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This work aims at exploring changes in cellular energetics by exploiting the Pasteur effect. We assumed that lactate overproduction arising from antimycin A-induced inhibition of mitochondrial respiration (delta-lactate = stimulated [lactate] -basal [lactate]) is indicative of the energy provided aerobically by the cell. Rat embryonal cardiomyocytes (H9c2), incubated with 2 micromol/L antimycin A, increased about 6 fold their lactate production in a manner linear with time and cell number. Antimycin A was also delivered to Langendorff-perfused rat hearts under control aerobic conditions or after 20 min-ischemia and 30 min-reperfusion. The test started at the end of each perfusion and lactate was measured into perfusate collected for further 25 min. A cardioplegic solution was also delivered during the test to exclude that lactate production was influenced by cardiac contraction. Control delta-lactate was 20.9 +/- 2.31 (S.E.M.) microg/mL and markedly decreased after reperfusion (7.66 +/- 0.51, p < 0.001), showing that energy production was impaired of about 70%. The determination of oxygen consumption by mitochondria isolated from reperfused hearts also suggested that the damage to the respiratory chain was similar to that evaluated by lactate overproduction (Respiratory Control Index: 75% lower than control, p < 0.001. Moreover, when delta-lactate was referred to the estimated cells which remained viable at the end of reperfusion (49.9%), it was 25% lower than control (p < 0.05). Therefore, we proposed this test as a tool for quantifying both physiological and pathological energetic modifications in living intact cardiomyocytes and in isolated and perfused hearts.

Metabolic flux control analysis of NADH oxidation in bovine heart submitochondrial particles revealed high flux control coefficients for both Complex I and Complex III, suggesting that the two enzymes are functionally associated as a single enzyme, with channelling of the common substrate, Coenzyme Q. This is in contrast with the more accepted view of a mobile diffusable Coenzyme Q pool between these enzymes. Dilution with phospholipids of a mitochondrial fraction enriched in Complexes I and III, with consequent increased theoretical distance between complexes, determines adherence to pool behavior for Coenzyme Q, but only at dilution higher than 1:5 (protein:phospholipids), whereas, at lower phospholipid content, the turnover of NADH cytochrome c reductase is higher than expected by the pool equation.

[1] On the basis of the quantitative study of diatom, radiolarian, and planktic foraminiferal assemblages, we estimated summer sea surface temperature (SSST) and sea-ice extent at 50 sediment core localities in the Atlantic and western Indian sector of the Southern Ocean to reconstruct the last glacial environment at the GLAMAP (18 to 15 ka, equal to 21,500 to 18,000 calendar (cal) years BP) and EPILOG (19.5 to 16.0 ka, equal to 23,000 to 19,000 cal years BP) time slices. Stratigraphic identification of the time slices was accomplished by a combination of AMS 14C measurements, benthic isotope, and siliceous microfossil abundance records. While the SSST estimates reveal greater surface water cooling than reconstructed by CLIMAP [1981], reaching a maximum in the area of the present Subantarctic Zone, the sea-ice reconstruction indicates that CLIMAP overestimated the expansion of the Antarctic sea-ice field, especially for austral summer. During winter the sea-ice field was expanded by 60–70% compared to the present. Last glacial summer sea surface isotherms indicate a northward shift of the zonal bands of the Antarctic Circumpolar Current and a relative expansion of the cold water realm south of the Subantarctic Front by ∼5° in latitude. This coincides with a northward displacement of the zone of enhanced biogenic silica deposition and iceberg occurrence. As a result of northward expansion of Antarctic cold waters and a relatively small displacement of the Subtropical Front, thermal gradients were steepened during the last glacial in the area of the present Subtropical Front. The northward displacement of Antarctic cold waters and the related deflection of Southern Ocean waters along the eastern boundary of South America may have resulted in a weakened “cold water route” across the Drake Passage. In contrast, the transport of warm and salty surface water from the Indian into the Atlantic Ocean via the “warm water route” was not blocked allowing continuous but reduced import of heat into the South Atlantic.

