Frequency of cancer events with saxagliptin in the SAVOR-TIMI 53 trial.

The Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus (SAVOR)-Thrombolysis in Myocardial Infarction (TIMI) 53 trial randomized trial of 16,492 patients (placebo, n = 8212; saxagliptin, n = 8280) treated and followed for a median of 2.1 years afforded an opportunity to explore whether there was any association with cancer reported as a serious adverse event. At least one cancer event was reported by 688 patients (4.1%): 362 (4.3%) and 326 (3.8%) in the placebo and saxagliptin arms, respectively (p = 0.13). There were 59 (0.6%) deaths adjudicated as malignancy deaths with placebo and 53 (0.6%) with saxagliptin. Stratification by gender, age, race and ethnicity, diabetes duration, baseline glycated haemoglobin and pharmacotherapy did not show any clinically meaningful differences between the two study arms. The overall number of cancer events and malignancy-associated mortality rates were generally balanced between the placebo and saxagliptin groups, suggesting a null relationship with saxagliptin use over the median follow-up of 2.1 years. Multivariable modelling showed that male gender, dyslipidaemia and current smoking were independent predictors of cancer. These randomized data with adequate numbers of cancer cases are reassuring but limited, by the short follow-up in a trial not designed to test this hypothesis.

Achieving the composite endpoint of glycated haemoglobin <7.0%, no weight gain and no hypoglycaemia in the once-weekly dulaglutide AWARD programme.

AIM: To compare the effectiveness of dulaglutide 1.5 and 0.75 mg with active comparators and placebo with regard to a composite endpoint of glycated haemoglobin (HbA1c), weight and hypoglycaemia, using post hoc analyses. METHODS: A logistic regression analysis was performed on the intention-to-treat population, using data from the last observation carried forward, and the composite endpoint of HbA1c <7.0% (53 mmol/mol), no weight gain (≤0 kg) and no hypoglycaemia (glucose <3.0 mmol/l or severe hypoglycaemia) after 26 weeks for each trial in the AWARD programme separately. RESULTS: At 26 weeks, within each study, 37-58% of patients on dulaglutide 1.5 mg, 27-49% of patients on dulaglutide 0.75 mg, and 9-61% of patients on active comparators achieved the composite endpoint. Significantly more patients reached the composite endpoint with dulaglutide 1.5 mg than with metformin, sitagliptin, exenatide twice daily or insulin glargine: odds ratio (OR) 1.5 [95% confidence interval (CI) 1.0, 2.2; p < 0.05], OR 4.5 (95% CI 3.0, 6.6; p < 0.001), OR 2.6 (95% CI 1.8, 3.7; p < 0.001) and OR 7.4 (95% CI 4.4, 12.6; p < 0.001), respectively, with no difference between dulaglutide 1.5 mg and liraglutide 1.8 mg. In addition, significantly more patients reached the composite endpoint with dulaglutide 0.75 mg than with sitagliptin or insulin glargine: OR 3.3 (95% CI 2.2, 4.8; p < 0.001) and OR 4.5 (95% CI 2.7, 7.8; p < 0.001), respectively. CONCLUSIONS: Dulaglutide is an effective treatment option, resulting in a similar or greater proportion of patients reaching the HbA1c target of <7.0% (53 mmol/mol), without weight gain or hypoglycaemia compared with active comparators.

Benefits of a simple glycaemic protocol in an orthopaedic surgery ward: a randomized prospective study.

