Low-dose IGF-I has no selective advantage over insulin in regulating glucose metabolism in hyperglycemic depancreatized dogs.

At supraphysiological levels, IGF-I bypasses some forms of insulin resistance and has been proposed as a therapeutic agent in the treatment of diabetes. Unfortunately, side effects of high-dose IGF-I (100-250 microg/kg) have precluded its clinical use. Low-dose IGF-I (40-80 microg/kg), however, shows minimal side effects but has not been systematically evaluated. In our previous study under conditions of declining glucose, low-dose IGF-I infusion was more effective in stimulating glucose utilization, but less effective in suppressing glucose production and lipolysis than low-dose insulin. However, under conditions of hyperglycemia, we could not observe any differential effects between high-dose infusions of IGF-I and insulin. To determine whether the differential effects of IGF-I and insulin are dose-related or related to the prevailing glucose level, 3 h glucose clamps were performed in the same animal model as in the previous studies, i.e. the moderately hyperglycemic (175 mg/dl) insulin-infused depancreatized dog, with additional infusions of low-dose IGF-I (67.8 microg/kg, i.e. 29.1 microg/kg bolus plus 0.215 microg/kg( )per min infusion; n=5) or insulin 49.5 mU/kg (9 mU/kg bolus plus 0.45 mU/kg per min; n=7). As in the previous study under conditions of declining glucose, low-dose IGF-I had significant metabolic effects in vivo, in our model of complete absence of endogenous insulin secretion. Glucose production was similarly suppressed with both IGF-I and insulin, by 54+/-3 and 56+/-2% s.e. (P=NS) respectively. Glucose utilization was stimulated to the same extent (IGF-I 5.2+/-0.2, insulin 5.5+/-0.3 mg/kg per min, P=NS). Glucagon, free fatty acid, glycerol, alanine and beta-hydroxybutyrate, were suppressed, while lactate and pyruvate levels were raised, similarly with IGF-I and insulin. We conclude that: (i) differential effects of IGF-I and insulin may be masked under hyperglycemic conditions, independent of the hormone dose; (ii) low-dose IGF-I has no selective advantage over additional insulin in suppressing glucose production and lipolysis, nor in stimulating glucose utilization during hyperglycemia and subbasal insulin infusion when insulin secretion is absent, as in type 1 diabetes mellitus.

In situ duct carcinoma of the breast: clinical and histopathologic factors and association with recurrent carcinoma.

There has been a recent increase in the diagnosis of in situ duct carcinoma of the breast (DCIS) as a result of mammographic screening. DCIS is heterogeneous in appearance and likely in prognosis. There is no generally accepted model to predict progression to invasive carcinoma. We investigated the prognostic effect of clinical presentation and pathologic factors for women diagnosed with primary DCIS. A cohort of 124 patients was accrued between 1979 and 1994 and was followed to 1997; 78 had DCIS detected mammographically, and 88 underwent lumpectomy alone. In this article, we provide details about characteristics affecting the choice of primary therapeutic modality, and we examine the effects of factors on progression for the two patient subgroups. Presentation with bloody nipple discharge was associated with a significant increase in DCIS recurrence (p=0.07). The pattern of duct distribution was important: DCIS in which the involved ducts were more widely separated had a significantly greater recurrence of DCIS than when the involved ducts were more concentrated (p=0.08 for mammographically detected DCIS, p=0.07 for patients who underwent lumpectomy alone). For mammographically detected DCIS, younger patients had more DCIS recurrence (p=0.07). We found considerable heterogeneity in nuclear grade; 50% of patients exhibited more than one grade. Nuclear grade, necrosis, and architecture were not significantly associated with either recurrence of DCIS or development of invasive carcinoma. Longer follow-up will allow further evaluation of the prognostic relevance of the factors assessed.

Factors associated with local breast cancer recurrence after lumpectomy alone: postmenopausal patients.

