PubMed Health⌕ Search

Biomedical subjects

M R Davis

Publications and source records attributed to M R Davis.

At least 37 records · Page 2Linked to original sources
PubMed1994

Patho- and immunobiology of malignant mesothelioma: characterisation of tumour infiltrating leucocytes and cytokine production in a murine model.

Malignant mesothelioma (MM) is an aggressive, uniformly fatal serosal tumour, usually associated with asbestos exposure, for which there currently is no effective treatment. In order to gain insight into the mechanism(s) whereby MM might escape immune surveillance, a murine model for MM was used (a) to characterise the tumour-infiltrating lymphocytes (TIL) and macrophages (TIM) phenotypically, (b) to examine systemic immune recognition of MM, and (c) to examine the possible influence of tumour-derived cytokines on systemic and local pathobiological manifestations of MM. A profound down-regulation of lymphocyte surface markers, known to be involved in T cell activation, was found in TIL. Likewise, although TIM were present in large numbers, their expression of MHC class II antigen and integrins was weak or absent, suggestive of altered functional activity. Significant amounts of cytokines, in particular transforming growth factor beta, interleukin-6 (IL-6), IL-1 and tumour necrosis factor were produced during the course of MM tumour development-directly by the MM cells and/or indirectly in response to tumour growth. These factors may contribute both to derangement of antitumour effector mechanisms and to the clinical and pathological manifestations of the disease.

Animals↗
PubMed1994

Metabolic activation of unsaturated derivatives of valproic acid. Identification of novel glutathione adducts formed through coenzyme A-dependent and -independent processes.

The ability of 2-n-propyl-4-pentenoic acid (delta 4-VPA) and 2-n-propyl-2(E)-pentenoic acid ([E]-delta 2-VPA), two unsaturated metabolites of valproic acid (VPA), to form reactive intermediates, deplete hepatic glutathione (GSH) and cause accumulation of liver triglycerides was investigated in the rat. With the aid of ionspray liquid chromatography-tandem mass spectrometry (LC-MS/MS), three GSH adducts were detected in the bile of delta 4-VPA-treated animals and were identified as 4-hydroxy-5-glutathion-S-yl-VPA-gamma-lactone, 5-glutathion-S-yl-(E)-delta 3-VPA and 3-oxo-5-glutathion-S-yl-VPA. A fourth conjugate was identified tentatively as 4-glutathion-S-yl-5-hydroxy-VPA. Quantitative analysis of the corresponding N-acetyl-cysteine (NAC) conjugates in urine indicated that metabolism of delta 4-VPA via the GSH-dependent pathways accounted for approximately 20% of an acute dose (100 mg kg-1 i.p.). In contrast, when rats were given an equivalent dose of (E)-delta 2-VPA, only one GSH adduct (5-glutathion-S-yl-(E)-delta 3-VPA) was detected at low concentrations in bile. In vitro experiments with rat liver mitochondria demonstrated that delta 4-VPA undergoes coenzyme A- and ATP-dependent metabolic activation in this organelle via the beta-oxidation pathway to intermediates which bind covalently to proteins. When liver homogenates and hepatic mitochondria from rats injected with delta 4-VPA, (E)-delta 2-VPA or VPA were analyzed for GSH content, it was found that only delta 4-VPA depleted GSH pools significantly. Treatment of rats with delta 4-VPA and (to a lesser extent) VPA led to an accumulation of liver triglycerides, whereas (E)-delta 2-VPA had no measurable effect. It is concluded that delta 4-VPA undergoes metabolic activation by both microsomal cytochrome P-450-dependent and mitochondrial coenzyme A-dependent processes, and that the resulting electrophilic intermediates, which are trapped in part by GSH, may mediate the hepatotoxic effects of this compound. In contrast, (E)-delta 2-VPA is not transformed to any appreciable extent to reactive metabolites, which thus accounts for the apparent lack of hepatotoxicity of this positional isomer in the rat.

Acetylcysteine↗
PubMed1994

Effect of antecedent hypoglycemia on cognitive function and on glycemic thresholds for counterregulatory hormone secretion in healthy humans.

