Key points
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Glucagon‐like peptide‐1 (Glp1) regulates hepatic glucose production (HGP) and muscle glucose uptake (MGU) via its ability to stimulate insulin secretion.
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Using exercise as a means to ...stimulate glucose flux independently of insulin secretion, we observed that Glp1 receptor (Glp1r) knockout (Glp1r−/−) mice become hyperglycaemic but display normal rates of MGU.
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Since euglycaemia during exercise is typically maintained by matching rates of HGP to rates of MGU, we hypothesize that exercise‐induced hyperglycaemia in Glp1r−/− mice is due to excessive HGP.
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Using innovative catheterization and isotope dilution techniques, we demonstrate that hyperglycaemia in exercising Glp1r−/− mice is associated with excessive HGP and glucagon secretion.
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These results suggest an essential and novel role for basal Glp1r signalling in the suppression of alpha cell secretion during exercise.
In response to oral glucose, glucagon‐like peptide‐1 receptor (Glp1r) knockout (Glp1r−/−) mice become hyperglycaemic due to impaired insulin secretion. Exercise also induces hyperglycaemia in Glp1r−/− mice. In contrast to oral glucose, exercise decreases insulin secretion. This implies that exercise‐induced hyperglycaemia in Glp1r−/− mice results from the loss of a non‐insulinotropic effect mediated by the Glp1r. Muscle glucose uptake (MGU) is normal in exercising Glp1r−/− mice. Thus, we hypothesize that exercise‐induced hyperglycaemia in Glp1r−/− mice is due to excessive hepatic glucose production (HGP). Wild‐type (Glp1r+/+) and Glp1r−/− mice implanted with venous and arterial catheters underwent treadmill exercise or remained sedentary for 30 min. 3‐3Hglucose was used to estimate rates of glucose appearance (Ra), an index of HGP, and disappearance (Rd). 214Cdeoxyglucose was used to assess MGU. Glp1r−/− mice displayed exercise‐induced hyperglycaemia due to an excessive increase in Ra but normal Rd and MGU. Exercise‐induced glucagon levels were ∼2‐fold higher in Glp1r−/− mice, resulting in a ∼2‐fold higher glucagon:insulin ratio. Since inhibition of the central Glp1r stimulates HGP, we tested whether intracerebroventricular (ICV) infusion of the Glp1r antagonist exendin(9–39) (Ex9) in Glp1r+/+ mice would result in exercise‐induced hyperglycaemia. ICV Ex9 did not enhance glucose levels or HGP during exercise, suggesting that glucoregulatory effects of Glp1 during exercise are mediated via the pancreatic Glp1r. In conclusion, functional disruption of the Glp1r results in exercise‐induced hyperglycaemia associated with an excessive increase in glucagon secretion and HGP. These results suggest an essential role for basal Glp1r signalling in the suppression of alpha cell secretion during exercise.
Although important predictors of survival in myeloma patients have been identified, it is well recognized that better prognostic factors for this disease are needed. Because cytogenetics play a ...dominant role in the outcome of patients with acute leukemia, their prognostic value was evaluated in a large group of newly diagnosed and previously treated myeloma patients receiving autotransplants.
A total of 427 either newly diagnosed (26%) or previously treated patients (74%) received tandem transplants, supported by mobilized peripheral-blood stem cells. Numerous variables, including cytogenetics, were analyzed for their impact on complete remission, event-free survival (EFS), and overall survival (OS).
Abnormal karyotypes were detected in 37% of our patients and were very complex, irrespective of the duration of standard therapy before the first autotransplant. In addition to previously recognized unfavorable implications of partial or complete deletion of chromosome 13 and 11q abnormalities, we now observed that the presence of any translocation likewise portended poor outcome (unfavorable karyotypes). On multivariate analysis, the absence of an unfavorable karyotype was the most favorable variable for both EFS (P = .0001) and OS (P = .0001). Other favorable factors were duration of standard therapy and a low beta-2 microglobulin (B2M) level before the first autotransplant. A risk-based classification system was developed according to the number of these favorable variables present, showing highly significant differences in event-free and overall survival.
Cytogenetics play a dominant role in myeloma and were independent of previously recognized important prognostic factors, such as B2M and duration of prior standard therapy.
To compare, in the setting of tandem autotransplantations for multiple myeloma (MM), two established methods of peripheral-blood stem-cell (PBSC) procurement with chemotherapy or hematopoietic growth ...factor alone.
