M Aragona

Reducing insulin resistance with metformin: the evidence today

Insulin resistance, defined as the inability of insulin to exert a normal biological action at the level of its target tissues, is one of the principal pathogenetic defects of type 2 diabetes. Metformin, the most widely-prescribed insulin-sensitizing agent in current clinical use, improves blood glucose control mainly by improving insulin-mediated suppression of hepatic glucose production, and by enhancing insulin-stimulated glucose disposal in skeletal muscle. Experimental studies show that metformin-mediated improvements in insulin sensitivity may be associated with several mechanisms, including increased insulin receptor tyrosine kinase activity, enhanced glycogen synthesis, and an increase in the recruitment and activity of GLUT4 glucose transporters. In adipose tissue, metformin promotes the re-esterification of free fatty acids and inhibits lipolysis, which may indirectly improve insulin sensitivity through reduced lipotoxicity. The improved glycaemia with metformin is not associated with increased circulating levels of insulin, and the risk of hypoglycaemia with metformin is minimal. The therapeutic profile of metformin supports its use for the control of blood glucose, in diabetic patients and for the prevention of diabetes in subjects with impaired glucose tolerance. Moreover, the improvement by metformin of cardiovascular risk factors associated with the dysmetabolic syndrome may account for the significant improvements in macrovascular outcomes observed in the UK Prospective Diabetes Study.

In Type 1 diabetic patients with good glycaemic control, blood glucose variability is lower during continuous subcutaneous insulin infusion than during multiple daily injections with insulin glargine

Aims  The superiority of continuous subcutaneous insulin infusion (CSII) over multiple daily injections (MDI) with glargine is uncertain. In this randomized cross‐over study, we compared CSII and MDI with glargine in patients with Type 1 diabetes well controlled with CSII. The primary end‐point was glucose variability.

Effects of pancreas-kidney transplantation on diabetic retinopathy

The effects of pancreas transplantation (PTx) on diabetic retinopathy (DR) are still debated. We studied the course of DR in 48 patients (age: 40 ± 7 years; males/females 26/22, body mass index (BMI): 23.0 ± 2.4 kg/m2, duration of diabetes: 24 ± 8 years) bearing a successful PTx (combined with a kidney). Follow‐up ranged 6–60 months (median: 17 months). Before transplantation, according to the Eurodiab Study classification, 12 patients (25%) had nonproliferative retinopathy (NPDR; mild, moderate or severe), and 36 patients (75%) had laser‐treated and/or proliferative retinopathy (LT/PDR). During the follow‐up, in the NPDR group improvement/deterioration was defined as regression/progression to a lower/higher retinopathy grade; in the LT/PTD group, stabilization was defined as no new neo‐vessel formation or development of new lesions requiring laser‐treatment. In the NPDR group, five (41.7%) patients improved of one or more lesion grading, three (25%) patients showed no change, and four (33.3%) patients progressed of one grade. In the LT/PDR group, the post‐transplant data were: stabilization in 35 (97%) patients, and worsening in one (3%) patient. The number of improved/stabilized patients was significantly higher in the transplanted than in a control group of nontransplanted type 1 diabetic patients. In conclusion, despite a relatively short follow‐up period, successful PTx in our cohort of patients was associated with improvement and/or stabilization of DR in the majority of recipients.

Pancreas transplant alone determines early improvement of cardiovascular risk factors and cardiac function in type 1 diabetic patients

Background. The effects of pancreas transplant alone (PTA) on cardiovascular risk factors (CRF) and cardiac function in type 1 diabetes mellitus (T1DM) patients are still unsettled. Methods. We studied 13 T1DM patients who received PTA with portal drainage and 11 matched control patients. Parameters of glucose and lipid metabolism and several additional classic CRF were assessed before and up to 6 months posttransplant. Cardiac morphology and function were assessed by Doppler echocardiographic examination. Results. Insulin independence was promptly achieved and then maintained after PTA. Total and low-density lipoprotein cholesterol levels were significantly lower after transplantation, whereas high-density lipoprotein cholesterol and triglyceride concentrations did not change. Both systolic and diastolic blood pressure values and fibrinogen levels improved significantly. In addition, PTA determined a significant amelioration of several morphologic and functional cardiac indices. None of the measured parameters changed in the control patients. Conclusions. PTA with portal drainage induces an early improvement of CRF and ameliorates cardiac function in patients with T1DM.