BACKGROUND: Hyperglycaemia and diabetes mellitus are common in patients hospitalized in the orthopaedic surgery ward. However, glycaemic control obtained during hospitalization is often suboptimal. No method for achieving adequate glycaemic control in this population has been validated in an in-hospital setting. INTERVENTION: An intervention including an intensive subcutaneous insulin protocol in the orthopaedic department. METHODS: All diabetic patients admitted to the Department of Orthopaedic Surgery were prospectively randomized during a 6-month period. One group (n = 30) received standard care with sliding scale insulin and the other group (n = 35) received the intervention protocol. During the intervention period, the staff was briefed on the importance of glucose monitoring and control. An intensive multiple-injection protocol consisting of four daily regular/neutral protamine hagedorn (NPH) insulin injections was initiated in diabetic patients. The programme was followed up by a consulting diabetologist. RESULTS: Mean blood glucose levels throughout the hospitalization were 161.48 ± 3.8 mg/dL in the intervention group versus 175.29 ± 2.3 mg/dL in the control group (p < 0.0005). Hospitalization was shorter by 2 days in the intervention group (p < 0.05). The number of severe hyperglycaemic events (blood glucose level above 400 mg%) was significantly lower (p < 0.05) in the intervention group. There was no significant difference in the number of hypoglycaemic events. CONCLUSIONS: The suggested four-step intervention regimen improved glycaemic control of hospitalized patients in the orthopaedic department and simplified the 'in-house' treatment of the diabetic patient. Hospital stays were reduced on average by two days (p < 0.05).

Treatment of new-onset type 1 diabetes with peptide DiaPep277 is safe and associated with preserved beta-cell function: extension of a randomized, double-blind, phase II trial.

BACKGROUND: Treatment with DiaPep277, a peptide derived from HSP60, has been shown to preserve beta-cell function in non-obese diabetic mouse (NOD) mice and in a trial with newly diagnosed human patients with type 1 diabetes treated over a 10-month period. This article extends the clinical trial observations to a total of 20 months of treatment to determine the safety and the effects of repeated doses of DiaPep277 on endogenous insulin secretion, metabolic control, and exogenous insulin requirements. METHODS: Thirty-five male patients (aged 16-58) with a basal C-peptide greater than 0.1 nmol/L were assigned to periodic treatment with DiaPep277 (1 mg) or placebo for a 12-month treatment and 18-month observation protocol, later extended to an additional year of treatment. Stimulated C-peptide, HbA1c, and an exogenous insulin dose were the clinical endpoints. RESULTS: At 18 months, stimulated C-peptide concentrations had fallen in the placebo group (p = 0.0005) but were maintained in the DiaPep277 group. The need for exogenous insulin was higher in the placebo group than in the DiaPep277 group. Mean HbA1c concentrations were similar in both groups. After extension of the study, patients continuing treatment with DiaPep277 and those switched from placebo to DiaPep277 manifested a trend towards a greater preservation of beta-cell function compared to patients maintained on or switched to placebo. The safety profile of DiaPep277 was similar between the treatment and placebo groups, and no drug-related adverse events occurred. CONCLUSIONS: Periodic treatment of subjects with DiaPep277 over 2 years was safe and associated preservation of endogenous insulin secretion up to 18 months was observed.

Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy in patients with type 2 diabetes mellitus.

AIMS/HYPOTHESIS: The aim of this study was to assess the efficacy and safety of sitagliptin (MK-0431) as monotherapy in patients with type 2 diabetes mellitus and inadequate glycaemic control (HbA(1c) > or =7% and < or =10%) on exercise and diet. METHODS: A total of 521 patients aged 27-76 years with a mean baseline HbA(1c) of 8.1% were randomised in a 1:2:2 ratio to treatment with placebo, sitagliptin 100 mg once daily, or sitagliptin 200 mg once daily, for 18 weeks. The efficacy analysis was based on an all-patients-treated population using an analysis of covariance, excluding data obtained after glycaemic rescue. RESULTS: After 18 weeks, HbA(1c) was significantly reduced with sitagliptin 100 mg and 200 mg compared with placebo (placebo-subtracted HbA(1c) reduction: -0.60% and -0.48%, respectively). Sitagliptin also significantly decreased fasting plasma glucose relative to placebo. Patients with higher baseline HbA(1c) (> or =9%) experienced greater placebo-subtracted HbA(1c) reductions with sitagliptin (-1.20% for 100 mg and -1.04% for 200 mg) than those with HbA(1c) <8% (-0.44% and -0.33%, respectively) or > or =8% to 8.9% (-0.61% and -0.39%, respectively). Homeostasis model assessment beta cell function index and fasting proinsulin:insulin ratio, markers of insulin secretion and beta cell function, were significantly improved with sitagliptin. The incidence of hypoglycaemia and gastrointestinal adverse experiences was not significantly different between sitagliptin and placebo. Sitagliptin had a neutral effect on body weight. CONCLUSIONS/INTERPRETATION: Sitagliptin significantly improved glycaemic control and was well tolerated in patients with type 2 diabetes mellitus who had inadequate glycaemic control on exercise and diet.