Between June 1994 and July 1995, 44 patients with MM were randomized to PBSC mobilization with either granulocyte colony-stimulating factor (G-CSF) 16 microg/kg (group 1; n = 22) or high-dose cyclophosphamide (HDCTX) 6 g/m2 plus G-CSF 5 microg/kg (group 2; n = 22). All 44 patients received melphalan 200 mg/m2 with their first autograft and 32 patients proceeded to a second transplantation.
Group 2 required a significantly longer time interval for completion of PBSC collection than group 1 (median, 22 v 8 days; P = .0001), greater frequency of hospitalization (100% v 32%; P = .0001), and increased transfusion of platelets (86% v 18%; P = .0001) and packed RBCs (86% v 55%; P = .02). Likewise, the incidence of fever and pneumonia/sepsis were higher in group 2 (P = .02 and P = .04, respectively). Surprisingly, despite greater CD34 cell quantities infused in group 2, median recovery times of granulocytes (both > 500/microL and 2,500/microL) and platelets (both > 50,000/microL and > 100,000/microL) were similar (all P > .7). Posttransplant toxicities were also similar.
Compared with HDCTX plus G-CSF, high-dose G-CSF alone is associated with lower morbidity, shorter duration of PBSC mobilization, and comparable hematopoietic recovery after transplantation, which should result in significant cost reduction. Considering the relatively limited antitumor activity of HDCTX (10% with > or = 50% tumor cytoreduction), PBSC mobilization with HDCTX should be limited to selected patients with persistent MM despite induction chemotherapy.
Of 496 consecutive patients with multiple myeloma (MM) enrolled in clinical trials of tandem transplants with peripheral blood stem cells support, 470 (95%) completed the first autotransplant with ...melphalan 200 mg/m2 (MEL 200) and 363 (73%) completed the second transplant with either MEL 200 (40%), MEL 140 mg/m2 (MEL 140) with total-body irradiation (17%), or a combination of alkylating agents (16%), depending on the response status prior to the second transplant; 31 patients up to age 60 years received an allograft as the second transplant. The median interval from first to second transplant was 5 months. Treatment-related mortality during the first year after transplantation was 7%, and complete remission (CR) was obtained in 36%; the median durations of event-free survival (EFS) and overall survival (OS) after transplant were 26 and 41 months, respectively. Low β2-microglobulin (B2M c2.5 mg/L) and C-reactive protein (CRP c0.4 mg/dL) were the most significant standard parameters associated with both prolonged EFS and OS. Median OS exceeded 5.5 years in the one third of patients with both low B2M and CRP. When cytogenetics were included in the analysis, the presence of 11q abnormalities and/or complete or partial deletion of chromosome 13 (“unfavorable karyotype”) became a dominant negative feature for both EFS and OS. In addition to these pretransplant parameters, attainment of CR and application of two transplants within 6 months both significantly extended EFS and OS. The group of patients (7%) with high B2M and CRP with either IgA isotype or unfavorable karyotype had the worst prognosis (EFS, c10 months; median OS, c12 months) and will require novel therapy. We conclude that tandem transplants are feasible in the majority of patients up to age 70 years, effecting CR in one third of all patients. Median OS was greater than 5.5 years, regardless of pretransplant features, if the first transplant was applied within 12 months of initial treatment and the second transplant no more than 6 months later.
R. M. O'Doherty, D. P. Bracy, D. K. Granner and D. H. Wasserman
Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennesse 37232, USA.
A single ...bout of acute exercise increases hexokinase (HK) II mRNA and
enzyme activity R. M. O'Doherty, D. P. Bracy, H. Osawa, D. H. Wasserman,
and D. K. Granner. Am. J. Physiol. 266 (Endocrinol. Metab. 29): E171-E178,
1994. The present study addresses the mechanism of the increase in HK II
mRNA. Male rats undertook a single bout of treadmill exercise and were then
killed immediately or after a predetermined recovery period. The
gastrocnemius/plantaris muscle complex, composed of mixed fiber types, was
excised; the nuclei were isolated; and HK I, HK II, beta-actin, and
alpha-tubulin gene transcription rates were measured. Genomic DNA and
plasmid DNA were used as positive and negative controls, respectively.
Immediately after the cessation of 30, 45, or 90 min of exercise, HK II
gene transcription rates were 1.3 +/- 0.3-,2.9 +/- 0.3-, and 4.0 +/-
0.6-fold, respectively, above those of sedentary controls. The increases
after 45 and 90 min of exercise were statistically significant (P <
0.01). One hour after the cessation of 30 min of exercise, HK II gene
transcription was significantly increased (1.40 +/- 0.03-fold; P <
0.05). At all time points, transcription of the HK I, beta-actin, and
alpha-tubulin genes was unchanged. We conclude that the exercise-induced
increase in HK II gene transcription appears to play a major role in the
increase of HK II mRNA and activity.
