pregnancy less than 105 mg/dl without insulin therapy; (2) group A2: any fasting serum glucose levels greater than 105 and less than 140 mg/dl before insulin therapy; (3) group B1: any pregnancy with fasting serum glucose levels greater than 140 mg/dl. Overall, 48 (19%) of the patients had an abnormal oral glucose tolerance test in the early postpartum period; 25 (10%) had impaired glucose tolerance and 23 (9%) had diabetes mellitus. The prevalence of postpartum diabetes mellitus (2% in group A1, 9% in group A2 and 44% in group B1) increased in parallel with the degree of maternal metabolic decompensation during pregnancy (p less than 0.05 for A1 versus A2; p less than 0.001 for A2 versus B1). The prevalence of impaired glucose tolerance was likewise greater in the B1 group (26%) than in either the A1 or the A2 group (p less than 0.05). Gestational age less than 24 weeks at diagnosis of gestational diabetes mellitus was an additional risk factor for postpartum glucose intolerance. Our findings support the use of an oral glucose tolerance test in the early puerperium, especially for patients with elevated fasting serum glucose levels during pregnancy.

Blood Glucose↗
PubMed1990

Autonomic function in Holmes Adie syndrome.

Autonomic function was studied in a group of 11 patients with Holmes Adie Syndrome. Autonomic function was assessed by the measurement of cardiovascular reflexes. Heart rate responses to respiration, valsalva manoeuvre and standing were studied. The change in systolic blood pressure on moving from the lying to the standing position was measured. Abnormalities of parasympathetic function were found in three patients, compared with matched controls. Autonomic dysfunction in Holmes Adie Syndrome may be more widespread than previously suspected.

Adie Syndrome↗
PubMed1989

In vivo kinetics of a covalent growth hormone-binding protein complex.

The biologic function of the newly recognized binding proteins (BP) for human growth hormone (hGH) in human plasma is largely unknown; hGH circulates in part in complexed form in association with the BP. In a previous study we showed that the in vivo kinetics of hGH were altered in the presence of the BP. However, that study gave only qualitative information because the BP was present in excess and the complex was subject to dissociation in vivo. To gain more quantitative information about the in vivo behavior of complexed hGH, metabolic clearance (MCR), distribution volume (Vd), and degradation rate of a covalently crosslinked, stoichiometrically correct, chemically stable hGH-BP complex were measured. The MCR and the degradation rate of complexed hGH were tenfold lower than those of free hGH (P less than .001), and its Vd was significantly smaller than that for free hGH (P less than .001). The covalent complex was fully immunoreactive with polyclonal anti-hGH antibodies. We conclude that complexed hGH is protected from clearance and degradation by being restricted from access to degradation sites, including the proximal renal tubule and receptor-mediated delivery to intracellular proteolygic organelles. The data developed also yield preliminary information about the in vivo distribution of the BP itself. These data provide important guidelines for future studies regarding the in vivo effects of the BP. In addition, the results indicate that the principal epitope(s) of hGH remain(s) exposed on the outer surface of the complex.

Animals↗
PubMed1989

Lack of teratogenic effect of brief maternal insulin-induced hypoglycemia in rats during late neurulation.

We have previously shown that 1 h of maternal insulin-induced hypoglycemia is teratogenic to rat embryos during the initial stages of neurulation, when they are dependent on uninterrupted glycolysis (day 9.5-9.7 of development). To determine whether this vulnerability persists in later stages of neural tube and cardiac development, we infused insulin into 16 conscious pregnant rats for 1 h beginning after embryos had developed the capacity for aerobic glucose metabolism (day 10.6 of development). Half of the pregnant animals were allowed to become hypoglycemic (44 +/- 2 mg/dl) during the insulin infusions. The other half received glucose infusions to maintain normoglycemia (130 +/- 3 mg/dl). Normal plasma glucose levels were maintained in all animals after the insulin infusions. Embryos were examined on day 11.5 of development. At that time, 1 of 111 embryos from the normoglycemic group and 1 of 109 embryos from the hypoglycemic group were grossly malformed (P greater than .5). Means of embryo crown-rump length (4.15 +/- 0.03 vs. 4.14 +/- 0.03 mm), somite number (29.7 +/- 0.1 vs. 29.8 +/- 0.2), and total protein content (320 +/- 5 vs. 326 +/- 6 micrograms) were also similar in the two groups (P greater than .5). Thus, we could not detect an embryotoxic effect of 1 h of maternal insulin-induced hypoglycemia beginning at day 10.6 of development. This finding is in contrast to our prior demonstration that a similar period of hypoglycemia occurring earlier in neurulation (day 9.7) caused growth retardation and developmental anomalies in embryos.(ABSTRACT TRUNCATED AT 250 WORDS)