OBJECTIVE: To determine whether reduced hormonal, symptomatic, and/or cognitive responses to hypoglycemia are caused by an increase in the plasma glucose concentration required to stimulate these counterregulatory parameters after antecedent hypoglycemia. RESEARCH DESIGN AND METHODS: We studied nine healthy volunteers during stepped hypoglycemia clamps (plasma glucose targets from 80 to 50 mg/dl in 10 mg/dl steps) on two separate days. The study was preceded either by a 2-h period of hypoglycemia (plasma glucose 58 +/- 2 mg/dl) or a 2-h period of euglycemia (plasma glucose 94 +/- 2 mg/dl) for 90 min. RESULTS: The plasma glucose that triggered secretion of plasma norepinephrine (NE) was lower after antecedent hypoglycemia (control = 74 +/- 2 and experimental = 67 +/- 2 mg/dl, respectively, P < 0.005). In contrast, a relatively higher plasma glucose stimulated secretion of other counterregulatory hormones after antecedent hypoglycemia: growth hormone (GH) (65 +/- 2 to 72 +/- 2 mg/dl, P < 0.01); glucagon (63 +/- 2 to 70 +/- 2 mg/dl, P < 0.01); and epinephrine (EPI) (68 +/- 2 to 76 +/- 2 mg/dl, P < 0.01) when comparing control days with experimental days. Hypoglycemic symptoms were first observed at a plasma glucose plateau of 59 +/- 2 mg/dl. Motor function reflected by Digit Symbol Substitution deteriorated equally whether there had been antecedent hypoglycemia or euglycemia. Logical (immediate) memory deteriorated in the control study at a plasma glucose of 54 +/- 2 mg/dl but remained unchanged at equivalent hypoglycemia in the experimental study (P < 0.03). CONCLUSIONS: Our conclusions are as follows: 1) symptoms of moderate hypoglycemia occur at plasma glucose levels averaging approximately 5-15 mg/dl lower than the plasma glucose concentrations required to trigger counterregulatory hormone release; 2) after acute antecedent hypoglycemia, glucagon, EPI, and GH secretion occur at higher plasma glucose concentrations and NE is released at lower plasma glucose concentrations; and 3) there may be CNS adaptation to prior hypoglycemia reflected in preservation of logical memory function at plasma glucose levels of approximately 50 mg/dl. These findings suggest that thresholds for hormone secretion and for changes in cognitive function can be altered very acutely by foregoing hypoglycemia in healthy humans.

Adult↗
PubMed1993

Physiologic hyperinsulinemia enhances counterregulatory hormone responses to hypoglycemia in IDDM.

We evaluated the effect of physiologic hyperinsulinemia (plasma insulin 329 +/- 62 vs 687 +/- 62 pmol/L) on counterregulatory hormone responses in 8 IDDM subjects studied during a 2-hour hypoglycemic clamp study with an equivalent degree of hypoglycemia (plasma glucose 3.1 +/- 0.1 and 3.0 +/- 0.1 mmol/L, respectively). Plasma epinephrine levels were increased by 71% during the last 60 minutes of hypoglycemia in the high insulin study (840 +/- 180 vs 1440 +/- 310 pmol/L, respectively p = 0.006). In addition, plasma cortisol and norepinephrine were also increased in the high insulin study (by 19% and 24% respectively, p < 0.01, for both). Plasma growth hormone and glucagon concentrations were not altered by high dose insulin infusion. In spite of increased epinephrine secretion, the glucose infusion rate required to maintain glucose was 2-fold greater in the high insulin study, and there was greater suppression of lipolysis in that group. We conclude that hyperinsulinemia may enhance counterregulatory hormone secretion in IDDM.

Adult↗
PubMed1992

Establishment of a murine model of malignant mesothelioma.