Antidiabetic effect of novel modulating peptides of G-protein-coupled kinase in experimental models of diabetes.

AIMS/HYPOTHESIS: G-protein-coupled receptor kinases (GRKs) play a key role in agonist-induced desensitisation of G-protein-coupled receptors (GPCRs) that are involved in metabolic regulation and glucose homeostasis. Our aim was to examine whether small peptides derived from the catalytic domain of GRK2 and -3 would ameliorate Type 2 diabetes in three separate animal models of diabetes. METHODS: Synthetic peptides derived from a kinase-substrate interaction site in GRK2/3 were initially screened for their effect on in vitro melanogenesis, a GRK-mediated process. The most effective peptides were administered intraperitoneally, utilising a variety of dosing regimens, to Psammomys obesus gerbils, Zucker diabetic fatty (ZDF) rats, or db/db mice. The metabolic effects of these peptides were assessed by measuring fasting and fed blood glucose levels and glucose tolerance. RESULTS: Two peptides, KRX-683(107) and KRX-683(124), significantly reduced fed-state blood glucose levels in the diabetic Psammomys obesus. In animals treated with KRX-683(124) at a dose of 12.5 mg/kg weekly for 7 weeks, ten of eleven treated animals responded with mean blood glucose significantly lower than controls (4.7+/-0.4 vs 16.8+/-0.8 mmol/l, p

Biosynthesis of estragole and methyl-eugenol in sweet basil (Ocimum basilicum L). Developmental and chemotypic association of allylphenol O-methyltransferase activities.

Sweet basil (Ocimum basilicum L., Lamiaceae) is a common herb, used for culinary and medicinal purposes. The essential oils of different sweet basil chemotypes contain various proportions of the allyl phenol derivatives estragole (methyl chavicol), eugenol, and methyl eugenol, as well as the monoterpene alcohol linalool. To monitor the developmental regulation of estragole biosynthesis in sweet basil, an enzymatic assay for S-adenosyl-L-methionine (SAM):chavicol O-methyltransferase activity was developed. Young leaves display high levels of chavicol O-methyltransferase activity, but the activity was negligible in older leaves, indicating that the O-methylation of chavicol primarily occurs early during leaf development. The O-methyltransferase activities detected in different sweet basil genotypes differed in their substrate specificities towards the methyl acceptor substrate. In the high-estragole-containing chemotype R3, the O-methyltransferase activity was highly specific for chavicol, while eugenol was virtually not O-methylated. In contrast, chemotype 147/97, that contains equal levels of estragole and methyl eugenol, displayed O-methyltransferase activities that accepted both chavicol and eugenol as substrates, generating estragole and methyl eugenol, respectively. Chemotype SW that contains high levels of eugenol, but lacks both estragole and methyl eugenol, had apparently no allylphenol dependent O-methyltransferase activities. These results indicate the presence of at least two types of allylphenol-specific O-methyltransferase activities in sweet basil chemotypes, one highly specific for chavicol; and a different one that can accept eugenol as a substrate. The relative availability and substrate specificities of these O-methyltransferase activities biochemically rationalizes the variation in the composition of the essential oils of these chemotypes.