BACKGROUND: We have been following a cohort of patients who underwent a lumpectomy without receiving adjuvant radiotherapy or adjuvant systemic therapy. We now report the experience of a postmenopausal subgroup. METHODS: The postmenopausal subgroup included 244 patients accrued between 1977 and 1986 and followed up. The end point was ipsilateral local breast cancer recurrence. The factors studied were the patient's age in years; tumor size (in mm); nodal status (N-, Nx, N+); estrogen and progesterone receptor status (< 10, - 10 fmol/mg protein); presence or absence of lymphovascular/perineural invasion; presence or absence, and type, of DCIS (none, non-comedo, comedo); percentage of DCIS; histological grade (1,2,3); and nuclear grade (1,2,3). Univariate analyses consisted of Kaplan-Meier plots and the Wilcoxon (Peto-Prentice) test statistic; the multivariate analyses were step-wise Cox and log-normal regressions. RESULTS: The median follow-up of those patients still alive was 9.1 years, and the overall relapse rate was 24% (59/244). The univariate results indicated that the characteristics of smaller tumor size, negative nodes, positive ER status, and no lymphovascular or perineural invasion were associated with significantly (P <.05) lower relapse. From the multivariate analyses, the factors lymphovascular or perineural invasion, age, and amount of DCIS were all significantly associated with local relapse with both Cox and log-normal regressions. Additionally, there was weak evidence of an association between ER (P = .08 in the Cox regression and in the log-normal) and nodal status (P = .09 in the log-normal regression) with local relapse. We also are able to define a low-risk subgroup (N-, age -65, no comedo, ER positive, no emboli) with a crude 10-year local recurrence rate of 9%. CONCLUSION: With longer follow-up, and for postmenopausal patients, there continues to be support for the theory that local relapse is affected by the factors lymphovascular or perineural invasion, age, amount of DCIS, ER, and nodal status. A low risk subgroup has been identified.

Factors affecting distant disease-free survival for primary invasive breast cancer: use of a log-normal survival model.

BACKGROUND: Invasive breast cancer is a frequently diagnosed disease that now comes with an ever expanding array of therapeutic management options. We assessed the effects of 20 prognostic factors in a multivariate context. METHODS: We accrued clinical data for 156 consecutive patients with stage 1-3 primary invasive breast cancer who were diagnosed in 1989-1990 at the Henrietta Banting Breast Center, and followed to 1995. There is complete follow-up for 91% of patients (median follow-up of 4.9 years). The event of interest was distant recurrence (for distant disease-free survival, DFS). We used Cox and log-normal step-wise regression to assess the multivariate effects of the following factors on DFS: age, tumor size, nodal status, histology, tumor and nuclear grade, lymphovascular and perineural invasion (LVPI), ductal carcinoma-in-situ (DCIS) type, DCIS extent, DCIS at edge of tumor, ER and PgR, ERICA, adjuvant systemic therapy, ki67, S-phase, DNA index, neu oncogene, and pRb. RESULTS: There was strong evidence against the Cox assumption of proportional hazards for nodal status, and nodal status was not in the Cox step-wise model. With step-wise log-normal regression, a large tumor size (P < .001), positive nodes (P = .002), high nuclear grade (P = .01), presence of LVPI (P = .03), and infiltrating duct carcinoma not otherwise specified (P = .05) were associated with a reduction in DFS. CONCLUSIONS: For nodal status, there was strong evidence against the Cox assumption of proportional hazards, and it was not included in the Cox model although it was in the log-normal model. Only traditional factors were included in the step-wise models. Thus, this statistical management of prognostic markers in breast cancer appears to be very important.

Assessment of treatment for patients with primary ductal carcinoma in situ in the breast.

BACKGROUND: Current mammographic technology has resulted in increased detection of ductal carcinoma in situ (DCIS). It is necessary to assess which patients presenting with DCIS are good candidates for breast conservation and which of these patients should receive adjuvant radiation. METHODS: We accrued clinical data for 124 patients with a primary diagnosis of DCIS from 1979 through 1994. Primary therapy was a mastectomy for 18 patients, and a lumpectomy for 106 patients. Only 18 of the latter group of patients received adjuvant radiotherapy. For the 88 lumpectomy-alone patients (median follow-up, 5.2 years), we evaluated the effects of clinical (age and initial presentation) and pathologic (nuclear grade, architecture, parenchymal involvement, calcifications, and measured margins) factors on recurrence of DCIS or the development of invasive breast cancer. RESULTS: Patients who underwent lumpectomy with or without adjuvant radiotherapy (median follow-up, 5.0 years) were significantly more likely to have recurrence of DCIS (P=.05) than those who underwent mastectomy (median follow-up, 6.7 years): 18% (19/106) versus 0% (0/18), respectively; lumpectomy-alone patients experienced a 19% (17/88) rate of DCIS recurrence. All recurrent DCIS was ipsilateral. For lumpectomy-alone patients, the factors associated with ipsilateral recurrence of DCIS were extent of involvement of the parenchyma (P=.01, for univariate; P=.07, for multivariate) and initial presentation (P=.05, for univariate; P=.07, for multivariate). Eleven lumpectomy-alone patients developed invasive breast cancer (6 ipsilateral, 5 contralateral); none of the 18 lumpectomy patients who received adjuvant radiation developed invasive disease. None of the factors investigated, including primary surgery and adjuvant radiotherapy, were associated with a significant effect on the development of invasive disease. CONCLUSIONS: Longer follow-up is required to determine if the benefits of either mastectomy or radiotherapy following lumpectomy persist. There is a suggestion that patients under 40 years of age or women who present with nipple discharge might be considered for either adjuvant radiotherapy following lumpectomy or a simple mastectomy.

