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The discovery of insulin in 1921 – due to the efforts of the Canadian research team based in Toronto – has been a landmark achievement in the history of medicine. Lives of people with diabetes were changed forever, considering that in the pre-insulin era this was a deadly condition. Insulin, right after its discovery, became the first hormone to be purified for human use, the first to be unraveled in its amino acid sequence and to be synthetized by DNA-recombinant technique, the first to be modified in its amino acid sequence to modify its duration of action. As such the discovery of insulin represents a pivotal point in medical history. Since the early days of its production, insulin has been improved in its pharmacokinetic and pharmacodynamic properties in the attempt to faithfully reproduce diurnal physiologic plasma insulin fluctuations. The evolution of insulin molecule has been paralleled by evolution in the way the hormone is administered. Once-weekly insulins will be available soon, and glucose-responsive “smart” insulins start showing their potential in early clinical studies. The first century of insulin as therapy was marked by relentless search for better formulations, a search that has not stopped yet. New technologies may have, indeed, the potential to provide further improvement of safety and efficacy of insulin therapy and, therefore, contribute to improvement of the quality of life of people with diabetes.

MG53 is a myokine modulating insulin signaling in several tissues; its relationship to glucose tolerance or risk of developing type 2 diabetes mellitus (T2DM) is unknown. This observational, prospective study aimed at evaluating the relationship between MG53 and glucose tolerance, testing whether its circulating levels may be associated with disease progression in a cohort at high risk of T2DM.Five hundred and fifteen subjects who underwent a deep characterization of their glucose tolerance in the years 2003-2005 participated in this study. MG53 levels were measured at baseline. Glucose tolerance status was available over a follow-up of 15 ± 2 years for 283 of them; their vital status as of December 2020 was also retrieved.MG53 levels were significantly lower in subjects with normal glucose tolerance than in subjects with impaired glucose regulation (IGR) or T2DM. Individuals in the highest MG53 levels quartile had more frequently 1h-post load glucose ≥ 155 mg/dL (54% vs 39%; p = 0.015), worse proportional control of β-cell function (p 0.05-0.01), as determined by mathematical modeling, and worse Disposition Index (DI) (0.0155 ± 0.0081 vs 0.0277 ± 0.0030; p 0.0001). At follow-up, baseline MG53 levels were higher in progressors than in non-progressors (120.1 ± 76.7 vs 72.7 ± 63.2 pg/ml; p = 0.001; ROC curve area for incident diabetes of 0.704). In a multivariable regression with classic risk factors for T2DM and DI, MG53 remained independently associated with progression with T2DM.MG53 may be a novel biomarker of glucose dysregulation associated with β-cell dysfunction, likely improving our ability to identify, among high-risk subjects, those more likely to develop T2DM.

In spite of being at target for glucose (1) or traditional cardiovascular (CV) risk factors (2), individuals with type 1 diabetes (T1D) still have an excess of CV mortality and morbidity implying a role for other mechanisms including insulin resistance (IR). Impaired insulin action in T1D was established by clamp technique long ago (3). Estimated glucose disposal rate (eGDR) correlates well with the clamp technique (4) and is a risk marker for microangiopathy (5,6), diabetic kidney disease (DKD) (6), CV risk, and mortality (5,7). In this observational single-center study, we investigated to what extent eGDR is a predictor of CV events, coronary artery disease (CAD), and all-cause mortality irrespective of CV risk factors and DKD in 774 subjects with T1D over a 10-year follow-up, as previously described (8). eGDR (mg/kg/min) was calculated at baseline as follows (4): eGDR = 21.158 − (0.09 × WC) − (3.407 × HTN) − (0.551 × HbA1c), where WC is waist circumference (cm), HTN is hypertension (yes = 1, no = 0), and HbA1c is in %. Follow-up data were retrieved from the national and regional health care registers (ICD-9, Clinical Modification, codes) by searching for CV outcomes (primary outcome) up to 31 December 2017 and for all-cause death up to 31 October 2018. Incidence of CV outcomes was available for 736 participants (95.1%), and vital status was available for all individuals (8). We used univariate and multivariate Cox proportional hazards models to …

