Antonio E. Pontiroli

Chronic hyperglycemia impairs insulin secretion by affecting insulin receptor expression, splicing, and signaling in RIN beta cell line and human islets of Langerhans.

Recent evidence suggests that insulin signaling through the insulin receptor A type (Ex11−), regulates insulin gene transcription. Because chronic hyperglycemia negatively affects insulin receptor function and regulates alternative splicing of the insulin receptor, we inquired whether chronic exposure of pancreatic β‐cells to high glucose results in alterations in insulin signaling due to changes in insulin receptor expression and relative abundance of its spliced isoforms. Our results demonstrate that the insulin receptor is localized in insulin secretory vescicles in human pancreatic β‐cells. Furthermore, we find that alterations in insulin expression and secretion caused by chronic exposure to high glucose are paralleled by decreased insulin receptor expression and increased relative abundance of the Ex11+ isoform in both human islets and RIN β‐cells. PDX‐1 and HMGI(Y) transcription factors are down‐regulated by high glucose. These changes are associated with defects in insulin signaling involving insulin receptor‐associated PI 3‐kinase/Akt/PHAS‐I pathway in RIN β‐cells. Re‐expression in RIN β‐cells chronically exposed to high glucose of the Ex11−, but not the Ex11+, isoform restored insulin mRNA expression. These data suggest that changes in early steps of insulin receptor signaling may play a role in determining β‐cell dysfunction caused by chronic hyperglycemia.

Laparoscopic bilateral adrenalectomy for persistent Cushing's disease after transsphenoidal surgery ☆

BACKGROUND We performed bilateral laparoscopic adrenalectomies on four patients (three women and one man) with Cushings disease (pituitary-dependent Cushings syndrome) showing persistent hypercortisolism after transsphenoidal surgery. METHODS The technique for bilateral transperitoneal laparoscopic adrenalectomy was derived from the one previously adopted by our group for unilateral adrenalectomy and previously described. Eight trocars were used, of which two were used for both left and right adrenalectomy. RESULTS Bilateral laparoscopic adrenalectomy was performed in a one-stage procedure in the three women and, because of the abundant abdominal fat of the patient, in a two-stage procedure (after a 1-week interval) in the man. Operating times for the three women were 255 minutes, 230 minutes, and 220 minutes, and for the man 170 minutes for right adrenalectomy and 140 minutes for left adrenalectomy. No surgical or anesthesiologic complications were encountered. All patients were discharged from the hospital within 5 days after operation. At present, after follow-up periods of 23, 8, 6, and 18 months, all patients show remission of Cushings disease and undetectable cortisol levels. CONCLUSIONS Our experience suggests that bilateral laparoscopic adrenalectomy is a safe and effective procedure and a valid therapeutic option in patients with Cushings disease showing persistent hypercortisolism after transsphenoidal surgery. However, the decision to remove both adrenal glands in such patients needs to be weighed against the risk of their having Nelsons syndrome or other long-term complications.

Metabolic effects of intranasally administered glucagon: Comparison with intramuscular and intravenous injection

SummaryIntranasal administration of glucagon, 1 mg, plus sodium glycocholate 15 mg as a surfactant, raised blood glucose levels and plasma levels of immunoreactive glucagon (IRG) and immunoreactive insulin (IRI). Spray solutions were more effective than drops, and neither the surfactant alone nor glucagon alone had any effect. Blood glucose levels were similarly affected by intravenous glucagon, while intramuscular glucagon was slightly more effective. The highest IRG concentrations were reached after intravenous administration, while intramuscular injection of glucagon was accompanied by the highest IRI release. These data indicate that intranasal administration of glucagon exerts metabolic effects similar to intramuscular and intravenous administrations. Further studies are needed to improve bioavailability and efficacy of intranasally administered glucagon.