Abnormalities, Drug-Induced↗
PubMed1989

Access of maternal insulin to the rat conceptus prior to allantoic placentation.

We have investigated the availability of circulating maternal insulin to the postimplantation rat conceptus during early organogenesis, before the insulin-impermeable allantoic placeta is established. Virtual distribution equilibrium for "tracer" quantities of 125I-porcine insulin was achieved by continuous infusions into pregnant rats on day 11 of gestation (day 10.3 of embryo development). During continuing infusion, following 210 min of iodoinsulin delivery, intact conceptuses (embryo, amnion, and yolk sac), and portions of adjacent decidua, liver, and spleen were excised, rinsed, and frozen in liquid N2 within 2 min. Subsequent analysis by trichloroacetic acid (TCA) precipitation or immunoprecipitation revealed the presence of intact iodoinsulin in all tissues. Both analytical approaches disclosed the same pattern of iodoinsulin distribution, i.e., liver and spleen greater than decidua and conceptus. Assayable iodoinsulin could not be demonstrated in embryos excised from the intact conceptuses; however the embryo observations were limited by the amount of accessible tissue and the requisite preparative delay. Our studies indicate that during early organogenesis, before the establishment of the allantoic placenta, maternal insulin has access to at least the outer portion of the postimplantation rat conceptus, including yolk sac, where insulin-specific receptors are known to occur.

Allantois↗
PubMed1988

Retinal ultrastructural findings in cone degeneration.

We studied an eye from a 73-year-old man with a sporadic type of retinal cone degeneration and choroidal melanoma. Histologic and ultrastructural studies of the nasal retina unaffected by the choroidal melanoma showed alterations at the outer retina predominantly involving the photoreceptors and retinal pigment epithelium. A wide spectrum of pathologic changes were observed, ranging from near normal retina showing only photoreceptor outer segment disease (distortion and kinking) to grossly pathologic regions where photoreceptor cell bodies were sparse and their outer segments absent. The retinal pigment epithelium in minimally affected regions of the retina showed an increased proportion of the melanin complement of the cell within complex granules. In severe disease, many cells showed only giant complex granules with no free melanin. Retinal pigment epithelial cell migration and relocation around blood vessels was also noted in severe disease.

Aged↗
PubMed1988

Fuel-mediated teratogenesis: symmetric growth retardation in the rat fetus at term after a circumscribed exposure to D-mannose during organogenesis.

We previously infused the D-glucose epimer D-mannose into pregnant rats to deliver a brief metabolic insult to the early postimplantation conceptus. This insult caused developmental anomalies and growth retardation that were apparent in the embryos 2 days later. We now report the long-range effects on intrauterine development of such a circumscribed metabolic insult during organogenesis. Ten pregnant animals were infused with D-mannose for 12 hours during early neurulation (day 9.5 to 10 of development). Ten control animals were infused with equimolar D-glucose during this same time interval. Mannose infusions produced maternal plasma mananose concentrations in the embryotoxic range; glucose infusions caused only slight and transient hyperglycemia. Fetuses were removed at term and examined for evidence of developmental anomalies and growth retardation. None of 137 fetuses from the mannose group or 138 fetuses from the glucose group exhibited gross anomalies. However, an excess of resorbed conceptions in the mannose group (21 versus six in the glucose group; p less than 0.01) suggested some lethal toxicity from mannose exposure during embryogenesis. Among viable fetuses, the mean body weight of those from the mannose group was significantly reduced compared with those from the glucose group (5.62 +/- 0.04 versus 5.89 +/- 0.03 gm, respectively; p less than 0.001). Reductions of a similar magnitude were noted in the mean wet weight and protein content of fetal brains, hearts, livers, and kidneys from the mannose group (range, 3.4% to 7.1% below the glucose group), indicating a symmetric pattern of fetal growth retardation. In addition, analysis of fetal ossification sites after Alizarin Red S staining revealed a significant delay of skeletal development in the mannose group. These results indicate that a relatively brief metabolic insult to embryos during early organogenesis may cause lethal developmental anomalies as well as growth retardation and delayed skeletal development that are manifested in the fetus at term.