Background and aims Screening for Gestational Diabetes (GDM) is usually recommended between 24 and 28 weeks of pregnancy; however available evidence suggests that GDM may be already present before recommended time for screening, in particular among high-risk women as those with prior GDM or obesity. The purpose of this retrospective study was to evaluate whether early screening (16–18 weeks) and treatment of GDM may improve maternal and fetal outcomes. Methods and results In 290 women at high-risk for GDM, we analyzed maternal and fetal outcomes, according to early or standard screening and GDM diagnosis time. Early screening was performed by 50% of high-risk women. The prevalence of GDM was 62%. Among those who underwent early screened, GDM was diagnosed at the first evaluation in 42.7%. Women with early diagnosis were more frequently treated with insulin and had a slightly lower HbA1c than women with who were diagnosed late. No differences were observed in the prevalence of Cesarean section, operative delivery, gestational age at the delivery, macrosomia, neonatal weight, Ponderal Index and Large-for-Gestational-Age among women with early or late GDM diagnosis or NGT. However, compared to NGT women, GDM women, irrespective of the time of diagnosis, had a lower gestational weight gain, lower prevalence of macrosomia (3.9% vs. 11.4%), small (1.7% vs. 8.3%) as well as large for gestational age (3.3% vs. 16.7%), but higher prevalence of pre-term delivery (8.9% vs. 2.7%). Conclusion Early vs. standard screening and treatment of GDM in high-risk women is associated with similar short-term maternal-fetal outcomes, although women with an early diagnosis were treated to a greater extent with insulin therapy.

In this observational study, we assessed the association between use of non-nutritive-sweetened soft drink (NNSSD) and risk of gestational diabetes (GDM) in 376 pregnant women consecutively screened for GDM, observing that NNSSD consumption is common among pregnant women and is associated with an increased risk of GDM, independently from traditional risk factors.

Genome-wide association studies have identified numerous genetic variants for type 2 diabetes (T2D). Most genetic loci discovered to date were studied in Caucasians or Asian ancestry, however, there are no data regarding a quite large Italian sample. Therefore, we investigated T2D genetic susceptibility of 143 single nucleotide polymorphisms (SNPs) within 30 genes involved in glucose metabolism in a large Italian case-control study. For the study, 1875 Caucasian patients were selected from three Italian cohorts. Age, gender, BMI and fasting plasma glucose (FPG) values were collected. Population was split in cases and controls based on FPG values or T2D diagnosis. T2D subjects and whom with FPG higher that 126 mg/dL were recruited as cases whereas subjects with normal values of FPG were considered controls. In each subject 143 SNPs were genotyped. To evaluate the association between genetic variations and diabetes status, a logistic regression analysis, adjusted for age, sex and BMI, was performed. Overall, 948 (50.6%) had T2D. Twenty out of 143 variants within 11 different genes resulted significantly associated to T2D. Four of them were located into TCF7L2 gene and presented the highest odd ratio (from 1.42 to 1.57). At least two SNPs were located within KCNJ11, WFS1, ABCC8, JAZF1 and HNF1B genes and one SNP each was identified in ADAMTS9, IGF2BP2, FTO, G6PC2 and GCK genes. Our findings support the role of 11 genes involved in glucose homeostasis in T2D risk development in a large Italian population. We found that such genetic information may be advantageous for predicting T2D.

to evaluate the effect of home confinement related to COVID-19 lockdown on metabolic control in subjects with T2DM in Italy.we evaluated the metabolic profile of 304 individuals with T2DM (65% males; age 69 ± 9 years; diabetes duration 16 ± 10 years) attending our Diabetes Unit early at the end of lockdown period (June 8 to July 7, 2020) and compared it with the latest one recorded before lockdown.There was no significant difference in fasting plasma glucose (8.6 ± 2.1 vs 8.8 ± 2.5 mmol/L; P = 0.353) and HbA1c (7.1 ± 0.9 vs 7.1 ± 0.9%; P = 0.600) before and after lockdown. Worsening of glycaemic control (i.e., ΔHbA1c ≥ 0.5%) occurred more frequently in older patients (32.2% in 80 years vs 21.3% in 61-80 years vs 9.3% in 60 years; P = 0.05) and in insulin users (28.8 vs 16.5%; P = 0.012). On multivariable analysis, age 80 years (OR 4.62; 95%CI: 1.22-16.07) and insulin therapy (OR 1.96; 95%CI: 1.10-3.50) remained independently associated to worsening in glycaemic control.Home confinement related to COVID-19 lockdown did not exert a negative effect on glycaemic control in patients with T2DM. However, age and insulin therapy can identify patients at greatest risk of deterioration of glycaemic control.