Primary breast cancer in the elderly.

OBJECTIVES: With respect to breast cancer in the elderly, to define "old" in the context of comorbidity and physiologic rather than chronologic age. In addition, after discussion of factors influencing decisions regarding screening, stage at presentation and treatment decisions, to present an approach to the treatment of primary breast cancer in the elderly, taking into account quality of life, expected outcomes and cost-effectiveness. DATA SOURCES: A review of the medical literature from 1980 to 1996, using the MEDLINE database and 2 relevant studies from The Henrietta Banting Breast Centre Research Programme at Women's College Hospital, Toronto. STUDY SELECTION: A large number of breast cancer studies that might provide a better understanding of primary breast cancer in the elderly. DATA SYNTHESIS: The studies reviewed demonstrated that the annual incidence of breast cancer increases with age, along with a longer life expectancy for women. There appears to be a delay in presentation for elderly women with breast cancer, related in part to patient and physician knowledge. Biennial mammography and physical examination are effective in women aged 50 to 74 years, but compliance with screening recommendations decreases with age. Although treatment goals are the same for women of all ages, most treatment decisions are based on studies that seldom include women over 65 years of age. Physicians tend to underestimate life expectancy and older women are less likely to seek information. Breast conserving surgery, partial mastectomy and even axillary dissection can be carried out under local anesthesia with little physiologic disturbance, but unless axillary dissection is required to make a treatment decision, it may be foregone in clinically node-negative elderly women. The role of adjuvant radiotherapy in the elderly is not yet well established; tamoxifen is the usual adjuvant systemic therapy given to older women. For those who are truly infirm, tamoxifen alone can be considered. Studies to date do not clarify whether breast cancer in older women runs a more or less favourable course. However, locoregional recurrence appears to decrease with age. Deaths from competing causes are a confounding issue. CONCLUSIONS: It is imperative to develop a coherent strategy for the treatment of primary breast cancer in the elderly that takes into account functional status and quality of life. Clinical trials must include older women and there must be good clinical trials designed specifically for older women.

Five versus more than five years of tamoxifen therapy for breast cancer patients with negative lymph nodes and estrogen receptor-positive tumors.