Octreotide, a somatostatin analogue, fails to inhibit hypoxia-induced retinal neovascularization in the neonatal rat.

OBJECTIVE: Octreotide, a somatostatin analogue, has been shown to prevent angiogenesis in diverse in vitro models. We evaluated its effect on retinal neovascularization in vivo, using a neonatal rat retinopathy model. METHODS: We used, on alternating days, hypoxia (10% O2) and hyperoxia (50% O2) during the first 14 days of neonatal rats, to induce retinal neovascularization. Half of the rats were injected subcutaneously with octreotide 0.7 microg/g BW twice daily. At day 18 the eyes were evaluated for the presence of epiretinal and vitreal hemorrhage, neovascularization and epiretinal proliferation. Octreotide pharmacokinetics and its effect on serum growth hormone (GH) and insulin-like growth factor I (IGF-I) were examined in 28 rats. RESULTS: Serum octreotide levels were 667 microg/l two hours after injection, 26.4 microg/l after nine hours and 3.2 microg/l after 14 hours. GH levels were decreased by 40% (p = 0.002) two hours after injection but thereafter returned to baseline. IGF-I levels were unchanged two hours after injection and were elevated by 26% 14 hours after injection (p = 0.02). Epiretinal membranes were highly associated with epiretinal hemorrhages (p < 0.001), while retinal neovascularization was notably associated with vitreal hemorrhages (p < 0.001). CONCLUSIONS: Twice-daily injections of octreotide failed to produce sustained decrease in serum GH, but produced rebound elevation of serum IGF-I. Accordingly, no statistically significant effect of injections on retinal pathology was noted. This finding, however, does not contradict our assumption that GH suppression may decrease the severity of retinopathy.

Maggot therapy for the treatment of intractable wounds.

BACKGROUND: Fly maggots have been known for centuries to help debride and heal wounds. Maggot therapy was first introduced in the USA in 1931 and was routinely used there until the mid-1940s in over 300 hospitals. With the advent of antimicrobiols, maggot therapy became rare until the early 1990s, when it was re-introduced in the USA, UK, and Israel. The objective of this study was to assess the efficacy of maggot therapy for the treatment of intractable, chronic wounds and ulcers in long-term hospitalized patients in Israel. METHODS: Twenty-five patients, suffering mostly from chronic leg ulcers and pressure sores in the lower sacral area, were treated in an open study using maggots of the green bottle fly, Phaenicia sericata. The wounds had been present for 1-90 months before maggot therapy was applied. Thirty-five wounds were located on the foot or calf of the patients, one on the thumb, while the pressure sores were on the lower back. Sterile maggots (50-1000) were administered to the wound two to five times weekly and replaced every 1-2 days. Hospitalized patients were treated in five departments of the Hadassah Hospital, two geriatric hospitals, and one outpatient clinic in Jerusalem. The underlying diseases or the causes of the development of wounds were venous stasis (12), paraplegia (5), hemiplegia (2), Birger's disease (1), lymphostasis (1), thalassemia (1), polycythemia (1), dementia (1), and basal cell carcinoma (1). Subjects were examined daily or every second day until complete debridement of the wound was noted. RESULTS: Complete debridement was achieved in 38 wounds (88.4%); in three wounds (7%), the debridement was significant, in one (2.3%) partial, and one wound (2.3%) remained unchanged. In five patients who were referred for amputation of the leg, the extremities was salvaged after maggot therapy. CONCLUSIONS: Maggot therapy is a relatively rapid and effective treatment, particularly in large necrotic wounds requiring debridement and resistant to conventional treatment and conservative surgical intervention.

Expression of the insulin-like growth factors and their receptors in adenocarcinoma of the colon.