Department of Molecular Physiology and Biophysics, Vanderbilt
University School of Medicine, Nashville, Tennessee 37232-0615
The hypothesis
of this investigation was that insulin and muscle ...contraction, by
increasing the rate of skeletal muscle glucose transport, would bias
control so that glucose delivery to the sarcolemma (and t tubule) and
phosphorylation of glucose intracellularly would exert more influence
over glucose uptake. Because of the substantial increases in blood flow
(and hence glucose delivery) that accompany exercise, we predicted that
glucose phosphorylation would become more rate determining during
exercise. The transsarcolemmal glucose gradient (TSGG; the glucose
concentration difference across the membrane) is inversely related to
the degree to which glucose transport determines the rate of glucose
uptake. The TSGG was determined by using isotopic methods in conscious
rats during euglycemic hyperinsulinemia Ins; 20 mU/(kg · min); n = 7, during treadmill exercise (Ex,
n = 6), and in sedentary,
saline-infused rats (Bas, n = 13).
Rats received primed, constant intravenous infusions of trace
3- O - 3 H methyl - D -glucose
and U- 14 Cmannitol.
Then
2-deoxy- 3 Hglucose
was infused for the calculation of a glucose metabolic index
(R g ). At the end of experiments,
rats were anesthetized, and soleus muscles were excised. Total soleus
glucose concentration and the steady-state ratio of intracellular to
extracellular
3- O - 3 H methyl - D -glucose
(which distributes on the basis of the TSGG) were used to calculate
ranges of possible glucose concentrations (G) at the
inner and outer sarcolemmal surfaces
(G im and
G om , respectively).
Soleus R g was increased in Ins and
further increased in Ex. In Ins, total soleus glucose,
G om , and the TSGG
were decreased compared with Bas, while
G im remained near 0. In Ex, total soleus glucose and
G im were increased
compared with Bas, and there was not a decrease in
G om as was observed
in Ins. In addition, accumulation of intracellular free
2-deoxy- 3 Hglucose
occurred in soleus in both Ex and Ins. Taken together, these data
indicate that, in Ex, glucose phosphorylation becomes an important
limitation to soleus glucose uptake. In Ins, both glucose delivery and
glucose phosphorylation influence the rate of soleus glucose uptake
more than under basal conditions.
glucose phosphorylation; glucose delivery; countertransport; 3- O - methyl - D -glucose; 2-deoxyglucose
Multiple myeloma (MM) is usually characterized by production of a single serum monoclonal protein of constant isotype and light-chain restriction. Multiple Ig isotypes and isotype switches, which are ...rare in untreated patients, are reported to be more common in patients undergoing myeloablative therapy. These additional protein bands, detected by immunofixation electrophoresis (IFE), could be due to altered paraprotein production by the malignant plasma cell clone or oligoclonal Ig production during recovery of B-cell function after myeloablative therapy. We analyzed abnormal protein bands (APB), distinct from the presenting paraprotein, in 550 patients receiving high-dose therapy with autologous hematopoietic cell transplantation at a single institution. Fifty-five patients (10%) had APB, 48 had oligoclonal bands (OB), and 23 had an apparent isotype switch (IS) on IFE (16 had both OB and IS). Morphologic and flow cytometric examination of bone marrow in 17 patients with IS showed no evidence of a clonal plasma cell isotype switch. Patients with APB had significantly higher complete response to therapy (67% v 37%, P = .001). To assess the independent prognostic relevance of APB, a multivariate analysis was performed among 471 patients surviving at least 12 months from first transplant (all patients developing APB had done so by 12 months from first transplant). APB (in 50 patients) was a favorable feature for both event-free (rank 3, P = .004) and overall survival (rank 3, P = .0005). We propose that OB and IS are likely to be due to recovery of Ig production rather than alterations in the biology of the malignant plasma cell clone.