BACKGROUND: In 1982, the National Surgical Adjuvant Breast and Bowel Project initiated a randomized, double-blinded, placebo-controlled trial (B-14) to determine the effectiveness of adjuvant tamoxifen therapy in patients with primary operable breast cancer who had estrogen receptor-positive tumors and no axillary lymph node involvement. The findings indicated that tamoxifen therapy provided substantial benefit to patients with early stage disease. However, questions arose about how long the observed benefit would persist, about the duration of therapy necessary to maintain maximum benefit, and about the nature and severity of adverse effects from prolonged treatment. PURPOSE: We evaluated the outcome of patients in the B-14 trial through 10 years of follow-up. In addition, the effects of 5 years versus more than 5 years of tamoxifen therapy were compared. METHODS: In the trial, patients were initially assigned to receive either tamoxifen at 20 mg/day (n = 1404) or placebo (n = 1414). Tamoxifen-treated patients who remained disease free after 5 years of therapy were then reassigned to receive either another 5 years of tamoxifen (n = 322) or 5 years of placebo (n = 321). After the study began, another group of patients who met the same protocol eligibility requirements as the randomly assigned patients were registered to receive tamoxifen (n = 1211). Registered patients who were disease free after 5 years of treatment were also randomly assigned to another 5 years of tamoxifen (n = 261) or to 5 years of placebo (n = 249). To compare 5 years with more than 5 years of tamoxifen therapy, data relating to all patients reassigned to an additional 5 years of the drug were combined. Patients who were not reassigned to either tamoxifen or placebo continued to be followed in the study. Survival, disease-free survival, and distant disease-free survival (relating to failure at distant sites) were estimated by use of the Kaplan-Meier method; differences between the treatment groups were assessed by use of the logrank test. The relative risks of failure (with 95% confidence intervals [CIs]) were determined by use of the Cox proportional hazards model. Reported P values are two-sided. RESULTS: Through 10 years of follow-up, a significant advantage in disease-free survival (69% versus 57%, P < .0001; relative risk = 0.66; 95% CI = 0.58-0.74), distant disease-free survival (76% versus 67%, P < .0001; relative risk = 0.70; 95% CI = 0.61-0.81), and survival (80% versus 76%, P = .02; relative risk = 0.84; 95% CI = 0.71-0.99) was found for patients in the group first assigned to receive tamoxifen. The survival benefit extended to those 49 years of age or younger and to those 50 years of age or older. Tamoxifen therapy was associated with a 37% reduction in the incidence of contralateral (opposite) breast cancer (P = .007). Through 4 years after the reassignment of tamoxifen-treated patients to either continued-therapy or placebo groups, advantages in disease-free survival (92% versus 86%, P = .003) and distant disease-free survival (96% versus 90%, P = .01) were found for those who discontinued tamoxifen treatment. Survival was 96% for those who discontinued tamoxifen compared with 94% for those who continued tamoxifen treatment (P = .08). A higher incidence of thromboembolic events was seen in tamoxifen-treated patients (through 5 years, 1.7% versus 0.4%). Except for endometrial cancer, the incidence of second cancers was not increased with tamoxifen therapy. CONCLUSIONS AND IMPLICATIONS: The benefit from 5 years of tamoxifen therapy persists through 10 years of follow-up. No additional advantage is obtained from continuing tamoxifen therapy for more than 5 years.

An improved statistical approach: can it clarify the role of new prognostic factors for breast cancer?

Recently, there has been a proliferation of new biomarkers, some of which may lead to an improved prognostic index or may influence treatment selection. However, there are methodological and statistical issues that require attention in assessing the role and use of these prognostic factors. Between 1977 and 1986, 1097 primary breast cancer patients were accrued for multidisciplinary research at the Henrietta Banting Breast Centre, Women's College Hospital; follow-up to 1990 is complete for 96% of the patients. Data for these patients are used here to illustrate strategies: (1) for the comparison of results from diverse assessments of biomarkers; (2) for the improved comparability of inter-laboratory results; (3) for the examination of the results from monoclonal or polyclonal antibody assays for possible clinically relevant bimodality; (4) for good statistical resolution of overlapping distributions; (5) that involve the use of quantitative values for prognostic factors whenever possible; and (6) for improved multivariate analyses. Good data handling and analyses may enable more accurate and rapid assessment of new prognostic factors, thereby expediting and improving their clinical application.

Alternative multivariate modelling for time to local recurrence for breast cancer patients receiving a lumpectomy alone.

Certain prognostic factors (patient and/or tumour characteristics) may be associated with low (or high) risk for local recurrence. Patients with these characteristics could be candidates for less (or more) adjuvant therapy or a less (or more) aggressive surgical approach. However, the assessment of many factors can be problematic with the standard multivariate technique-a Cox proportional hazards model and step-wise regression. We compared the results obtained when using a Cox model with those from four alternative models (exponential, Weibull, log logistic and log Normal) in step-wise and all subset regressions. Between 1977 and 1986, 293 primary invasive breast cancer patients were treated at the Henrietta Banting Breast Centre with a lumpectomy with or without an axillary dissection, and with no postoperative adjuvant therapy. The variables considered were age, lymph node status, tumour size, estrogen receptor (ER), progesterone receptor (PgR), histologic grade, nuclear grade, carcinoma in situ (CIS), amount of CIS, and presence of tumour emboli. With follow-up to 1991, nodal status was not found to be included in the step-wise Cox model, although it was in the step-wise exponential, Weibull and log Normal models, and in the best all subset models for all model types. The variables tumour emboli, ER, age, CIS and nodal status were consistently included in the best all subset regressions, regardless of model type. In the 1993 follow-up, the variables in the step-wise Cox model were tumour emboli, ER, age, CIS and nodal status. The multivariate consideration of all possible subsets of regression variables led to an earlier indication of the importance of nodal status, while the data strongly supported accelerated failure time models over the Cox model.

Factors associated with local breast cancer recurrence after lumpectomy alone.