Malignant mesothelioma (MM) is an aggressive tumour of the serosal cavities which is associated with previous asbestos exposure and is generally found to be resistant to conventional forms of therapy. Adequate scientific and clinical assessment of this disease has been severely limited by the relatively low incidence of mesothelioma and the lack of representative cell lines and animal models. The purpose of this study was to develop an asbestos-induced murine model of MM both as an in vivo-passaged malignancy and as in vitro-established cell lines. Such a model system would be invaluable for use in the study of various cellular, molecular and genetic aspects of the disease, and for the pre-clinical evaluation of potential therapeutic agents. BALB/c and CBA mice were injected intraperitoneally with crocidolite asbestos. Seven to 25 months after exposure, 35% of the mice developed mesothelioma (5 BALB/c, 9 CBA), as determined by standard cytological and histological parameters. From these primary tumours, 12 continuously growing cell lines (5 BALB/c, 7 CBA) were established in culture. All have been confirmed as mesothelioma by cytological and ultrastructural (electron microscopy) analyses. These lines have been in culture for 7 to 24 months and have achieved passages above 32 (range 32 to 106). As in the human disease, the murine mesothelioma lines vary in their morphology and growth rates (doubling times ranging from 14 to 30 hr). All cell lines produced tumours when injected into syngeneic mice.

Animals↗
PubMed1992

Impaired glucose disposal following mild hypoglycemia in nondiabetic and type I diabetic humans.

Insulin-mediated glucose disposal was studied immediately prior to and following moderate hypoglycemia in nondiabetic subjects and subjects with insulin-dependent (type I) diabetes mellitus (IDDM), the latter having varying epinephrine secretory capacities. Plasma insulin concentration was fixed throughout the study at approximately 300 to 400 pmol/L to avoid effects of waning insulin action and plasma glucose was clamped at either 5 mmol/L (euglycemic control) or at 3.1 mmol/L (hypoglycemic) periods of 120 minutes. Baseline (clamp 1) and postexperiment (clamp 2) periods were assessed for net glucose disposal (as a function of the exogenous glucose infusion rate) and glucose kinetics using 3H-glucose. In normal subjects, glucose disposal increased progressively by 132% during control studies but only by 57% with intervening hypoglycemia (P less than .005). Similarly, 33% during hypoglycemia, P less than .025). These changes were mediated by reduction of whole-body glucose uptake (rate of glucose disappearance [Rd], [3H]-3-glucose) and metabolic clearance rates with comparable suppression of hepatic glucose production in both groups. The increase in plasma free-fatty acids (FFA) following hypoglycemia was modest but greater in subjects with IDDM (P less than .01), whereas IDDM had reduced concentrations of epinephrine (P less than .01) and glucagon (P less than .005) during hypoglycemia. In subjects with IDDM but not in normal subjects, the change in posthypoglycemia glucose disposal was inversely correlated with the increase in plasma norepinephrine (R2 = .54, P less than .004) and epinephrine (R2 = .32, P less than .04). Glucose disposal did not correlate with other counterregulatory hormones, plasma FFA, or antecedent glycemic control.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1992

Cardiovascular reactivity assessment: effects of choice of difficulty on laboratory task responses.

This laboratory study of cardiovascular reactivity was designed to examine how a choice of difficulty element in a mental arithmetic task would affect cardiovascular responses. 20 healthy male subjects were tested on a computer-controlled mental arithmetic task, designed to standardize performance across subjects by keeping constant the proportion of correct responses. This was achieved by automatic adjustment of problem difficulty according to ongoing performance. Subjects were led to believe that they could take either a 'difficult' or an 'easy' version of the mental arithmetic task and were asked to make a choice; in fact, all subjects were given the same task. Subjects who chose the 'difficult' mental arithmetic task (N = 10) showed significantly greater increases in myocardial contractility, cardiac output and systolic blood pressure during task performance than those who chose 'easy' (N = 10). However, subjects who chose 'difficult' were presented with more difficult problems presumably due to their exerting greater levels of effort during the task. The differences in cardiovascular responses associated with choice of difficulty were absent during testing on four subsequent tasks which did not incorporate any choice options (reaction-time, speech, mirror trace, cold pressor). These findings are interpreted as being provocative, rather than in any way conclusive. Nevertheless, they are suggestive of the possibility that choice of difficulty in laboratory tasks may be one strategy for improving the ecological validity of laboratory reactivity assessment procedures.