This study addresses the potential role of skeletal muscle hexokinase (HK) II in the regulation of glucose uptake and metabolism in vivo. Male rats undertook a single bout of treadmill exercise and ...were then killed immediately or after a predetermined recovery period. Three muscles soleus (Sol), gastrocnemius/plantaris (Gc), and white vastus were excised, and HK II mRNA, GLUT-4 mRNA, total HK (HK I and HK II) and heat-stable HK (predominantly HK I) activities were assessed. Three hours after the cessation of a single bout of exhaustive exercise, HK II mRNA was significantly increased in all three muscles. Ninety or thirty minutes of exercise, with a 3-h recovery, increased Gc HK II mRNA to the same extent as exhaustive exercise, but 15 min of exercise had no effect. Gc HK II mRNA continued to increase up to 8 h after the cessation of 90 min of exercise but returned to basal by 24 h postexercise. In contrast to HK II mRNA, Gc GLUT-4 mRNA was unchanged at 0, 3, 8, and 24 h after the cessation of 90 min of exercise. Total HK activity was significantly increased in Sol and Gc, 8 and 24 h after the cessation of 90 min of exercise. Heat-stable HK activity was unchanged in all three muscles. The increase in total HK activity, inferred to be an increase of HK II, may be important in the persistence of the postexercise increase in insulin action.
Melphalan (MEL) is probably the most effective chemotherapeutic agent in multiple myeloma (MM) with a clear dose-response
effect. It can be escalated without excessive toxicity to 200 mg/m2, a ...myeloablative dose requiring hematopoietic stem cell
support. Patients with marked renal insufficiency, not an infrequent finding in MM, have either received reduced doses or
have been excluded from therapy with high-dose MEL. A prospective study was performed to evaluate the relationship between
MEL pharmacokinetics and renal function in 20 patients with MM. Six patients had severe renal insufficiency (creatinine clearance,
<40 ml/min), including five on chronic hemodialysis. Three patients with severe renal impairment first received a low test
dose of MEL (16 mg/m2) for pharmacokinetic studies. All patients received 200 mg/m2 MEL divided into two equal doses of 100
mg/m2 i.v. on 2 consecutive days, followed by the administration of peripheral blood stem cells. MEL pharmacokinetics, performed
after the first dose of 100 mg/m2, was not adversely affected by impaired renal function. The median half-life (t1/2), area
under the concentration curve, and clearance of MEL were 1.1 h, 5.5 mg h/liter, and 27.5 liter/h, respectively, in patients
with a creatinine clearance of <40 ml/min compared to 1.9, 7.9, and 23.6 for the others. Renal insufficiency also had no apparent
negative impact on the quality of peripheral blood stem cell collections and did not adversely affect posttransplant engraftment,
transfusion requirements, incidence of severe mucositis, or overall survival. However, it was associated with longer durations
of fever (P = 0. 0005) and hospitalization (P = 0.004). No transplant-related deaths were observed. Plasma t1/2 and area under
the concentration curve differed by a factor of 10 and MEL clearance by a factor of 5 between patients with the lowest and
highest values. These large variations in MEL elimination could not be explained by patient or disease characteristics. We
conclude that renal failure does not require dose reduction of MEL in autologous transplant. Due to marked interindividual
variation in MEL elimination, pharmacokinetically guided dosing as well as cellular pharmacology studies may be helpful in
achieving a more uniform antitumor effect.
Multiple myeloma (MM) is usually characterized by production of a single serum monoclonal protein of constant isotype and light-chain restriction. Multiple Ig isotypes and isotype switches, which are ...rare in untreated patients, are reported to be more common in patients undergoing myeloablative therapy. These additional protein bands, detected by immunofixation electrophoresis (IFE), could be due to altered paraprotein production by the malignant plasma cell clone or oligoclonal Ig production during recovery of B-cell function after myeloablative therapy. We analyzed abnormal protein bands (APB), distinct from the presenting paraprotein, in 550 patients receiving high-dose therapy with autologous hematopoietic cell transplantation at a single institution. Fifty-five patients (10%) had APB, 48 had oligoclonal bands (OB), and 23 had an apparent isotype switch (IS) on IFE (16 had both OB and IS). Morphologic and flow cytometric examination of bone marrow in 17 patients with IS showed no evidence of a clonal plasma cell isotype switch. Patients with APB had significantly higher complete response to therapy (67% v 37%,P = .001). To assess the independent prognostic relevance of APB, a multivariate analysis was performed among 471 patients surviving at least 12 months from first transplant (all patients developing APB had done so by 12 months from first transplant). APB (in 50 patients) was a favorable feature for both event-free (rank 3, P = .004) and overall survival (rank 3, P = .0005). We propose that OB and IS are likely to be due to recovery of Ig production rather than alterations in the biology of the malignant plasma cell clone.
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