BACKGROUND: The purpose was to determine the rate of local breast relapse in patients with breast cancer uniformly treated with partial mastectomy but without postoperative radiotherapy and without systemic adjuvant therapy. We also systematically examined the factors associated with local recurrence to determine whether a low-risk subgroup existed. METHODS: A retrospective review of a prospectively followed (median, 8 years) cohort of 293 patients was performed. The end-point was ipsilateral local breast cancer recurrence. The patient's age, tumor size, nodal status, estrogen and progesterone receptor status, histology, and tumor and nuclear grade were studied, as were the presence and amount of carcinoma in situ and the presence of tumor emboli using univariate Kaplan-Meier and Cox step-wise multivariate analyses. RESULTS: The overall local relapse rate was 26% (77 recurrences). Univariate factors significantly associated with decreased local relapse included older age, negative nodes, small tumor size, positive estrogen receptor status, and absence of tumor emboli. Significant multivariate variables were age, nodal status, estrogen receptor status, absence of comedo carcinoma in situ, and tumor emboli. A low-risk subgroup of 66 patients was defined with a 6% 10-year local recurrence rate. CONCLUSION: Important patient and tumor variables associated with local breast cancer relapse after breast-conserving surgery can define a low-risk subgroup.

A moderate decline in specific activity does not lead to an underestimation of hepatic glucose production during a glucose clamp.

We have previously shown that modeling errors lead to underestimation of hepatic glucose production (HGP) during glucose clamps when specific activity (SA) declines markedly. We wished to assess whether the failure to keep SA constant substantially affects calculation of HGP during insulin infusion when glucose requirements to maintain the glucose clamp are moderate. Therefore, 150-minute hyperinsulinemic (5.4 pmol - kg (-1) - min (-1) clamps were performed in depancreatized dogs that were maintained hyperglycemic (approximately 10 mmol/L with either (l) unlabeled glucose infusate (COLD Ginf, n = 5) or (2) labeled glucose infusate (HOT Ginf, n = 6) containing high-performance liquid chromatography (HPLC purified [6-3H]glucose. Insulinemia and glucagonemia were similar between the two groups. Additionally, glucose infusion rates were equivalent with COLD and HOT Ginf, indicating comparable insulin effects on overall glucose metabolism. The SA decreased a maximum of 32% with COLD Ginf, but remained constant with HOT Ginf. HGP was suppressed equally with COLD or HOT Ginf treatments at each time point during the clamp (mean suppression during last hour of clamp, 69% +/- 4% and 69% +/- 5%, P = NS, COLD and HOT Ginf, respectively). We conclude that when glucose requirements are moderate and SA changes slowly, as in the diabetic dog, it is not necessary to keep SA perfectly constant to avoid significant modeling errors when calculating HPG during hyperinsulinemic clamps.

Clinical behavior of untreated axillary nodes after local treatment for primary breast cancer.

BACKGROUND: The purpose of this study was to examine the rate of axillary failure in patients with primary breast cancer treated without axillary dissection or radiation and to determine what factors may be associated with axillary failure. METHODS: We studied 112 patients with invasive breast cancer treated for primary disease with breast-conserving surgery without axillary dissection or radiation to the breast or axilla, accrued between 1977 and 1986. Data for these patients were prospectively gathered for a research database and reviewed retrospectively to determine axillary failure. The effects of age, tumor size, estrogen receptor (ER) status, progesterone receptor (PgR) status, histologic grade, nuclear grade, and tumor emboli on time to axillary failure were examined. RESULTS: The median follow-up was 9.6 years. There were 26 axillary recurrences, resulting in a 10-year actuarial nodal control rate of 72%. Patients with nodal failure proceeded to axillary dissection with minimal morbidity. In both univariate and multivariate analyses, only tumor size was significantly associated with axillary failure (p = 0.04 and p = 0.06, respectively). CONCLUSIONS: This study demonstrates a significant effect of tumor size on axillary failure and a reasonable rate of local control in small tumors. Further research should examine the utility of axillary dissection in women with small breast cancers.

An investigation of cut-points for primary breast cancer oestrogen and progesterone receptor assays.