AIMS: To study changes in the expression of insulin-like growth factors (IGFs) and their receptors, as well as production of the IGF-I and IGF-II polypeptides, in adenocarcinoma of the colon. METHODS: Malignant tissue obtained at operation was used. Total RNA was extracted and specific IGF-I and IGF-II and their receptor mRNAs were measured by a solution hybridisation RNase protection assay. IGF-I and IGF-II polypeptides were measured by specific immunoassays. RESULTS: All normal tissues expressed IGF-II, IGF-I receptor, and IGF-II/mannose-6-phosphate (Man-6-P) receptor. IGF-I mRNA could not be detected but the polypeptide was present in small but equal amounts in normal and malignant tissue. IGF-II was expressed 40 times more abundantly in colonic tumours than in adjacent normal tissue and the concentration of the corresponding polypeptide was twice as high in the malignant tissue. IGF-I receptor expression was increased by a factor of 2.5 and IGF-II/Man-6-P receptor by a factor of 4. CONCLUSIONS: This study confirms that in adenocarcinoma of the human colon there is increased expression of IGF-I receptor and IGF-II. Furthermore, IGF-II/Man-6-P receptor message is increased and the increase in IGF-II message is accompanied by a doubling of the IGF-II protein in the tumour tissue compared with the adjacent normal tissue. These findings suggest that the IGF-II/Man-6-P receptor may also be involved in development of adenocarcinoma of the colon. There is rapidly accumulating evidence implicating the IGF system in the development of malignancy of the large bowel.

Comparison of factors associated with 30-day mortality after coronary artery bypass grafting in patients with versus without diabetes mellitus. Israeli Coronary Artery Bypass (ISCAB) Study Consortium.

The purpose of this study was to identify factors associated with 30-day mortality after coronary artery bypass graft surgery (CABG) among diabetic patients, and to compare them with risk factors among nondiabetics. A subanalysis of a prospective national cohort study was performed which included patients who underwent CABG in 14 medical centers in Israel during 1994. Data including patient demographic and historical information, comorbidity, and cardiac catheterization results were collected by trained nurses. Data were derived from direct patient interviews, charts, catheterization reports, surgical reports, and national vital records. Multivariate logistic regression analysis was used to identify factors associated with a 30-day mortality in diabetic and nondiabetic patient populations. The results showed that crude mortality was 5.0% among diabetic patients (n = 1,034) and 2.5% among nondiabetics (n = 3,350; p < 0.001). The risk profile in diabetics was found to be worse. Multivariate logistic regression analysis identified female gender, 3-vessel disease, and left main disease as independent risk factors for 30-day, past-CABG mortality unique to diabetic patients. Left ventricular dysfunction was found to effect a greater risk among diabetic patients, whereas chronic renal failure was associated with greater risk among nondiabetics. In conclusion, we found differences in patterns of risk factors for post-CABG mortality between diabetics and nondiabetics. These findings may help physicians to identify patients at high risk for CABG mortality.

Dyslipidaemia in polycystic ovarian syndrome: different groups, different aetiologies?