Cardiovascular diseases represent, today, the principal cause of mortality in the general population, especially in subjects with type 2 diabetes mellitus. In these patients the risk of death from cardiovascular diseases is equal to that of non-diabetic subjects with a previous episode of myocardial infarction. Many factors concur to determine such high risk. Hyperglycaemia contributes to the increase in morbidity and cardiovascular mortality associated with diabetes mellitus. Hyperglycaemia acts as a multiplier of cardiovascular risk due to frequent association of multiple risk factors in diabetic patients. Therefore, effective treatment requires a more complete assessment of quantitative and qualitative aspects of glycemic control as well as all components of the diabetic syndrome or, more commonly, metabolic syndrome.

The pattern of cytochrome c oxidase inhibition by nitric oxide (NO) was investigated polarographically using Keilin-Hartree particles, mitochondria and human neuroblastoma cells. NO reacts with purified cytochrome c oxidase forming either a nitrosyl- or a nitrite-inhibited derivative, displaying distinct kinetics and light sensitivity of respiration recovery in the absence of free NO. Keilin-Hartree particles or cells, respiring either on endogenous substrates alone or in the presence of ascorbate, as well as state 3 and state 4 mitochondria respiring on glutamate and malate, displayed the rapid recovery characteristic of the nitrite derivative. All systems, when respiring in the presence of tetramethyl-p-phenylenediamine, were characterised by the slower, light-sensitive recovery typical of the nitrosyl derivative. Together the results suggest that the reaction of NO with cytochrome c oxidase in situ follows two alternative inhibition pathways, depending on the electron flux through the respiratory chain.

Central to global climate evolution is the paleoceanographic development of the South Atlantic as it represents the passageway for inter-hemispheric heat exchange within global thermohaline circulation (THC). Processes in the adjacent Southern Ocean regulate the heat import into the South Atlantic via the Agulhas “warm water route” (WWR) and the Drake Passage “cold water route” (CWR), and amplify climate change through various feedback mechanisms and teleconnections. For paleoceanographic reconstruction an inventory of new data sets and methods is now available, allowing for the estimation of Pleistocene sea-surface water temperatures and sea-ice distribution on time-slices and time-series based on the calcareous and siliceous microfossil record. Reconstruction of the Last Glacial Maximum (LGM) reveals distinct cooling in the Southern Ocean (up to 4 – 6 °C) accompanied by an expansion of winter and summer sea ice, cooling in the African upwelling regimes (up to 10°C) and in the Equatorial Atlantic ( 4 – 5 °C), but the Subtropical Gyre region remains relatively warm and unchanged compared with the present. While the WWR was not strongly altered during the LGM, heat transport via the CWR was most probably much weaker. The reconstruction of time-slices representing a warm climate end-member at the onset of the last climate cycle documents a distinct lead of southern high-latitudes in global climate development that also affects the south-west African upwelling regions. It is at the Marine Isotope Stage (MIS) 6/MIS 5 transition when Southern Ocean surface temperatures reach maximum values and sea ice is at a minimum, marking a period of South Atlantic heat piracy. During the isotopic minimum of MIS 5.5, the tropical South Atlantic was slightly colder than at present, likely the result of an enhanced poleward heat export. Time-series studies from key areas document that climate variability related to orbital forcing is overprinted by THC changes driven by meltwater injections into the North Atlantic and the Southern Ocean, changes in atmospheric circulation and greenhouse gas concentration, as well as sea ice that amplify climate change at global, hemispheric and regional scales. The study of centennial-scale variability during interglacial optima, such as MIS 5.5 and MIS 11, suggests that the presence of large ice sheets, meltwater events, changes in greenhouse gas concentration and sea-ice distribution are not the only prerequisite to trigger millennial-centennial-scale variability, but that another external agent, changes in solar irradiance, must be considered as an important factor in climate development.

The products of the human ARG gene and the human ABL gene characterize the Abelson family of non-receptor tyrosine protein kinases. Both genes are ubiquitously expressed. The interactions of these two similar protein kinases are still not well known, although it has been suggested that they could cooperate, with redundant actions, to provide intracellular signals in the cells. Lymphopenia occurs in mice with homozygous disruption of c-abl, indicating that in certain tissues Arg is unable to substitute c-abl functions. In B and T lymphoid cell lines at different stages of differentiation, we studied, by a reverse transcriptase-competitive polymerase chain reaction and Western blotting, Arg and c-abl in order to evaluate whether the expression pattern of the two genes could give insight as to why they do not exhibit overlapping roles in lymphocytes and whether the product levels of the two genes are related to lymphoid differentiation. The data showed that their expression is differently modified in lymphoid B cell lines. The highest Arg transcript and protein levels are in the mature B cells. (C) 2002 Published by Elsevier Science B.V. on behalf of the Federation of European Biochemical Societies