Adolescent↗
PubMed1992

Effect of physiological hyperinsulinemia on counterregulatory hormone responses during hypoglycemia in humans.

UNLABELLED: We evaluated the effect of continuous physiological hyperinsulinemia on counterregulatory hormone responses in seven healthy subjects, each studied on two occasions. Hormone responses were measured during identical 2-h periods of hypoglycemia (plasma glucose target 3.5 mmol/L) at insulin levels of 350 pmol/L or 640 pmol/L. During hypoglycemia, there were significant (50-1400%) increases in glucagon, epinephrine, norepinephrine, GH, and cortisol which were comparable in the two groups. We further evaluated the influence of the duration of mild hyperinsulinemia on the responses in an additional group of normal subjects (n = 7). Brief (30 min) exposure to insulin was compared to a prolonged (3.5 h) insulin infusion, each followed by identical hypoglycemia. Plasma insulin (approximately 350 pmol/L) and plasma glucose (target 3.3 mmol/L) were similar in both groups. The increases in epinephrine, norepinephrine, GH, and cortisol during hypoglycemia were virtually identical in the two groups. However, the secretion of glucagon was blunted following prolonged hyperinsulinemia, increasing to levels of 249 +/- 17 ng/L in the brief studies and to only 185 +/- 20 ng/L in the prolonged studies (P < 0.005). The insulin-induced decrement in plasma amino acids were similar in the two studies and could not account for the impaired glucagon secretory response. CONCLUSIONS: 1) Brief exposure to even high physiological levels of insulin do not alter the magnitude of counterregulatory hormone secretion during hypoglycemia; 2) prolonged hyperinsulinemia results in a selective blunting of the plasma glucagon response to hypoglycemia, perhaps due to a direct suppressive effect of insulin on alpha-cell secretion.

Adult↗
PubMed1992

Further defects in counterregulatory responses induced by recurrent hypoglycemia in IDDM.

We evaluated the effect of previous experimental hypoglycemia on counterregulatory responses to hypoglycemia in 13 IDDM patients. These patients had defects in counterregulatory responses to hypoglycemia compared with 7 nondiabetic control subjects. Plasma EPI and glucagon responses to hypoglycemia in IDDM patients were approximately 60% of levels in nondiabetic subjects (P less than 0.02 and P less than 0.001, respectively). Hepatic glucose output ([3-3H]glucose) was reduced by approximately 60% of normal (P less than 0.005), and the glucose infusion rate required to maintain plasma glucose was correspondingly greater in people with IDDM (P less than 0.001). With a modified glucose clamp (plasma insulin approximately 330 pM), the diabetic subjects underwent two sequential 120-min periods of hypoglycemia (approximately 3.0 mM) with an intervening 60-min euglycemic recovery period. In the IDDM patients, there were 30-50% decreases in plasma GH (P less than 0.005) and cortisol (P less than 0.001) responses during the second hypoglycemic period compared with the first. In addition, glucose output, already defective compared with that in nondiabetic subjects, was further reduced by 33% (P = 0.03) during the second period of experimental hypoglycemia. There was no effect of repeated hypoglycemia on the responses of plasma glucagon, EPI, or NE, though plasma EPI was correlated directly with glucose output (P less than 0.001) and inversely with glucose uptake (P less than 0.05). There was no correlation between the rise in glucose output during hypoglycemia and antecedent glycemic control as measured by HbA1.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1991

Interaction between dactinomycin and tumor necrosis factor in mesothelioma. Cachexia without oncolysis.