AIMS: The aim of this study was to evaluate the effect the lockdown imposed during COVID-19 outbreak on the glycemic control of people with Type 1 diabetes (T1D) using Continuous (CGM) or Flash Glucose Monitoring (FGM). MATERIALS AND METHODS: We retrospectively analyzed glucose reading obtained by FGM or CGM in T1D subjects. Sensor data from 2 weeks before the lockdown (Period 0, P0), 2 weeks immediately after the lockdown (period 1, P1), in mid-lockdown (Period 2, P2) and immediately after end of lockdown (Period 3, P3) were analyzed. RESULTS: The study included 63 T1D patients, (FGM: 52, 82%; CGM:11, 18%). Sensor use (91%) were slightly reduced. Despite this reduction, Time in Range increased in P1 (62%), P2 (61%) and P3 (62%) as compared to P0 (58%, all p

Clear cell renal cell carcinoma (ccRCC) is fundamentally a metabolic disease. Given the importance of lipids in many cellular processes, in this study we delineated a lipidomic profile of human ccRCC and integrated it with transcriptomic data to connect the variations in cancer lipid metabolism with gene expression changes. Untargeted lipidomic analysis was performed on 20 ccRCC and 20 paired normal tissues, using LC-MS and GC-MS. Different lipid classes were altered in cancer compared to normal tissue. Among the long chain fatty acids (LCFAs), significant accumulations of polyunsaturated fatty acids (PUFAs) were found. Integrated lipidomic and transcriptomic analysis showed that fatty acid desaturation and elongation pathways were enriched in neoplastic tissue. Consistent with these findings, we observed increased expression of stearoyl-CoA desaturase (SCD1) and FA elongase 2 and 5 in ccRCC. Primary renal cancer cells treated with a small molecule SCD1 inhibitor (A939572) proliferated at a slower rate than untreated cancer cells. In addition, after cisplatin treatment, the death rate of tumor cells treated with A939572 was significantly greater than that of untreated cancer cells. In conclusion, our findings delineate a ccRCC lipidomic signature and showed that SCD1 inhibition significantly reduced cancer cell proliferation and increased cisplatin sensitivity, suggesting that this pathway can be involved in ccRCC chemotherapy resistance.

For women with previous gestational diabetes (GDM), international guidelines recommend 75 g oral glucose tolerance test (OGTT) at 4-12 weeks after delivery to assess glucose tolerance, considering their increased risk of type 2 diabetes. We evaluated prevalence of postpartum impaired glucose regulation (IGR) and identified associated risk factors.We retrospectively collected data from 749 women with previous GDM (IADPSG criteria) who underwent postpartum OGTT for type 2 diabetes screening between 2011 and 2019. IGR was identified according to ADA criteria.Prevalence of IGR was 12.7%, lower in women with pre-pregnancy normal weight, higher in women with family history of type 2 diabetes and in those treated with insulin during pregnancy. Prevalence of IGR raised with increasing number of altered glucose values at OGTT performed during pregnancy for GDM screening. HbA1c and triglycerides measured during the third trimester of pregnancy were higher in women with postpartum IGR. At postpartum screening, women with IGR had higher BMI, waist, blood pressure. At multivariate logistic regression analysis, family history of diabetes (OR 2.21; 95% CI: 1.33-3.69; p 0.01) and presence of all three glucose values exceeding threshold at OGTT during pregnancy (OR 2.89; 95% CI: 1.42-5.86; p 0.01) were independently associated with IGR.In women with GDM, persistence of IGR in the immediate postpartum period is associated with family history of diabetes and the presence of all three glucose values exceeding diagnostic threshold for GDM at OGTT in pregnancy, suggesting that these women should undergo specific diabetes monitoring and prevention programs.

Diet and physical activity are cornerstones in prevention and treatment of Gestational Diabetes (GDM) though some caution may be required under specific circumstances. The aims of this study were to evaluate activity habits during pregnancy and contraindications to physical activity in women at risk for GDM536 pregnant women (age 35 ± 5 years; gestation week 25 ± 4; pre-pregnancy BMI 24.6 ± 12.9 kg/mOf 536 women, 73.4% reported regular exercise before pregnancy and 95.5% of them continued during pregnancy. 8.2% had absolute contraindications to exercise, such as placenta praevia /vaginal bleeding and incompetent cervix/cerclage. Physical activity during the last month was reported by 66.2% of women; frequency was 1-2 times/week (44%); intensity was light (83%) and duration on average (44%) 20-40 min/day. 48% of women spent most of their time in sedentary behaviors (sitting). Among women with GDM, physical activity was associated with better metabolic profile and lower needed of insulin therapy.Women at risk for GDM spent most of their time in sedentary behaviors, despite a low prevalence of contraindications to exercise. Therefore, our data call for the need of motivational counseling aimed to implement physical activity during pregnancy.