Arginine:glycine amidinotransferase (AGAT, EC 2.1.4.1) deficiency is a recently recognized autosomal recessive inborn error of creatine biosynthesis, characterized by mental retardation and severe language impairment. We extensively investigated a third 5-year-old patient with AGAT deficiency, discovered in the pedigree of the same Italian family as the two index cases. At the age of 2 years he presented with psychomotor and language delay, and autistic-like behavior. Brain MRI was normal, but brain 1 H-MRS disclosed brain creatine depletion, which almost completely normalized following creatine monohydrate supplementation. A remarkable clinical improvement paralleled the restoration of brain creatine concentration. AGAT and GAMT (guanidinoacetate:methyltransferase) genes were analyzed in the proband and in 26 relatives, including the two cousins with AGAT deficiency. Sequencing of the proband’s AGAT gene disclosed the same homozygous mutation at nt position 9093 converting a tryptophan (TGG) to a stop codon (TAG) at residue 149 (W149X), as already described in the two previously reported cases. The proband’s parents and 10 additional subjects of the pedigree were carriers for this mutation. AGAT deficiency was further confirmed by undetectable AGAT activity in the patient’s lymphoblasts. Mutation analysis of the GAMT gene revealed a sequence variation in exon 6 (T209M), not in the proband, but in 15 additional subjects from the pedigree. The silent nature of this sequence variation is supported by its homozygosity in one AGAT deficient cousin and in one asymptomatic adult, both with normal GAMT activity.

Glycemic control remains the major therapeutic objective to prevent or delay the onset and progression of complications related to diabetes mellitus. Insulin therapy represents a cornerstone in the treatment of diabetes and has been used widely for achieving glycemic goals. Nevertheless, a large portion of the population with diabetes does not meet the internationally agreed glycemic targets. Moreover, insulin treatment, especially if intensive, may be associated with emergency room visits and hospitalization due to hypoglycemic events. Therefore, fear of hypoglycemia or hypoglycemic events represents the main barriers to the attainment of glycemic targets. The burden associated with multiple daily injections also remains a significant obstacle to initiating and maintaining insulin therapy. The most attractive insulin treatment approach should meet the patients' preference, rather than demanding patients to change or adapt their lifestyle. Insulin degludec/insulin aspart (IDegAsp) is a new combination, formulated with ultra-long-acting insulin degludec and rapid-acting insulin aspart, with peculiar pharmacological features, clinical efficacy, safety, and tolerability. IDegAsp provides similar, noninferior glycemic control to a standard basal-bolus regimen in patients with type 1 diabetes mellitus, with additional benefits of significantly lower episodes of hypoglycemia (particularly nocturnal) and fewer daily insulin injections. Moreover, although treatment strategy and patients' viewpoint are different in type 1 and type 2 diabetes, trial results suggest that IDegAsp may be an appropriate and reasonable option for initiating insulin therapy in patients with type 2 diabetes inadequately controlled on maximal doses of conventional oral agents. This paper will discuss the role of IDegAsp combination as a novel treatment option in diabetic patients.

Cerebral metabolic abnormalities have been previously detected by 1H-MRS in infants with the Zellweger syndrome as young as 3 months. We hypothesized that metabolic abnormalities could also be found shortly after birth. Two fullterm infants with Zellweger syndrome were studied at 12 days and two months of age, respectively, using single voxel 1H-MRS. In the first case 1H-MRS was performed using PRESS with variable TE (31, 136, 272 ms); in the second, STEAM and PRESS sequences were used with different TE (STEAM at 30 and 144 ms; PRESS at 270 ms). In both cases a significant decrease of N-acetylaspartate (NAA) and an abnormal signal at 1.33 and 0.9 ppm, consisting of lactate (Lac) and lipids (Lip) were found. The reported MRS abnormalities, although not specific for peroxisomal dysfunctions, may support the suspicion of Zellweger syndrome and may indicate direct referral to the specific laboratory and molecular studies necessary to establish the diagnosis and prognosis of this syndrome.