There is no effective therapy for human malignant mesothelioma, and its susceptibility to recombinant cytokines has not been studied extensively. Recombinant human tumor necrosis factor alpha (rHuTNF alpha) was evaluated for its in vitro and in vivo antitumor activity using a human malignant mesothelioma cell line [DeH128(m)], both in culture and heterotransplanted in nude mice. In vitro, rHuTNF alone had no direct antimesothelioma activity assessed using the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl-tetrazolium bromide assay, but in combination with the transcription inhibitor, dactinomycin (AD), mesothelioma cell metabolic activity was inhibited (80% of control). The effects of this combination of agents were studied on DeH128(m) cells heterotransplanted as subcutaneous tumors in nude mice. In vivo there was no significant inhibition of tumor growth by combined rHuTNF alpha and AD therapy, but the combination produced marked cachexia in doses at which each component (rHuTNF alone or AD alone) was well tolerated. The authors conclude that the well-described in vitro interaction between AD and rHuTNF also operates in vivo to produce cachexia and that the combination of these two agents is likely to have a low therapeutic index in malignant mesothelioma.

Animals↗
PubMed1991

Establishment and characterization of five human malignant mesothelioma cell lines derived from pleural effusions.

Malignant mesothelioma (MM) is an aggressive tumour of the serosal cavities which is associated with exposure to asbestos. Studies of this tumour have been limited by a paucity of well-characterized human MM cell lines. In this study, 5 human MM cell lines were established from pleural effusions of patients with this malignancy. All 5 patients were males with known crocidolite asbestos exposure, who had received no treatment for their disease and in whom the diagnosis was confirmed by cytology, histology and electron microscopy (EM). These lines have been in culture from 11 to 25 months, and all of them for more than 18 passages. The appearance of the cells in culture was extremely varied; in 3 of the lines they were spindle-shaped with few vacuoles (JU77, LO68 and ONE58); in 1 line they had a thick, stellate shape with vacuoles (NO36) and in 1 they were very pleomorphic in both shape and size with irregular membranes and numerous vacuoles [DeH128 (M)]. Upon reaching confluence, cells in 3 of the 5 lines assumed the cobblestone-like pattern characteristic of epithelial-type cells, whereas in the other 2 (LO68 and ONE58) they remained spindle-shaped. All 5 lines demonstrated a loss of contact inhibition (i.e., piling) at confluence. Minimum doubling times varied significantly from 18 hr (JU77) to more than 30 hr [DeH128 (M)]. Cytological examination showed characteristic mesothelial/mesothelioma morphology, and epithelial membrane antigen (EMA) and cytokeratin were demonstrated in cells from all 5 lines. These cells lacked CEA and epithelial mucin. The presence of cell junctions, glycogen and numerous long, thin, branching microvilli was readily demonstrable by EM. All lines had abnormal karyotypes, with the modal chromosome number varying from 40 to 80. Variable chromosome numbers, numerous structural rearrangements and unrecognizable marker chromosomes were readily observed; however, the only consistent change seen was del 6q21 in 4 of the 5 lines. The establishment of these 5 cultured human MM cell lines now provides an opportunity for comparative study of several aspects of the biology of MM in vitro as well as screening new treatment modalities.

Adult↗
PubMed1991

Chemosensitivity and cytokine sensitivity of malignant mesothelioma.

Malignant mesothelioma arises in serosal tissues, is locally invasive, and is usually resistant to chemotherapeutic agents used clinically. To determine whether resistance to cytotoxic drugs was an inherent characteristic of mesothelioma cells, we performed in vitro chemosensitivity testing on five fully characterised human malignant mesothelioma cell lines and, for comparison, on three lines representative of clinically drug-resistant solid-tissue carcinomas using the MTT (tetrazolium bromide) assay system. Mesothelioma cell lines were intrinsically resistant to eight common antineoplastic drugs, with concentrations that produced a 50% reduction in optical density (IC50 values) for all drugs being equivalent, if not higher, for mesothelioma cell lines as compared with lung and colon carcinoma cell lines. We then investigated the direct anti-mesothelioma activity of recombinant human cytokines with their antineoplastic properties. All five mesothelioma cell lines were resistant to tumour necrosis factor, but they displayed varying degrees of sensitivity to interferons (IFNs). IFN gamma directly inhibited the growth of two of five mesothelioma lines. IFN alpha displayed little activity against four of five mesothelioma lines. The mesothelioma cells that were sensitive to IFN alpha were resistant to IFN gamma, indicating that sensitivity to IFNs is not a genetic characteristic of malignant mesothelioma cells. Significant interactions between cytokines in combination were not observed.