Continuous subcutaneous insulin infusion and multiple dose insulin injections in Type 1 diabetic pregnant women: a case-control study

The aim of this study was to evaluate the effects of continuous subcutaneous insulin infusion (CSII) on glycemic control and pregnancy outcomes in Type 1 diabetic pregnant women. We retrospectively evaluated 42 subjects, 20 treated with CSII and 22 with multiple dose insulin injections (MDI). The two groups were comparable for age, pre-pregnancy BMI, and primiparous rate, whereas women in the CSII group showed a tendency toward a longer diabetes duration (p = 0.06). Pre-pregnancy diabetic retinopathy and/or nephropathy were present in nine women of CSII and three of MDI. In all women metabolic control improved during pregnancy, without differences between the two groups and at the end of gestation HbA1c was 6.3 ± 0.6 in CSII and 6.1 ± 1.1% in MDI. Moreover, there were no differences in weight gain, whereas insulin requirement resulted significantly (p = 0.009) lower in CSII than in MDI. We recorded only one severe hypoglycaemic episode in both groups. No cases of deteriorations of the chronic diabetic complications were observed. The delivery occurred at 36.4 ± 2.2 weeks; birth weight, the rate of large for gestational age, and the parameters of foetal morbidity were similar in both groups. In conclusions, CSII and MDI are both effective in improving maternal glucose control and have both similar pregnancy outcomes.

Insulin release form isolated, human islets after acute or prolonged exposure to glimepiride

longed second phase [2]. Studies performed by using isolated rodent (mouse and rat) islets showed a glimepirideinduced increase of insulin secretion that was mainly monophasic in some cases [3], and biphasic in others [4]. To date, the in vitro action of the drug has been investigated with laboratory animal cells only, and no information is currently available as for the direct effect of glimepiride on human pancreatic endocrine cells. In the present study, we prepared human pancreatic islets by collagenase digestion and density gradient centrifugation as previously described [5, 6], and then challenged them with varying concentrations of glimepiride and glucose acutely. In addition, the effect of the sulphonylurea on insulin release in response to the non-fuel secretagogue arginine was evaluated. Finally, insulin release in response to glucose after a 24-h exposure to glimepiride was assessed. The islets from the pancreases of seven human cadaver donors, four males and three females, aged 24-48 years, were used in this study. All the protocols had been approved by our local Ethics Committee. The insulin secretion studies were performed according to the procedures usually employed in our laboratory [5, 6]. Within 8-10 days from the isolation (during this period the cells had been kept at 37° C in M199 culture medium containing 5.5 mmol/l glucose), groups of approximately 10 islets of comparable size (100-150 μm in diameter) were preincubated at 37° C for 45 min in Krebs-RingerBicarbonate solution (KRBS), supplemented with 3.3 mmol/l glucose and 0.5% bovine serum albumin. Then in a first set of experiments, the islets were washed, and incubated at 37° C for 45 min in KRBS, containing 2.5, 5.0, 10 or 20 mmol/l glucose. For each given glucose concentration, the effect of 0, 1.0, 10, and 100 μmol/l glimepiride was assessed (the number of replicates for any combination ranged from 5 to 8). In additional experiments, the effect of glimepiride (0, 1.0, 10 and 100 μmol/l) was evaluated on insulin response to 3.3 mmol/l glucose plus 20 mmol/l argiActa Diabetol (2000) 37:139-141

Prescribing exercise for prevention and treatment of gestational diabetes: review of suggested recommendations

Abstract Exercise has been proved to be safe during pregnancy and to offer benefits for both mother and fetus; moreover, physical activity may represent a useful tool for gestational diabetes prevention and treatment. Therefore, all women in uncomplicated pregnancy should be encouraged to engage in physical activity as part of a healthy lifestyle. However, exercise in pregnancy needs a careful medical evaluation to exclude medical or obstetric contraindications to exercise, and an appropriate prescription considering frequency, intensity, type and duration of exercise, to carefully balance between potential benefits and potential harmful effects. Moreover, some precautions related to anatomical and functional adaptations observed during pregnancy should be taken into consideration. This review summarized the suggested recommendations for physical activity among pregnant women with focus on gestational diabetes.