We describe a new creatine metabolism disorder in 2 young sisters who suffered from mental retardation and severe language delay. Blood examination, investigation of the most common neurometabolic disorders, and brain magnetic resonance imaging were normal. Diagnosis was established only by means of in vivo proton magnetic resonance spectroscopy, which disclosed generalized depletion of creatine in the brain. Creatine monohydrate oral administration led to almost complete brain creatine level restoration along with improvement of the patients' disabilities.

Many gadolinium-enhanced magnetic resonance imaging (MRI) studies focusing on the anatomy and pathology of the 7th cranial nerve have already been published. However, only scattered cases of herpes zoster oticus (HZO) have been described and only the MRI appearance of the soft temporal bone structures has been reported. Enhanced MRI was performed in 4 patients with HZO observed at the Department of Otorhinolaryngology of the University of Pisa. A good correlation was found between the clinical data and MRI findings in both the acute and chronic stages of the disease. The 2 cases with complete facial palsy presented prominent and diffuse enhancement of the 7th and 8th cranial nerves on postcontrast MRI, while the patient with grade III facial palsy showed more limited nerve enhancement. The patient with grade II facial palsy presented no MRI abnormalities. In our series, enhancement limited to the geniculate ganglion and to the labyrinthine segment of the facial nerve indicates a good prognosis while a widespread enhancement correlates with a poor prognosis. In conclusion, MRI with contrast may be useful during the acute stage of HZO because it can confirm the diagnosis and can provide prognostic information on the facial function.

Azo dyes and their derivatives have been linked to cases of bladder, prostate, esophagus, rectum, stomach and ovary cancer. These dyes are quite common on food, however, several countries have revised its use and reassessed what are the acceptable concentrations of these pigments. Twilight Yellow and Tartrazine are two azo dyes allowed on food in many countries around the world, they are used for the preparation of gelatins, cake, juices, ready soft drinks, candies, chewing gum, snacks, crackers and etc. Among children and adolescents, the consumption of these foods is common, which can lead to high dye levels in the body. This study examined the concentration of Twilight Yellow and Tartrazine dyes in food consumed by children in Brazilian schools. The results indicated that high consumption of sweets tends to exceed the acceptable daily intake of dyes. Moreover, many products have levels above the allowed by the Brazilian legislation, which increases the risk of cancer.

Background: Diabetes mellitus (DM) represents by itself a major risk factor for cardiovascular events and the coexistence of obesity with consequent left ventricular volumetric overload could be responsible for further damages on left ventricular function. Aim of this study was to demonstrate the effect of body mass index (BMI) on left ventricular function in diabetes patients with no cardiovascular complications and with normal ejection fraction (EF). Materials and Methods: We evaluated 71 stable asymptomatic diabetes patients in optimal medical treatment and 24 healthy controls (C) (45% females; mean age: 58.4 +/− 9.4 years; BMI: 23.5 +/− 1.5). We stratified diabetes patients into two groups according to BMI: BMI 30 kg/m2 (B: 27 patients; 37% females; mean age: 56.2 +/− 7.8 years; BMI: 33.0 +/− 2.1; Diabetes duration: 8.5 +/− 5.2 years). The following parameters were evaluated by conventional two dimensional (2D) echocardiography (GE VIVID 7) and tissue Doppler imaging (TDI): left ventricular dimensions (LVIDd; PWTd; IVSd), Left Ventricular Volumes (EDV, ESV), EF (by biplane Simpson’s method), Left Ventricular Mass (by ASE formula), peak mitral annular velocity at septal and lateral levels (Sm and Sl). Global longitudinal strain (GLS) was obtained off line by Speckle tracking imaging method using Echopac 10 software. Results: Groups A, B were comparable for diabetes duration and glycated hemoglobin level, history of hypertension, and lipid profile. The EF was similar in the three groups, (A: 64 +/− 6%; B: 63 +/− 4%; C: 61 +/−5%; P= NS). LVMass2.7 indexed for height was significantly higher in A and B in comparison with C (A: 45.2 +/− 8.1 g/m2.7; B: 46.1 +/− 9.6 g/m2.7; C: 39.5 +/− 4.9 g/m2.7; P < 0.05). The stroke volume index (SVi) was significantly lower in B vs A (B: 35.3 +/− 5.7 ml/m2; A: 39.3 +/7.1 ml/m2; P = 0.033). GLS was significantly lower in group B respect A and C (C: 20.9 +/− 1.3%; A: -20.3+/−2.6%; B: -19 +/− 2; P < 0.05; P < 0.01). Conclusions: In uncomplicated asymptomatic DM patients, the presence of first degree obesity plays an incremental role in adversely affecting left ventricular function and remodeling. The conventional echocardiographic methods such as the EF and the TDI are not so sensitive to identify the early LV dysfunction such as the evaluation of GLS by Speckle Tracking echocardiography. The longitudinal subendocardial fibers dysfunction in diabetes/obese patients could be derived by the complex interaction between metabolic (diabetes) and hemodynamic/endocrine abnormalities.