Thirty Months Experience with Laparoscopic Adjustable Gastric Banding

Introduction: Since June 1996 we performed laparoscopic adjustable silicone gastric banding (LASGB), because of low invasivity,absence of malabsorption, reversibility, and postoperative regulation. Materials and Methods: Criteria included body mass index (BMI) >40 or >35 with serious obesity-related conditions. 154 patients underwent LASGB. BMI ranged from 35 to 65.7 (mean 43.7±6.2). Results:The laparoscopic procedure was successfully completed in 150 patients (97.4%). One patient was converted to the laparotomic procedure because of hepatomegaly; 4 patients had to be converted for gastric laceration during the laparoscopic approach. In one of these patients, the band was removed 7 days later for sepsis, followed by an uneventful post-operative course. The mean length of postoperative hospitalization was 2.3±0.9 days. Per cent of excess weight loss was 42.5±22.4 after 1 year. Conclusions: LASGB was feasible and effective.

Association between chlorpropamide-alcohol flushing and fast acetylator phenotype in type I and type II diabetes

SummaryDifferent prevalences of chlorpropamide alcohol flushing (CPAF) have been reported by different authors in either type I or type II diabetics or in normal subjects and this could be due to different methodological approaches or to different criteria of evaluation of CPAF. Previous studies in small series of patients have also suggested the existence of an association between type I diabetes and the fast acetylator phenotype (AP). The first aim of this study was to find reliable criteria for the assessment of CPAF. The second was to evaluate the prevalence of CPAF and of AP in a large series of type I and type II diabetics; and the third was to evaluate possible associations of CPAF and AP. AP and CPAF were evaluated separately in 256 diabetics (110 with type I and 146 with type II diabetes) and in 183 diabetics (74 with type I and 109 with type II diabetes), respectively. In 156 of these subjects, the two markers were evaluated together. The occurrence of CPAF was studied by subjective and objective assessment and by thermographic recording; CPAF was quantified by the differential value of skin temperature increase [Δ T(C-P)] and by the value of differential speed of ascent, expressed in angle-degrees [Δ a(C-P)], after treatment with placebo and with chlorpropamide. The fast AP was more frequent in type I than in type II diabetics, was not related to family history of diabetes, sex of the patients, age at onset and duration of diabetes or metabolic control. The most reliable assessment of CPAF was represented by thermographic recording of speed of ascent of skin temperature. CPAF was more frequent in females than in males, more frequent in diabetics than in healthy controls, similarly frequent in type I and in type II diabetes and showed no relationship with family history of diabetes, age at onset, duration of diabetes or metabolic control. An association between fast AP and CPAF was found in type II, but not in type I diabetics: fast acetylators were more frequently CPAF-positive, while slow acetylators were more frequently CPAF-negative. In addition, a linear relationship was found between rate of acetylation and speed of ascent of facial skin temperature after chlorpropamide and alcohol in type II diabetics, not in type I diabetics. The meaning of this association is not clear and deserves further investigations.

Ageing and acetylator phenotype as determined by administration of sulphadimidine

Gachaly, Vas, Hajos and Kaldor [1] have recently shown that, amongst Hungarians of Caucasian origin, the fast acetylator phenotype is more frequent in elderly people, i.e. those more than 60years old. They concluded that the hepatic N-acetylation rate 90 7 declined with ageing. This view, however, is not held a,J by others [2, 3]. oq The acetylator phenotype has been evaluated in -~ ~ 55 normal subjects aged 15-77 years, and in 92 sub~s0~ jects affected by Type 2 (non-insulin-dependent) dia8 / betes mellitus, aged 31-80 years. Liver function tests ~ so-~ 40(SGOT, SGPT, 7GT and pseudo-cholinesterases) were always normal. 8_ 30 At 06.00 h, after a 12-h fast, all subjects received ~,, 20 sulphadimidine orally (kindly supplied by Farmitalia Carlo Erba, Milano, Italy), in doses of 1.75-4.25 g lo for body weights ranging from 28 to 104 kg (4,5); the average dose was 45 mg/kg. At 08.00 h, tea or coffee and a small breakfast were allowed, and at 12.00 h 9o] lunch was taken. At 14.00 h, 5 ml venous blood was 80 taken, the serum immediately separated and stored ~ 7 at 2 0 °C until assayed for total and free sulphadi~ so~ midine, according to the Bratton Marshall method as .~ so described by Varley [6]. According to Evans et al. [4] ~ 40. and Burrows et al. [7], 37.5-40.0% was chosen as the

Genetic and metabolic risk factors for the development of late complications in type I (insulin-dependent) diabetes.