Oestrogen and progesterone receptor (ER and PgR) assay values are frequently used in medical decision-making for breast cancer patients. We have proposed statistical standardization of receptor assay values to improve inter-laboratory comparability, and now report the use of standardized log units (SLU) to investigate the effects of ER and PgR cut-points on time to first recurrence outside the breast (DFS). Between 1980 and 1986, there were 678 primary breast cancer patients treated at the Henrietta Banting Breast Centre (HBBC). The effects of ER and PgR cut-points were examined with multivariate analyses considering the variables: age, tumour size, nodal status, weight and adjuvant treatment. We considered receptor assay cut-points ranging from - 1.0 to + 1.0 SLU (ER between 7 and 166 fmol/mg protein; PgR between 7 and 181 fmol/mg protein). PgR was included in the multivariate prognostic models more often than ER, although patients had a better prognosis with both larger ER and PgR values. There was no best cut-point for ER or PgR, and there was strong evidence that ER and PgR should be considered as continuous rather than dichotomous (negative, positive) variables. Patient prognosis should also be more comparable with SLU.

The Henrietta Banting Breast Centre database: a model for clinical research utilizing a hospital-based inception cohort.

The cohort study design has been used successfully in clinical cancer research. Cohorts, however, are valuable only if they produce results which are valid and generalizable. Some hospital-based inception cohorts satisfy both these requirements and may thus be useful research tools. The development of one such hospital-based cohort, the Henrietta Banting Breast Centre database, is described. This cohort is composed of 1097 women diagnosed with primary breast cancer at Women's College Hospital, Toronto, from January 1977 through December 1986. Details of diagnostic procedures, pathology, treatment, dates and sites of recurrence, and date of death are available on 96% of women. By comparison with published series and with the Ontario Cancer Registry, we have demonstrated validity and generalizability. A major advantage is the ready availability of paraffin tissue blocks on virtually all cases, facilitating analyses of the prognostic importance of specific biologic variables and immunocytochemical hormone assays. Other completed studies and future uses of the cohort are described.

Intracerebroventricular administration of somatostatin octapeptide counteracts the hormonal and metabolic responses to stress in normal and diabetic dogs.

Intracerebroventricular (ICV) injection of carbachol elicits hormonal and metabolic responses similar to moderate stress. In normal dogs, ICV carbachol stimulated marked counterregulatory hormone release, but altered plasma glucose only marginally because the marked increment in glucose production (Ra) was almost matched by the increment of utilization (Rd), even though plasma insulin was unchanged. In alloxan-diabetic dogs, Rd did not match Ra and plasma glucose increased substantially. Since somatostatin octapeptide (ODT8-SS) inhibits some sympathetic mechanisms of the stress response, we explored the extent to which ODT8-SS can alleviate the counterregulatory responses to stress induced by carbachol, and particularly whether it can restore glycemic control in diabetes. ODT8-SS (20 nmol) was ICV-injected (1) in normal dogs (n = 5), and (2) prior to ICV carbachol before (n = 7) and after (n = 6) the induction of alloxan-diabetes. ODT8-SS did not affect basal values, but when administered before ICV carbachol there were no significant increments in plasma epinephrine, cortisol, arginine vasopressin (AVP), insulin, glucose, or lactate. There were significant increases in norepinephrine, glucagon, Ra, Rd, and the glucose metabolic clearance rate (MCR), although they were much smaller than seen previously with ICV carbachol alone. After induction of alloxan-diabetes, Rd and MCR did not change with ICV ODT8-SS and carbachol as in normal dogs, but norepinephrine, epinephrine, glucagon, lactate, plasma glucose, and Ra increased, although with the exception of glucagon these increases were much smaller than seen previously with ICV carbachol alone. ODT8-SS administered before ICV carbachol in normal or diabetic animals resulted in increased free fatty acid (FFA) levels. The increases in glycerol were less than and those in FFA greater than seen previously with ICV carbachol alone. Since ODT8-SS does not alter basal counterregulatory hormone release but suppresses the release during stress, this is a useful probe to analyze some of the metabolic responses to stress. When the response to carbachol from our previous report is compared with the responses to carbachol + ODT8-SS, it is indicated that the stress-related increase in Ra was consistent with stimulation of the sympathetic nervous system, whereas increased Rd is related to an unknown stress-related neuroendocrine mechanism that requires a permissive effect of insulin, since it was not seen in the frankly diabetic animals. We hypothesize that the stress-induced increase in Rd occurs not only in muscle but also in adipocytes, and that the somatostatin-induced attenuation of Rd decreased FFA re-esterification and consequently markedly increased stress-induced FFA release.(ABSTRACT TRUNCATED AT 400 WORDS)

Insulin-like growth factor-I and insulin have no differential effects on glucose production and utilization under conditions of hyperglycemia.