Freestyle libre trend allows for the management of adults with insulin-treated diabetes: A practical approach

Freestyle Libre (FSL) system is a new method to detect glucose enabling a new paradigm in glucose monitoring and self-management. The sensor, reading the interstitial fluid glucose concentration, provides a numerical data of glucose level and a trend arrow that add context to static measurement of glucose level. Therefore, patients could easily follow the progression of their glucose levels over the time, allowing early detection and timely treatment of deviations from targeted glucose level range, thus preventing extreme fluctuations. In order to take full advantage of the system both the caregiver and the person with diabetes must appreciate the need of careful interpretation of the data generated by the FSL. To this purpose we have generated recommendations that are based on methods suggested for CGM, our clinical experience and discussion with experienced patients using FSL, to provide a pragmatic approach to use FSL trend arrow data for managing diabetes in adults.

Pre-pregnancy obesity, gestational diabetes or gestational weight gain: Which is the strongest predictor of pregnancy outcomes?

AIMS Both obesity and gestational diabetes (GDM) are risk factors for adverse pregnancy outcomes. The aim of our study is to ascertain the independent role of prepregnancy BMI (pp-BMI), gestational weight gain (GWG), and GDM on pregnancy outcomes. METHODS We analyzed data of 1198 pregnant women, who underwent selective screening for GDM. Data on pregnancy outcomes was collected from hospital discharge records. RESULTS Cesarean section (CS) was comparable in GDM and NGT women. Prevalence of fetal macrosomia was 5.9%, with no difference between GDM and normal glucose tolerance (NGT), neonatal hyperbilirubinemia were more frequent in newborns of GDM women (63.3% vs. 52.2%; p < 0.01). Offspring of women with excessive GWG weighed more than those of women with regular GWG (3405 ± 510 g vs. 3287 ± 524 g; p < 0.01). On a logistic regression analysis, GWG was an independent risk factor for macrosomia (OR 1.08, 95% CI 1.02-1.13; p < 0.01) and delivery at a gestational age <37 weeks (OR 0.29, 95% CI 0.16-0.53; p < 0.0001). GDM and pp-BMI were not independent risk factors for adverse outcomes in this cohort. CONCLUSIONS GWG rather than GDM is associated with adverse pregnancy outcomes. These findings call for an early education and implementation of a healthy lifestyle in women planning a pregnancy.

Microvascular Disease Burden and All-Cause Mortality in Type 1 Diabetes-A 10-Year Follow-Up Study

Type 1 diabetes (T1D) is associated with a sustantially increased risk of cardiovascular (CV) events and premature death. The effect of the microvascular disease (MD) burden, i.e., the cumulative burden of retinopathy, nephropathy and peripheral neuropathy on all-cause mortality was evaluated in 774 T1D (age 40.2±11.7; DD 19.4±12.2 years; HbA1c 7.8±1.2%) in a mean follow-up of 10.6±2.5 years. Distribution of MD was: no-MD: n. 425 (54.9%); MD1: 250 (32.3%); MD2: 75 (9.7%); MD3: 24 (3.1%). Distribution was unchanged after esclusion of 41 T1D (5.3%) with previous CV events (CV+; 57.0%, 32.2%, 8.5% and 2.3%, respectively). Compared to no-MD, MD1-3 groups showed an adverse CV risk profile with steeply increase in age, DD, BMI, WHR, BP, HbA1c, uric acid and EURODIAB PCS risk score for major vascular outcomes (p Disclosure M. Garofolo: None. R. Giannarelli: None. M. Aragona: None. D. Lucchesi: None. L. Giusti: None. V. Sancho-Bornez: None. G. Daniele: None. R. Miccoli: None. G. Penno: None. S. Del Prato: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, GlaxoSmithKline plc., Intarcia Therapeutics, Inc., Merck & Co., Inc., Novartis Pharmaceuticals Corporation, Novo Nordisk A/S, Servier, Sanofi, Takeda Pharmaceuticals U.S.A., Inc.. Research Support; Self; Merck & Co., Inc., Novartis Pharmaceuticals Corporation, Boehringer Ingelheim Pharmaceuticals, Inc., AstraZeneca. Speaker9s Bureau; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Novartis Pharmaceuticals Corporation, Takeda Pharmaceuticals U.S.A., Inc.. Advisory Panel; Self; Janssen Biotech, Inc., Abbott.