The objective was to study the pathophysiology of the dyslipidaemia in polycystic ovarian syndrome (PCOS) patients, and to determine how it is related to hyperinsulinaemia, hyperandrogenism and dehydroepiandrosterone sulphate (DHEA-S) concentrations. The lipoprotein lipid profile, anthropometric measurements, endocrine profile and the presence of insulin resistance were evaluated in 31 PCOS patients and 20 age-matched healthy women, who served as controls. PCOS patients had higher fasting insulin concentrations, higher body mass indexes (BMI) and were hyperlipidaemic, with higher total cholesterol, low density lipoprotein (LDL) and triglyceride (TG) concentrations. There were no relationships between plasma lipids and anthropometric variables in the patient group as a whole. Insulin-resistant (IR) and non-IR (NIR) PCOS patients were then evaluated separately. Obesity with marked hyperandrogenism were the predominant features in patients with IR. NIR patients were not obese and had significantly less hyperandrogenism. The adrenal androgen DHEA-S was at the upper limit of its normal range in both groups. However, both PCOS subgroups exhibited similar significant abnormalities in terms of their lipid parameters. Insulin and DHEA-S concentrations were positively correlated with total cholesterol, LDL and TG, and negatively correlated with high density lipoprotein, in IR patients. In NIR subjects, insulin was not correlated with any of the lipids and DHEA-S was negatively related to cholesterol and LDL. Anthropometric variables were related to lipids in only the NIR patients. Thus PCOS subjects as a group exhibit dyslipidaemia, characterized by increased total cholesterol, LDL and TG concentrations. When divided into IR and NIR subjects, there were no differences in the degree of lipid abnormalities, despite significant variations in the BMI and androgen status. Thus, in PCOS subjects, dyslipidaemia may occur irrespective of insulin resistance. Insulin and DHEA-S concentrations were positively correlated with an atherogenic lipid profile in the IR group only. As distinct from syndrome X when IR was present, dyslipidaemia was not related to body weight or the waist:hip ratio. In the NIR group there was no relationship between lipids and insulin; DHEA-S, on the other hand, was negatively related to cholesterol and LDL concentrations. Thus, dyslipidaemia in PCOS patients may occur irrespective of insulin resistance, and may have different metabolic aetiologies depending on DHEA-S metabolism. It remains to be seen whether the two types of PCOS are associated with different risks for ischaemic heart disease.

Insulin resistant and non-resistant polycystic ovary syndrome represent two clinical and endocrinological subgroups.

We studied the clinical and endocrine features of 35 patients with polycystic ovary syndrome (PCOS) who are either insulin resistant or non-insulin resistant. The occurrence of insulin resistance was determined by measuring insulin and glucose concentrations following a standard 75 g oral glucose load. All patients were evaluated by anthropometric measurements: body mass index (BMI), percentage of body fat (BCF) and waist-to-hip ratio (W/H), degree of hirsutism (Ferriman-Gallwey method) and endocrine profile. Fourteen patients had insulin resistance of unknown origin whereas four were due to a type A insulin receptor mutation, and 17 were non-insulin resistant. The insulin resistant patients were significantly more obese (higher BMI P < 0.0001, BCF P < 0.002 and W/H ratio P < 0.005) and were more hirsute (P < 0.002) than the non-insulin resistant patients. Testosterone concentrations were significantly higher in the insulin resistant group than in the non-insulin resistant group (2.65 versus 1.37 nmol/l; P < 0.027), whereas sex hormone-binding globulin was lower in insulin resistant patients (30.61 versus 19.48 nmol/l; P < 0.02). Non-insulin resistant patients showed a high luteinizing hormone to follicle stimulating hormone ratio, while a normal ratio was found in the insulin resistant subpopulation (2.94 versus 1.34; P < 0.0001). We concluded that PCOS comprises two subpopulations, one with insulin resistance of different aetiologies and the other which has no insulin resistance. These two groups differ in their anthropometric and endocrine features. The diagnosis of insulin resistance in PCOS can be easily determined by the insulin response to an oral glucose tolerance test.

Medical students' contribution to the development of a smoke-free hospital policy in a university medical centre: a relevant learning experience.

In a research methodology course, second-year medical students conducted a survey on 'Enforcing a Smoking Ban in the Soroka Medical Center: a Survey of Hospital Employees on Facilitating Factors and Obstacles'. They defined the study objectives and design, developed the study instrument, carried out the survey, coded and entered the data into mainframe computers, analysed the computer output, and prepared oral and written reports. The aims of the project were twofold: to survey employees' attitudes to a hospital smoking ban and to train medical students in the planning and conduct of a research project on public health or preventive medicine. Twelve students conducted a cross-sectional survey of 208 hospital employees (10% of the hospital staff). Employees were surveyed regarding smoking status, interest in quitting smoking, knowledge of the law banning smoking in public places, knowledge of the health effects of passive smoking, attitudes towards a hospital smoking ban and potential obstacles to its implementation. The students rated the course as excellent. They gained important research skills, as well as practical medical and public health experience through active participation in the design and execution of a study project with public health implications. At the first meeting of the hospital committee appointed to enforce a smoke-free hospital, the students' findings were reported in full, and their recommendations have guided policy decisions.

