Insulin administration and rate of glucose appearance in people with type 1 diabetes

OBJECTIVE—To assess whether prandial insulin, in addition to basal insulin, has an effect on the rate of glucose appearance from a meal in people with type 1 diabetes.RESEARCH DESIGN AND METHODS—The rate of glucose appearance from a mixed meal (Ra_meal) was investigated in six adult (aged 24 ± 2 years), lean (BMI 23.6 ± 1.5 kg/m²) subjects with well-controlled type 1 diabetes (duration 7.9 ± 6.9 years, A1C 7.6 ± 0.9%) with/without prandial insulin. Actrapid was infused to maintain euglycemia before meals were consumed. Subjects consumed two identical meals on separate occasions, and Ra_meal was measured using a dual isotope method. [6,6-²H₂]glucose was incorporated into the meal (0.081 g/kg body wt), and a primed constant/variable rate infusion of [1,2,3,4,5,6,6-²H₂]glucose was administered. In the tests with prandial insulin, an additional bolus dose of Actrapid was given 20 min before the meal at 0.1 units/kg body wt.RESULTS—Insulin concentration with prandial insulin was significantly higher than during basal insulin studies (119 ± 16 vs. 66 ± 15 pmol/l, P = 0.03 by paired t test). Despite differences in insulin concentration, there were no differences in total glucose appearance (3,398 ± 197 vs. 3,307 ± 343 μmol/kg) or time taken for 25% (33.1 ± 3.3 vs. 31.7 ± 3.5 min), 50% (54.6 ± 3.5 vs. 54.1 ± 4.7 min), and 75% (82.9 ± 7.1 vs. 82.8 ± 5.8 min) of total glucose appearance. The fraction of the glucose dose appearing in the circulation was the same for basal (73 ± 8%) and prandial (75 ± 4%) study days.CONCLUSIONS—These results suggest that meal glucose appearance is independent of prandial insulin concentration in people with type 1 diabetes.Plasma glucose concentration is determined by several factors: the production of glucose by the body, the uptake of glucose by splanchnic and peripheral tissue, and the appearance of exogenous glucose from meals (1). Plasma insulin regulates the production and uptake of glucose (2,3), but its role in regulating rates of glucose appearance from meals (Ra_meal) is uncertain.Ra_meal is determined by the rate at which glucose is emptied from the stomach and absorbed across the intestinal membrane, and by the extent of extraction during first pass of the liver and other splanchnic tissues, before reaching the general circulation. The modification by insulin of any of these processes would act to regulate postprandial glucose levels and would be an important consideration for people with diabetes. In particular, for people with type 1 diabetes, the effect of insulin on Ra_meal has important implications for the timings of prandial insulin injections and the appropriateness of pre-/post-meal insulin dosing.Research in this area is limited and, although there is some in vitro and in vivo evidence that insulin plays a role in regulating glucose appearance in rats (4–6), these findings have yet to be reproduced in human studies. In people with poorly controlled type 1 diabetes, Ra_meal was normal and unchanged with intensive insulin therapy (7). However, these studies were designed to investigate the effects of longer-term hyperglycemia/insulin deficiency, and the effect of acute insulin deficiency on Ra_meal was not independently investigated.No study to date has examined the immediate independent effect of bolus exogenous insulin administration on Ra_meal in people with type 1 diabetes. This study therefore aimed to compare Ra_meal in the presence of prandial insulin with that measured at basal insulin concentrations in people with type 1 diabetes.     

Activation of the immune system and sperm DNA fragmentation are associated with idiopathic oligoasthenoteratospermia in men with couple subfertility

Ejaculates from men without known causes for male subfertility and asymptomatic for genital tract inflammation showed infiltration of macrophages, and their activation state (HLA-DR(+)) was negatively correlated with semen parameters and positively correlated with sperm DNA damage. An activation of the immune system is thus detectable in idiopathic oligoasthenoteratozoospermia of unknown origin.     

Intracytoplasmic injection of morphologically selected spermatozoa (IMSI) improves outcome after assisted reproduction by deselecting physiologically poor quality spermatozoa

Purpose  

We used computer assisted sperm selection (MSOME) during cycles of intracytoplasmic sperm injection to test whether this technique improves results over traditional ICSI protocols. We also used the TUNEL assay to test whether MSOME could deselect physiologically abnormal spermatozoa.     