Abnormalities, Drug-Induced↗
PubMed1987

An experimental study of quinine blindness.

An experimental model of quinine induced blindness is presented. Electrophysiological, angiographical and morphological examinations were made. The occurrence of blindness and any recovery from blindness was dependent upon the dose of quinine taken. As no evidence of acute retinal ischaemia was found it is concluded that quinine is retinotoxic.

Animals↗
PubMed1987

The effect of circulating growth hormone-binding protein on metabolic clearance, distribution, and degradation of human growth hormone.

We recently described a specific binding protein for human GH (hGH) in human plasma, with which a substantial portion of circulating hGH is complexed. The biological function of the complexed fraction is unknown. To test the hypothesis that complexed hGH may have different in vivo kinetics than free hGH, we compared the MCRs, distribution volumes (Vd), and degradation rates of complexed and free [125I] hGH in the rat. A partially purified GH-binding protein preparation, generated by affinity chromatography on a hGH column, was used for this purpose. A mixture of hGH with binding protein (equivalent to the amount contained in 0.9 mL human plasma) was injected iv as a single dose. Parallel experiments were conducted with hGH in the absence of binding protein. Disappearance of total, immunoprecipitable, and trichloroacetic acid-precipitable radioactivity from rat plasma was followed, and MCR, Vd, and degradation rates were derived by standard mathematical techniques. The MCR was 6-fold slower for complexed than for free hGH (2.3 vs. 14 mL/min X kg), Vd was 4-fold smaller for complexed hGH than for free hGH (71 vs. 256 mL/kg), and initial degradation rate was 4.5-fold lower for complexed than for free hGH (13.2% vs. 59.9%/15 min). The Vd of complexed hGH was close to the intravascular volume, while the Vd for free hGH corresponded to the extracellular volume. We conclude that one function of the hGH-binding protein is relative confinement of hGH to the vascular compartment, thereby protecting it from degradation and prolonging its biological half-life.

Animals↗
PubMed1987

Specificity of immunoglobulin E and immunoglobulin G against human (recombinant DNA) insulin in human insulin allergy and resistance.

Using an enzyme-linked immunosorbent assay method, we have demonstrated immunoglobulin E (IgE) and immunoglobulin G (IgG) against human (recombinant DNA) insulin in serum samples of a patient whose insulin therapy was only with human insulin. Within 12 days of initiation of human insulin for gestational diabetes, large local reactions developed in the patient in association with high levels of IgE to human insulin. As the local reactions subsided, the levels of IgE to human insulin decreased. The patient's insulin requirement was unusually high for pregnancy and tended to decrease in parallel with falling levels of IgG to human insulin, suggesting an element of immunologic insulin resistance. In addition to IgE and IgG against human insulin, we were able to demonstrate the presence of IgE and IgG against porcine and bovine insulin in the serum samples of this patient. The patient had similar immediate cutaneous reactivity to each insulin. In inhibition studies, similar amounts of porcine insulin, bovine insulin, or human insulin were found to produce 50% inhibition of human insulin binding to IgE or IgG against human insulin. Excess porcine insulin or bovine insulin resulted in total inhibition of human insulin binding to IgE or IgG. Thus even in a patient whose initial form of insulin therapy was human insulin, there was development of insulin allergy and of IgG to human insulin that may have contributed to insulin resistance. Moreover, the antigenic determinants recognized by antibody induced by human insulin may also be present on bovine insulin and porcine insulin as demonstrated in this case.

Adult↗