We have previously shown that in moderately hyperglycemic depancreatized dogs, a glucose-lowering infusion of insulin-like growth factor-I (IGF-I) increased glucose utilization and lactate more, and suppressed glucose production and lipolysis less, than an equipotent glucose-lowering dose of insulin. Similar differences have been observed by others in nondiabetic and diabetic rats. To determine whether the decline in glycemia was important in detecting differential effects of IGF-I and insulin on glucose turnover, IGF-I (0.43 micrograms/kg.min; n = 6) or insulin (0.9 mU/kg.min; n = 9) were infused for 180 min, while hyperglycemia (approximately 180 mg/dl) was maintained. The decline of plasma glucose specific activity was minimized by using the matched step tracer infusion ([6-3H]- and [2-3H]glucose) method. Our results confirmed the approximately 10% potency of IGF-I on glucose metabolism compared to insulin and the lack of effect of IGF-I on insulin clearance. Under conditions of hyperglycemia, the glucose turnover findings were unexpected; there was no difference in the inhibition of glucose production (difference from basal, 2.7 +/- 0.4 mg/kg.min with IGF-I and 2.4 +/- 0.2 with insulin) or the stimulation of glucose utilization (difference from basal, 4.5 +/- 0.8 mg/kg.min with IGF-I and 4.7 +/- 1.3 with insulin). However, lactate increased more (P < 0.01) with IGF-I (from 1230 +/- 163 to a peak of 1903 +/- 349 microM) than insulin (from 1209 +/- 291 to 1535 +/- 340 microM) despite the same increment in glucose utilization. FFA and glycerol declined more with insulin, but the difference was not significant. IGF-I and insulin suppressed plasma amino acids to an equivalent extent. We concluded that 1) the differential effects of IGF-I and insulin on glucose turnover are masked under conditions of hyperglycemia; and 2) because insulin and IGF-I induced the same increment in glucose utilization, but lactate increased more with IGF-I, IGF-I might affect intracellular glucose metabolism differently from insulin. The failure of IGF-I to induce greater glucose utilization than insulin during hyperglycemia, the greater rise in lactate with IGF-I treatment, and the absence of differential effects on proteolysis indicate that IGF-I might have only limited clinical application in the treatment of diabetes.

The standardization of estrogen receptors.

Tumour estrogen receptor (ER) status may determine the medical treatment of a patient with breast cancer; yet inter-laboratory results can vary markedly, particularly when absolute cut-offs in fmol/mg cytosol protein are used. The use of standardized log units is proposed to permit greater inter-laboratory comparability. We have assessed the biochemical ER values using the dextran-coated charcoal method with three data sets, two quality control (QC) sets for Ontario laboratories and a data set with values for 184 primary breast cancer patients seen at Women's College Hospital (WCH) between 1985 and 1986. The distributions for all the raw data were skewed toward the lower end of the range; a log transformation improved the symmetry of the distributions. There was marked inter-laboratory variation in the QC data, and standardized log units greatly reduced this variability. The WCH data had similar differentiation by tumour size and nodal status with both the raw data and standardized log units. However, standardized log units provided more consistent evidence of an association between ER and immunohistochemical ERICA. The standardized log units provide quantitative receptor values suitable for multi-centre research, for future work with clinical outcomes, and for the daily management of patients.

Effects of subbasal insulin infusion on resting and exercise-induced glucose turnover in depancreatized dogs.

beta-Adrenergic blockade suppressed lipolysis and normalized the exercise-induced increments in glucose uptake (GlcU) and metabolic clearance rate (MCR) in alloxan-diabetic dogs with residual insulin, but not in insulin-deprived depancreatized dogs even when combined with methylpalmoxirate (MP), which suppresses fatty acid oxidation. The effects of a minimal amount of insulin (as in the alloxan-diabetic dog), were studied in depancreatized, 24-h insulin-deprived dogs during rest and treadmill exercise (6 km/h, 10% slope) using a 1/4 basal insulin infusion (50 microU.kg-1.min-1, insulin, n = 6) alone, or with MP (20 mg.kg-1.day orally, 2.5 days, MP+insulin, n = 6). At rest, insulin decreased circulating fatty acids (31%) and Glc (13%) and increased GlcU and MCR (86 and 72%). Glc production was unaffected. MP plus insulin markedly suppressed hepatic fatty acid oxidation, decreased Glc (44%) and Glc production (50%), and markedly increased MCR (128%). The exercise-induced increments in MCR were markedly improved only by MP plus insulin but were still lower than in the propranolol-treated alloxan-diabetic dogs. Plasma Glc inversely correlated with the exercise-induced increase in MCR (r = -0.86). We conclude that 1) acute infusion of subbasal insulin improved GlcU in depancreatized dogs at rest but not during exercise; 2) inhibition of fatty acid oxidation combined with subbasal insulin improved the exercise-induced increase in MCR; and 3) the difference in GlcU and MCR between the MP plus insulin-treated depancreatized dogs and the beta-blockade-treated alloxan-diabetic dogs suggests a difference between acute and chronic effects of insulin.