Comparison Among Clark's, Breslow's, and TNM classifications for cutaneous head and neck malignant melanoma

This retrospective study was carried out to assess the prognostic value of three classification systems used for staging cutaneous head and neck malignant melanoma (CHNME). Fifty-three patients with histologically proven CHNME were analyzed. Thirty patients were never treated before admission, whereas 23 (43.4%) had a second radical resection of the primary tumor location, 9 (17%) had neck nodes, none had distant metastasis, and all had a minimum of 5 years of follow-up. Results show that T-stage is the most important clinical prognostic parameter, whereas Clark's and Breslow's classifications have lower impact in defining prognosis. Sites of primary tumor determines different clinical outcomes, but this does not reach statistically significant values. A second surgery on the primary tumor location is possible and is effective toward survival. No statistical differences were noted between the previously untreated and treated groups. Neck nodes have to be removed with neck dissection, and this regimen can improve the clinical outcome; however, only 40% of neck positive patients survive more than 5 years.     

Levetiracetam therapy in patients with brain tumour and epilepsy

Epilepsy is a common clinical problem in patients with brain tumours, strongly affecting patientsȁ9 quality of life. Tumour-related seizures are often difficult to control, and the clinical picture is complicated by frequent interactions between antiepileptic drugs (AEDs) and antineoplastic agents. We studied the safety and efficacy of levetiracetam (LEV), a new AED with a different pharmacological profile from traditional anticonvulsants, in 19 patients (6 females; age range 28–70 years, mean 48 years) with supratentorial gliomas and epilepsy. Seizure types were simple partial in four patients, complex partial in 4, complex partial with secondary generalization in 7, and generalized tonic-clonic in 4. LEV was added to the existing AED treatment on account of persisting seizures, and titrated at dosages of 1,000–3,000 mg/day. Patients were seen at the Outpatientȁ9s Centre every 1–3 months, and followed-up for 7–50 months (mean 25 months, median 20 months). At the end of the observation period, nine patients were seizure free (seizure free period ranging from 7 to 33 months, mean 16, median 12) and five patients reported an improvement in seizure-frequency from daily to weekly (n = 1) or from weekly to monthly (n = 3). Seizure frequency was unmodified in four patients and increased (from monthly to weekly) in one. No LEV-related adverse effects were observed. LEV plasma concentrations monitored in 12 subjects ranged from 11.9 to 82.1 μg/ml. Our preliminary open data indicate that add-on treatment with LEV in patients with brain tumours is safe and appears to be effective in reducing seizure frequency. Controlled studies on larger populations are warranted to confirm these open observations.     

The synergistic apoptotic effects of thiophenfurin, an inosine monophosphate dehydrogenase inhibitor, in combination with retinoids in HL60 cells

New effective cytotoxic agents and combinations are urgently needed in cancer treatment. The enzyme inosine monophosphate dehydrogenase is a potentially useful target for drug development, since its activity has been shown to be amplified in malignant cells. Thiophenfurin, an inhibitor of the enzyme synthesized by us, is endowed with a significant apoptotic activity in promyelocytic leukaemia HL60 cells. Since retinoids were successfully employed in the treatment of patients with leukaemia, demonstrating significant differentiation-inducing and apoptotic effects, we carried out this study to evaluate the effects of the combination of thiophenfurin and several retinoid molecules, acting in different phases of the cell cycle in vitro. The results show that thiophenfurin is capable of eliciting significant S phase-specific antiproliferative effects in different sensitive and resistant cell lines with the IC50s ranging from 6.7 to 26 microM. When HL60 cells were treated with thiophenfurin in combination with retinoids, the effects on cell growth were additive or synergistic, depending on the kind of retinoid used and the sequence of treatment. In particular, we observed additive effects when the cells were exposed to thiophenfurin and all-transretinoic acid either simultaneously or sequentially. Instead, when the new heterocyclic retinoid isoxazole benzoic acid was used, synergism was obtained in the cells treated sequentially. The combination of thiophenfurin and isoxazole benzoic acid determined synergistic apoptotic effects through a mitochondrion-dependent mechanism, suggesting the possible usefulness of this combination in the treatment of leukaemia.