Antineoplastic Agents↗
PubMed1991

Capacity of tumor necrosis factor to augment lymphocyte-mediated tumor cell lysis of malignant mesothelioma.

Recombinant human tumor necrosis factor (rHuTNF) was evaluated both for direct anti-tumor action against human malignant mesothelioma and for its capacity to augment the generation and lytic phases of lymphocyte-mediated cytotoxicity against this tumor. rHuTNF was directly toxic by MTT assay to one of two mesothelioma cell lines evaluated, but had no effect on susceptibility to subsequent lymphocyte-mediated lysis of either line. TNF alone was incapable of generating anti-mesothelioma lymphokine-activated killer cell (LAK) activity. Furthermore, it did not augment the degree or LAK activity produced by submaximal interleukin-2 (IL-2) concentrations nor did it augment lysis of mesothelioma cells by natural killer (NK) or LAK effector cells during the 4-hr 51chromium release cytolytic reaction. The studies also suggest that mesothelioma targets are less responsive to TNF plus submaximal IL-2 concentrations than the standard LAK sensitive target Daudi, raising the possibility that intermediate LAK sensitive tumors such as mesothelioma may require separate and specific evaluation in immunomodulation studies. This in vitro study indicates that use of low-dose rHuTNF and IL-2 is unlikely to be an effective substitute for high-dose IL-2 in generation and maintenance of LAK activity in adoptive immunotherapy for mesothelioma.

Chromium Radioisotopes↗
PubMed1991

Asbestos fibres inhibit the in vitro activity of lymphokine-activated killer (LAK) cells from healthy individuals and patients with malignant mesothelioma.

Asbestos exposure is associated with an increased incidence of several malignancies, including malignant mesothelioma (MM). This study evaluates the relationship between asbestos exposure and the in vitro generation and function of LAK cells, an immune effector cell population with powerful lytic activity against MM cells. Both serpentine (chrysotile) and amphibole (amosite and crocidolite) forms of asbestos fibres suppress LAK cell generation, viability (by 5-11%, P less than 0.02) and cell recovery (by 13-15%, P less than 0.02). However, the LAK cells generated in the presence of the amphiboles were as effective as unexposed cells in lysing both standard tumour cell targets (K562, 56.4% lysis versus 61.5%, respectively, P greater than 0.5; NS; Daudi, 60.5% lysis versus 64.5% P greater than 0.5; NS), and MM tumour cell targets (mean of three MM cell lines 48.3% versus 46.3%, P greater than 0.5; NS), whereas the function of LAK cells generated in the presence of chrysotile was significantly reduced against three out of the five tumour cell targets tested (P less than 0.03). In the presence of asbestos fibres, LAK cell function was reduced against all five tumour cell targets (P less than 0.01), irrespective of whether the cell donors were healthy individuals or patients with MM. NK cell activity was also suppressed (P less than 0.01). The serpentine form of asbestos, chrysotile, was significantly more suppressive of both effector cell functions than either of the amphiboles (P less than 0.01). These findings suggest that asbestos exposure may suppress the function and in some instances the generation of immune effector cell mechanisms, thereby increasing the risk of disease and malignancy.

Asbestos↗
PubMed1991

HLA antigen expression and malignant mesothelioma.