Indirect effects of insulin in regulating glucose fluxes.

Metabolism of fuels is driven by the energy demand of the organism and its regulation is influenced by many hormonal and metabolic factors. Insulin is of utmost importance in regulating glucose metabolism by promoting glucose uptake in the insulin-sensitive tissues for energy consumption and/or storage. The effects of insulin on glucose metabolism can be both direct and indirect. Ample evidence has indicated that insulin directly stimulates glucose transport systems in the target tissues. However, the changes in glucose fluxes can also be brought out by indirect effects of insulin which are produced secondary to the insulin-induced changes in other hormones and metabolites. In this chapter, we discussed a number of examples of insulin's indirect effects on glucose metabolism. We demonstrated that insulin can indirectly promote muscle glucose uptake during exercise by restraining the release and oxidation of fatty acids and decrease of hyperglycemia. We have presented some evidence for an indirect regulation of glucose cycling by insulin. We have also demonstrated the importance of the peripheral levels of insulin for insulin-induced inhibition of hepatic glucose production. This presumably indirect effects of peripheral insulin might consist of 1) suppression of the release of energy substrates and gluconeogenic precursors; and 2) suppression of glucagon secretion. In a carbachol-induced stress model, insulin is not required for a putatively neural regulation of an increase in systemic glucose uptake but a "permissive" effect of insulin is essential. These studies underscore the importance of the interactions between insulin and other hormones and metabolites as opposed to insulin's direct actions per se.

Importance of peripheral insulin levels for insulin-induced suppression of glucose production in depancreatized dogs.

It is generally believed that glucose production (GP) cannot be adequately suppressed in insulin-treated diabetes because the portal-peripheral insulin gradient is absent. To determine whether suppression of GP in diabetes depends on portal insulin levels, we performed 3-h glucose and specific activity clamps in moderately hyperglycemic (10 mM) depancreatized dogs, using three protocols: (a) 54 pmol.kg-1 bolus + 5.4 pmol.kg-1.min-1 portal insulin infusion (n = 7; peripheral insulin = 170 +/- 51 pM); (b) an equimolar peripheral infusion (n = 7; peripheral insulin = 294 +/- 28 pM, P < 0.001); and (c) a half-dose peripheral infusion (n = 7), which gave comparable (157 +/- 13 pM) insulinemia to that seen in protocol 1. Glucose production, use (GU) and cycling (GC) were measured using HPLC-purified 6-[3H]- and 2-[3H]glucose. Consistent with the higher peripheral insulinemia, peripheral infusion was more effective than equimolar portal infusion in increasing GU. Unexpectedly, it was also more potent in suppressing GP (73 +/- 7 vs. 55 +/- 7% suppression between 120 and 180 min, P < 0.001). At matched peripheral insulinemia (protocols 2 and 3), not only stimulation of GU, but also suppression of GP was the same (55 +/- 7 vs. 63 +/- 4%). In the diabetic dogs at 10 mM glucose, GC was threefold higher than normal but failed to decrease with insulin infusion by either route. Glycerol, alanine, FFA, and glucagon levels decreased proportionally to peripheral insulinemia. However, the decrease in glucagon was not significantly greater in protocol 2 than in 1 or 3. When we combined all protocols, we found a correlation between the decrements in glycerol and FFAs and the decrease in GP (r = 0.6, P < 0.01). In conclusion, when suprabasal insulin levels in the physiological postprandial range are provided to moderately hyperglycemic depancreatized dogs, suppression of GP appears to be more dependent on peripheral than portal insulin concentrations and may be mainly mediated by limitation of the flow of precursors and energy substrates for gluconeogenesis and by the suppressive effect of insulin on glucagon secretion. These results suggest that a portal-peripheral insulin gradient might not be necessary to effectively suppress postprandial GP in insulin-treated diabetics.