The Philadelphia chromosome t(9;22)(q34;q11) is a cytogenetic marker for chronic myelogenous leukaemia (CML), and is also present in some acute leukaemias. The translocation in CML gives rise to two BCR/ABL chimeric transcripts (b3a2 and b2a2) encoding a 210-kD tyrosine kinase protein. These leukaemia-specific transcripts can be detected easily by the reverse transcriptase polymerase chain reaction (PCR). PCR has improved the possibility of detecting minimal residual leukaemia cells in Ph-positive patients, especially after bone marrow transplantation (BMT). With PCR, we looked for BCR/ABL transcripts in 30 patients with CML and 4 with essential thrombocythaemia at time of diagnosis, finding a significant difference in the platelet counts of CML patients carrying b3a2 or b2a2 transcripts. The BCR/ABL transcript was monitored by PCR in 6 CML patients after BMT. The usefulness of PCR in clinical practice at time of diagnosis, and the biological and clinical significance of positive/negative PCR results, in patients with transplants, are discussed.

Background Pelizaeus-Merzbacher disease (PMD) and a complicated form of familial spastic paraparesis (spastic paraplegia 2 [SPG2]) are X-linked development disorders of myelin formation caused by a mutation in the proteolipid protein ( PLP ) gene. Spastic paraplegia 2 is allelic to PMD. The wide range of PLP mutations results in a corresponding large spectrum of clinical severity in PMD, with a continuum of signs and symptoms to SPG2. Objective To report the results of genetic, neurophysiologic, and neuroimaging investigations performed in a child affected by a mild ataxic and spastic form of PLP -related disorder and in his relatives. Results A missense mutation in exon 6 of the PLP gene (Q233P) was found in the proband and in the female obligate carriers. In the proband, evoked potentials were altered and remained unchanged during the 7 years of follow-up. Magnetic resonance imaging of the child demonstrated patchy hyperintensities of the paraventricular white matter, with microcystic components. These latter findings, along with pallidal calcium deposition, were also present in 2 females heterozygous for PLP mutation. Conclusion The unusual genetic, magnetic resonance imaging, and clinical findings of this family confirm the wide variability of PLP -related disorders.

Arginine:glycine amidinotransferase (AGAT) catalyzes the first step of creatine synthesis, resulting in the formation of guanidinoacetate, which is a substrate for creatine formation. In two female siblings with mental retardation who had brain creatine deficiency that was reversible by means of oral creatine supplementation and had low urinary guanidinoacetate concentrations, AGAT deficiency was identified as a new genetic defect in creatine metabolism. A homozygous G-A transition at nucleotide position 9297, converting a tryptophan codon (TGG) to a stop codon (TAG) at residue 149 (T149X), resulted in undetectable cDNA, as investigated by reverse-transcription PCR, as well as in undetectable AGAT activity, as investigated radiochemically in cultivated skin fibroblasts and in virus-transformed lymphoblasts of the patients. The parents were heterozygous for the mutant allele, with intermediate residual AGAT activities. Recognition and treatment with oral creatine supplements may prevent neurological sequelae in affected patients.