Epinephrine inhibits insulin-mediated glycogenesis but enhances glycolysis in human skeletal muscle.

The effect of epinephrine (E) infusion on insulin-mediated glucose metabolism in humans has been studied. Eight glucose-tolerant men were studied on two separate occasions: 1) during 120 min of euglycemic hyperinsulinemia (UH, approximately 5 mM; 40 mU.m-2.min-1); and 2) during UH while E was infused (UHE, 0.05 microgram.kg-1.min-1). Biopsies were taken from the quadriceps femoris muscle before and after each clamp. Glucose disposal, correcting for endogenous glucose production, was 36 +/- 3 and 18 +/- 2 (SE) mumol.kg fat-free mass (FFM)-1.min-1 during the last 40 min of UH and UHE, respectively (P less than 0.001). Nonoxidative glucose disposal (presumably glycogenesis) averaged 23.0 +/- 3.0 and 4.0 +/- 1.1 (P less than 0.001), whereas carbohydrate oxidation (which is proportional to glycolysis) averaged 13.1 +/- 1.4 and 15.3 +/- 1.1 mumol.kg FFM-1.min-1 (P less than 0.05) during UH and UHE, respectively. UHE resulted in significantly higher contents of UDP-glucose, hexose monophosphates, postphosphofructokinase intermediates, and glucose 1,6-bisphosphate (G-1,6-P2) in muscle (P less than 0.05-0.001), but there were no significant differences in high-energy phosphates or fructose 2,6-bisphosphate (F-2,6-P2) between treatments. Fractional activities of phosphorylase increased (P less than 0.01), and glycogen synthase decreased (P less than 0.001) during UHE. It is concluded that E inhibits insulin-mediated glycogenesis because of an inactivation of glycogen synthase and an activation of glycogenolysis. E also appears to inhibit insulin-mediated glucose utilization, at least partly, because of an increase in G-6-phosphate (which inhibits hexokinase) and enhances glycolysis by G-1,6-P2-, fructose 6-phosphate-, and F-1,6-P2-mediated activation of PFK.

Epinephrine increases tricarboxylic acid cycle intermediates in human skeletal muscle.

The effects of epinephrine (E) and insulin infusions on the contents of tricarboxylic acid cycle intermediates (TCAI), adenine nucleotides and their catabolites, and amino acids in skeletal muscle have been investigated. Eight men were studied on two separate occasions: 1) during 120 min of euglycemic hyperinsulinemia (UH, approximately 5 mM; 40 mU.m-2.min-1) and 2) during UH while E was infused (UHE, 0.05 microgram.kg-1.min-1). Biopsies were taken from the quadriceps femoris muscle before and after each clamp. The sum of citrate, malate, and fumarate in muscle did not change significantly during UH (P greater than 0.05) but doubled during UHE (P less than 0.001). There were no significant changes in any of the adenine nucleotides, their catabolites (including inosine monophosphate), or aspartate during UH and UHE (P greater than 0.05); nor were there any significant changes in pyruvate or alanine contents during UH (P greater than 0.05). On the other hand, there were significant increases in pyruvate and alanine contents during UHE (P less than 0.01 and 0.05, respectively), suggesting that there was increased production of 2-oxoglutarate (a TCAI) via the alanine aminotransferase (ALT) reaction. It is concluded that E infusion increases the contents of TCAI in human skeletal muscle, and it is likely that at least part of the increase is attributable to increased flux through the ALT reaction.

Low urinary chiro-inositol excretion in non-insulin-dependent diabetes mellitus.