The expression of HLA antigens by a tumor may determine its progression and metastatic potential by influencing the immune response to that tumor. The upregulation of HLA antigen expression on some cell types by interferons (IFNs) may contribute to their antitumor activity. Malignant mesothelioma (MM) is a tumor that has a poor prognosis and is unaffected by conventional therapy, although immunotherapy has not been adequately assessed. In this study, we have examined the constitutive and IFN-inducible expression of class I and class II HLA antigens on MM cell lines using indirect immunofluorescence and Northern blotting. All MM cell lines constitutively expressed class I, but not class II, surface antigen, and all three class I loci (HLA-A, HLA-B, and HLA-C) were expressed. The MM cell lines were heterogeneous in their response to the IFNs. Treatment with IFN-alpha marginally increased class I surface expression, but not class II. Class I mRNA was, however, clearly increased in all cell lines after IFN-alpha treatment, suggesting that class I surface antigen was already maximally expressed. IFN-gamma increased class I mRNA expression in all but one cell line and induced DR expression on three of the cell lines. DQ-beta, but not DQ-alpha, mRNA was inducible in the same three cell lines, but DQ surface antigen was never demonstrable.(ABSTRACT TRUNCATED AT 250 WORDS)

Blotting, Northern↗
PubMed1991

Deficient counterregulatory hormone responses during hypoglycemia in a patient with insulinoma.

Counterregulatory hormone responses were evaluated in a 37-yr-old woman before and after removal of a benign insulin-producing islet cell tumor. Counterregulatory hormone concentrations were measured during a glucose clamp with graded reductions of plasma glucose from 5.2 to 2.6 mmol/L. In the study before surgery, the increase in plasma epinephrine concentration was markedly blunted (by greater than 90%) compared to that in the study after surgery. The peak plasma norepinephrine concentration was similarly reduced by 71%, and plasma cortisol by 63%. In addition, the glycemic thresholds for secretion of the counterregulatory hormones were lower before removal of the tumor. Peak plasma GH responses were equivalent before and after surgery, but the threshold for GH secretion was 21% lower in the first hypoglycemia study. We conclude 1) that there is evidence for abnormal glucose counterregulatory hormone secretion in this patient, which may contribute to the pathogenesis of hypoglycemia seen in patients with insulinoma; 2) the reversal of reduced counterregulatory hormone secretion after tumor resection suggests that these defective hormonal responses may be related to recurrent hypoglycemia, persistent hyperinsulinemia, or both; and 3) that abnormal glucose counterregulation may exist in the absence of type 1 diabetes.

Adult↗
PubMed1991

Counterregulatory adaptation to recurrent hypoglycemia in normal humans.

We evaluated the effect of antecedent hypoglycemia on glucose counterregulation during hypoglycemia in non-diabetic human subjects. In single hypoglycemia studies, glucose production [( 3H]3-glucose) and counterregulatory hormone concentrations were measured (after a 3.5-h baseline period of euglycemia) during 120 min of hypoglycemia (glucose clamped at 3.0 mmol/L). During the final 60 min of hypoglycemia, counterregulation resulted in significant increments in glucose production (12.88 +/- 0.83 mumol/kg.min), and plasma glucagon (IRG; 185 +/- 22 ng/L), GH (29.3 +/- 7.0 micrograms/L), cortisol (630 +/- 100 nmol/L), epinephrine (3.44 +/- 0.76 nmol/L), and norepinephrine (2.02 +/- 0.21 nmol/L). In the recurrent hypoglycemia experiment, an antecedent period of identical hypoglycemia was induced. Glucose counterregulation during the second of two periods of hypoglycemia (HYPO 2) was then compared to that in single hypoglycemia studies. During HYPO 2, there were decreased responses in Ra (by 32%; P less than 0.03), GH (by 67%; P less than 0.05), F (by 41%; P less than 0.03), and norepinephrine (by 20%; P = 0.03) compared to those in the single hypoglycemia study. In contrast, plasma IRG values were similar in the single hypoglycemia studies and HYPO 2, but were reduced relative to those during the first hypoglycemic period of recurrent hypoglycemia (IRG, 263 +/- 18 ng/L; P less than 0.025 vs. HYPO 2 and P less than 0.05 vs. single hypoglycemia). Our results suggest that 1) antecedent hypoglycemia may alter glucose counterregulation during hypoglycemia; and 2) recurrent hypoglycemia may result in alterations in reduction of hepatic glucose production.

Acclimatization↗