The size of soybean seeds needs further study because its relationships with physiological quality, field establishment, and yield are controversial. The aim of this study was to evaluate the effects of seed size on soybean establishment and seed physiological quality. In the field, a 2x3x3 factorial design was used, with two cultivars (M 5947 IPRO and 59HO124 IPRO), three seed sizes (5.5, 6.0, and 6.5 mm), and three sowing densities (280,000, 320,000, and 360,000 plants.ha-1). Agronomic traits and grain yield were evaluated. After harvest, only seeds from plots with a population of 320,000 plants were classified by size using circular sieves with 5.5-mm, 6.0-mm, 6.5-mm, and 7.0-mm mesh sizes. For the evaluation of physiological quality, a 2x4 factorial design was applied, with two cultivars and four seed sizes. Germination, seedling emergence, accelerated aging, seedling dry matter, and emergence speed index were evaluated. Smaller seeds gave rise to shorter plants with a lower first pod insertion height. Larger seeds had higher physiological quality. The M 5947 IPRO cultivar showed better seed performance and quality. Resumo: O tamanho das sementes de soja é um fator que ainda necessita de estudos, pois a relação tamanho das sementes, qualidade fisiológica, estabelecimento e produtividade no campo apresenta controvérsias. Objetivou-se avaliar os efeitos do tamanho das sementes no estabelecimento da cultura da soja e na qualidade fisiológica das sementes. Em campo utilizou-se fatorial 2 x 3 x 3, sendo, duas cultivares (M 5947 IPRO e 59HO124 IPRO), três tamanhos de sementes (5.5, 6.0 e 6.5 mm) e três estandes de plantas (280.000, 320.000 e 360.000 plantas.ha-1). Foram avaliados características agronômicas e produtividade de grãos. Após a colheita, as sementes das parcelas com população de 320.000 plantas foram classificadas por tamanho utilizando-se peneiras com crivos circulares, 5.5 mm, 6.0 mm, 6.5 mm e 7.0 mm de diâmetro. Para a avaliação da qualidade fisiológica, considerou-se esquema fatorial 2 x 4, sendo, 2 cultivares e 4 tamanhos de sementes. Avaliou-se germinação, emergência em canteiro, envelhecimento acelerado, matéria seca de plântulas e índice de velocidade de emergência. Sementes menores dão origem a plantas mais baixas e com menor altura de inserção do primeiro legume. Sementes maiores apresentam maior qualidade fisiológica. A cultivar M 5947 IPRO apresentou melhores desempenho e qualidade de sementes.

The introduction of magnetic resonance imaging (MRI) and magnetic resonance spectroscopy into clinical practice has permitted advances in the definition and categorization of unknown leukodystrophies in children. We report a new type of leukodystrophy, defined by particular MRI and clinical findings, in a child with uneventful pre- and perinatal histories, spasticity, severe mental impairment with absence of language, and deafness. Brain MRI showed lobar white-matter signal abnormalities with extensive cysts in the anterior temporal lobe. The results of all metabolic screening tests, including the specific investigations for leukodystrophy, have been negative. Six years of clinical and MRI—magnetic resonance spectroscopy patient follow-up indicate a nonprogressive clinical and magnetic resonance picture. Owing to the striking similarities with the previous eight patients reported, this additional case supports the identification of a new leukodystrophy. ( J Child Neurol 2002;17:773—776).

Left ventricular hypertrophy (LVH) is significantly related to adverse clinical outcomes in patients at high risk of cardiovascular events. In patients with atrial fibrillation (AF), data on LVH, that is, prevalence and determinants, are inconsistent mainly because of different definitions and heterogeneity of study populations. We determined echocardiographic-based LVH prevalence and clinical factors independently associated with its development in a prospective cohort of patients with non-valvular (NV) AF. From the "Atrial Fibrillation Registry for Ankle-brachial Index Prevalence Assessment: Collaborative Italian Study" (ARAPACIS) population, 1,184 patients with NVAF (mean age 72 ± 11 years; 56% men) with complete data to define LVH were selected. ARAPACIS is a multicenter, observational, prospective, longitudinal on-going study designed to estimate prevalence of peripheral artery disease in patients with NVAF. We found a high prevalence of LVH (52%) in patients with NVAF. Compared to those without LVH, patients with AF with LVH were older and had a higher prevalence of hypertension, diabetes, and previous myocardial infarction (MI). A higher prevalence of ankle-brachial index ≤0.90 was seen in patients with LVH (22 vs 17%, p = 0.0392). Patients with LVH were at significantly higher thromboembolic risk, with CHA2DS2-VASc ≥2 seen in 93% of LVH and in 73% of patients without LVH (p

Il trattamento insulinico nel diabete mellito tipo 2 avviene per la maggior parte dei casi tardivamente, quando già la terapia divenga definitivamente sostitutiva. E' invece auspicabile un trattamento più precoce, con un'insulinizzazione basale o con una insulinizzazione ai pasti, che sono poste in confronto nel presente studio.