BACKGROUND AND METHODS: Inositol is a major component of the intracellular mediators of insulin action. To investigate the possible role of altered inositol metabolism in non-insulin-dependent diabetes mellitus (NIDDM), we used gas chromatography and mass spectrometry to measure the myo-inositol and chiro-inositol content of urine specimens from normal subjects and patients with NIDDM: The study subjects were whites, blacks, and Pima Indians. The type of inositol and its concentration in insulin-mediator preparations from muscle-biopsy specimens from normal subjects and diabetic patients were also determined. RESULTS: The urinary excretion of chiro-inositol was much lower in the patients with NIDDM (mean [+/- SE], 1.8 +/- 0.8 mumol per day) than in the normal subjects (mean, 84.9 +/- 26.9 mumol per day; P less than 0.01). In contrast, the mean urinary myo-inositol excretion was higher in the diabetic patients than in the normal subjects (444 +/- 135 vs. 176 +/- 46 mumol per day; P less than 0.05). There was no correlation between chiro-inositol excretion and the age, sex, or weight of the diabetic patients, nor was there any correlation between urinary chiro-inositol and myo-inositol excretion in either group. The results were similar in a primate model of NIDDM, and chiro-inositol excretion was decreased to a lesser extent in animals with prediabetic insulin resistance. chiro-Inositol was undetectable in insulin-mediator preparations from muscle-biopsy samples obtained from patients with NIDDM: Similar preparations from normal subjects contained substantial amounts of chiro-inositol. Furthermore, the chiro-inositol content of such preparations increased after the administration of insulin during euglycemic-hyperinsulinemic-clamp studies in normal subjects but not in patients with NIDDM: CONCLUSIONS: NIDDM is associated with decreased chiro-inositol excretion and decreased chiro-inositol content in muscle. These abnormalities seem to reflect the presence of insulin resistance in NIDDM:

Influence of moderate exercise on glucose homeostasis and serum testosterone in young men with low HDL-cholesterol level.

Fifty-five healthy sedentary non smoking and non obese 24-26-year-old men with a low serum concentration of HDL-cholesterol were selected for a study of the effect of nine weeks of exercise on glucose homeostasis, and blood testosterone. The participants were randomized into two groups. Twenty-eight subjects were assigned to a nine-week program of submaximal aerobic exercise three times weekly, while 27 were assigned to a non exercising control group. The improvement in physical fitness was assessed by change in estimated oxygen consumption (EVO2 max) that was increased by 15% in the exercise group (p less than 0.001), but remained unchanged in the control group. During the study the body weight of both groups remained essentially unchanged. There was a significant reduction of mean plasma fructosamine in the exercise group, and non significant reduction in serum insulin. Serum testosterone, glycohemoglobin and HDL-cholesterol were not influenced by exercise, while serum triglycerides were significantly reduced.

Thymoma presenting as a superior vena cava syndrome remission following therapy.

A 45-year-old male developed myasthenia gravis 8 years ago. He received prednisone for 3 years, and resumed complete clinical remission. Five years later, he was admitted with obstruction of the superior vena cava. Invasive thymoma was diagnosed by chest X-ray and an open lung biopsy. Radiation followed by combination chemotherapy with cyclophosphamide, vincristine, and prednisone induced a complete remission. The patient remained disease-free for more than 20 months after the first admission to our department. To the best of our knowledge, superior vena cava syndrome as the presenting symptom of thymoma has never been reported previously.

Hairy cell leukemia associated with carcinoma: report of two patients and review of the literature.

The association of carcinoma and hairy cell leukemia (HCL) in two patients is recorded. One of the cases was a 58-year-old male who developed carcinoma of the kidney, while the second patient was a 48-year-old woman with carcinoma in the breast. This rare association is probably coincidental, as it is not described in most of the larger reported series of patients with HCL. It is of interest to note that the first patient had received radiation therapy thirty years before the diagnosis of HCL and carcinoma was made.