Non-albuminuric diabetic kidney disease (Alb-DKD) has been associated with a raised risk of CV outcomes and all-cause mortality in T1D. We report about the association between DKD phenotypes and CV outcomes in a single-centre, prospective, 10.4±2.9 years observation of 774 T1D. Rates of outcomes and vital status were censored on December 2017. Out of 774 T1D, 692 (89.4%) had no-DKD, 53 DKD 1-2 (6.8%), 17 (2.2%) Alb-DKD and 12 (1.6%) Alb+DKD. Incidences of CV outcomes, coronary events and ESRD were available for 736 subjects (95.1%). A CV event occurred in 49 T1D (6.7%; 6.42 events x 1000 PYs), rising from no-DKD (4.2%) to DKD 1-2 (28.6%) and Alb-DKD (35.3%). In Alb+DKD, due to competition with all-cause death, only 1 event occurred. Compared to no-DKD, the adjusted HRs were 4.43 (95%CI 2.27-8.61, p Disclosure M. Garofolo: None. E. Gualdani: None. F. Campi: None. M. Aragona: None. D. Lucchesi: None. C. Bianchi: None. R. Miccoli: None. P. Francesconi: None. G. Penno: None. S. Del Prato: Advisory Panel; Self; Applied Therapeutics, AstraZeneca, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novartis Pharmaceuticals Corporation, Novo Nordisk A/S. Research Support; Self; AstraZeneca, Boehringer Ingelheim International GmbH. Speaker’s Bureau; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novo Nordisk A/S, Sanofi, Takeda Pharmaceutical Company Limited.

Assisted reproduction technology (ART) treatment has been suggested to increase the risk of gestational diabetes (GDM), though the nature of this association remains unclear. In the attempt to gain more insight in such an association we have carried out a study to evaluate whether ART represents an independent risk factor for GDM in single pregnancies. We collected retrospectively clinical and anthropometric data of 221 ART- and 256 age and BMI matched women with natural conception (NC) screened for GDM between 2011-2019. Out of 477 women, 32 were excluded from the analysis due to multiple pregnancies (PMA: 24; CN: 8). Between the two groups there were no differences in age (ART: 39 ± 5; NC: 38 ± 3 years; ns), BMI (ART: 23.6 ± 4.4; NC: 22.9 ± 3.6 Kg/m2; ns) and family history of diabetes (ART: 31.4%; NC: 24.2%; ns). ART-women were more frequently primiparous (62.6% vs. 22.6%; p Disclosure C. Bianchi: None. C. Della Pelle: None. G. de Gennaro: None. M. Aragona: None. V. Cela: None. S. DelPrato: None. A. Bertolotto: None.

This study evaluates the adherence to postpartum type 2 diabetes mellitus (T2DM) screening in women with previous gestational diabetes (GDM) and identifies elements associated with poor attendance.We retrospectively collected data from 650 consecutive women with GDM between 2016 and 2018, who should had 75 g-OGTT, 4-12 weeks after delivery. Impaired glucose regulation (IGR) was defined according with ADA criteria.Only 41% of women had postpartum OGTT. Of these, 1.9% received T2DM diagnosis, with IGR prevalence of 18%. After introducing a recommendation letter, adherence to screening increased (47% in 2017 and 43% in 2018 vs. 32% in 2016). Screening procedure was less common in women with: no-family history of T2DM (38% vs. 46%; p 0.05), age35 (33% vs. 47%; p 0.01), lower level of education (32% no-high-school-diploma vs. 35% high-school-diploma vs. 49% university-degree; p 0.01) and unstable employment (35% vs. 44%; p 0.05). At multivariate logistic regression analysis, age35 years (OR 1.61; 95%CI: 1.14-2.28) and lowest educational level (OR 1.64; 95% CI: 1.13-2.37, compared to University degree) were independently associated with non-adherence.Only 41% of women had postpartum T2DM screening. Women with lower attendance are those with age35 years or low educational level. Further strategies are needed to implement postpartum test.