SummaryThe genetic background seems to be involved in the development of type I diabetes and it might also be involved in the development of diabetic complications, but studies carried out so far have yielded conflicting results. The aim of this study was to evaluate the influence of some genetic markers and metabolic factors in the development of late diabetic complications. One hundred and twenty-seven patients (69 males, 58 females) with type I diabetes were evaluated for ABO and Rh blood groups, chlorpropamide alcohol flush (CPAF) and acetylator phenotype (AP) as well as for life-habits (smoking, alcohol use, diet and drug compliance), metabolic indexes (M-value, HbA1, cholesterol and triglyceride levels) and late complications of diabetes [coronary heart disease (CHD), arterial hypertension (AH), retinopathy and nephropathy]. Diabetic patients were more frequently fast acetylators and CPAF positive than controls and CPAF was more frequent among females than among males. None of the genetic markers used in this study appeared as a risk factor for the development of diabetic complications. At multiple logistic analysis different risk factors appeared for each microangiopathic complication. For retinopathy: female sex, duration of disease and triglyceride levels; for nephropathy: male sex, cholesterol levels and hypertension. These risk factors have already been recognized in previous studies, while the genetic markers evaluated in our study do not identify a greater or smaller risk for the development of late complications.

EMEA extends indications for metformin. A decision that relies on evidence-based medicine

their patients, and this means assuring optimal metabolic control to prevent long-term complications, especially macroangiopathic complications in type 2 diabetes. This requires appropriate “disease management” and “evidencebased medicine”. Disease management is an approach to patient care that emphasizes coordinated, comprehensive care along the continuum of a given disease (type 2 diabetes and its susceptibility to life-threatening complications) and across health care systems that are available (diabetes clinics and/or general practitioners) [1]. Evidence-based medicine is an approach to practice and teaching that integrates pathophysiological rationale, caregiver experience, and patient preference with valid clinical research evidence [1]. In type 2 diabetes, the results of the UKPDS study indicate that reducing glycosylated haemoglobin improves patient outcomes, and that medical intervention to achieve near-normal glycaemic control is important unless a patient has a very limited life expectancy [2]. Randomized controlled trials (RCTs) remain the standard for defining the practice of evidence-based medicine, as RCTs are fundamental to establish causality, i.e. to document efficacy and safety of therapeutic interventions. Complementary to RCTs are observational studies that should be considered as a lens to re-evaluate the results of RCTs and to help optimize delivery of care [3, 4]; observational studies should be carried out routinely to ensure that the quality of health care is compatible with success rates achievable elsewhere, so that cost-effective care is offered to all (diabetic) patients [3, 4]. The value of information coming from RCTs or from observational studies has recently been reviewed by Collins and MacMahon [5], who addressed the question: why are some types of evidence about the effects of treatment on survival and on the other major aspects of chronic disease outcome more reliable than others? To yield reliable, not evanescent, results in complex diseases such as type 2 diabetes, studies should have a reduced bias, i.e. proper randomization and proper analysis of large samples of patients, and a significant number of deaths or of other relevant outcomes [5]. The patients under study should also be as close as possible to the “average patient”. On the other hand, observational studies have an important role in the identification of infrequent but serious side-effects (that are unlikely to emerge during RCTs) and in providing information about the risk of death and of other adverse outcomes in particular circumstance (for instance selected patients) [6]. In January 2001, the European Agency for the Evaluation of Medicinal Products (EMEA) evaluated the results of UKPDS, and in particular the section (UKPDS 34) dealing with overweight patients [7]. UKPDS 34 showed that in intensively diet-treated overweight patients, metformin significantly reduced absolute risk of: (1) any diabetes-related complications and overall mortality vs. diet alone and vs. treatment with either a sulphanylurea or with insulin; and (2) diabetes-related deaths and myocardial Acta Diabetol (2001) 38:151–152