In a retrospective, observational, cross-sectional, single-centre study, we assessed the prevalence and correlates of different CKD phenotypes (with and without albuminuria) in a large cohort of patients of white ethnicity with type 1 diabetes. From 2001 to 2009, 408 men and 369 women with type 1 diabetes (age 40.2 ± 11.7 years, diabetes duration 19.4 ± 12.2 years, HbA1c 7.83 ± 1.17% [62.0 ± 12.9 mmol/mol]) were recruited consecutively. Albumin-to-creatinine ratio (ACR) and eGFR (Modification of Diet in Renal Disease) were obtained for all individuals, together with CKD stage. Diabetic retinopathy and peripheral polyneuropathy were detected in 41.5% and 8.1%, respectively, and cardiovascular disease (CVD) occurred in 8.5%. Adjudications of CKD phenotype were made by blinded investigators. Normo- (ACR

In recent years guidelines for the treatment of type 2 diabetes (T2DM) have evolved substantially. Initially limited to a few glucose lowering agents, early guidelines predicated strict glycemic control as a main goal in the attempt to reduce the risk of long-term diabetic complications. Nowadays, guidelines are not limited to such a goal but include cardiovascular (and renal) protection. This rapid evolution was made possible by the introduction of new glucose lowering agents, which have been extensively tested in randomized clinical studies including large cardiovascular outcome trials (CVOTs). In this review we will specifically consider the use of incretin-based medications in T2DM as recommended in the recent ADA/EASD consensus, and other international guidelines, with special consideration of their glucose-lowering efficacy, their cardiovascular (and renal) benefit, their effect on body weight and risk of hypoglycemia, as well as the economic implications for their use.

The adipocyte-like morphology of clear cell renal cell carcinoma (ccRCC) cells results from a grade-dependent neutral lipid accumulation; however, the molecular mechanism and role in renal cancer progression have yet to be clarified. ccRCC shows a gene expression signature consistent with adipogenesis, and the phospholipid-binding protein annexin A3 (AnxA3), a negative regulator of adipocyte differentiation, is down-regulated in RCC and shows a differential expression pattern for two isoforms of 36 and 33 kDa. Using primary cell cultures and cell lines, we investigated the involvement of AnxA3 isoforms in lipid storage modulation of ccRCC cells. We found that the increased accumulation of lipids into ccRCC cells correlated with a decrease of the 36/33 isoform ratio. Treatment with adipogenic medium induced a significant increment of lipid storage in ccRCC cells that had a low 36-kDa AnxA3 expression and 36/33 ratio. The 36-kDa AnxA3 silencing in ccRCC cells increased lipid storage induced by adipogenic medium. These data suggest that 36-kDa AnxA3 negatively modulates the response to adipogenic treatment and may act as negative regulator of lipid storage in ccRCC cells. The subcellular distribution of AnxA3 in the cellular endocytic compartment suggests its involvement in modulation of vesicular trafficking, and it might serve as a putative mechanism of lipid storage regulation in ccRCC cells, opening novel translational outcomes.

To date treatment protocols in Respiratory and or Internal departments across Italy for treatment of chronic obstructive pulmonary disease (COPD) patients at hospital admission with relapse due to exacerbation do not find adequate support in current guidelines. Here we describe the results of a recent clinical audit, including a systematic review of practices reported in literature and an open discussion comparing these to current real-life procedures. The process was dived into two 8-hour-audits 3 months apart in order to allow work on the field in between meeting and involved 13 participants (3 nurses, 1 physiotherapist, 2 internists and 7 pulmonologists). This document reports the opinions of the experts and their consensus, leading to a bundle of multidisciplinary statements on the use of inhaled drugs for hospitalized COPD patients. Recommendations and topics addressed include: i) monitoring and diagnosis during the first 24 h after admission; ii) treatment algorithm and options (i.e., short and long acting bronchodilators); iii) bronchodilator dosages when switching device or using spacer; iv) flow measurement systems for shifting to LABA+LAMA within 48 h; v) when nebulizers are recommended; vi) use of SMI to deliver LABA+LAMA when patient needs SABA 30 litres/min; viii) contraindication to use DPI; ix) continuation of LABA-LAMA when patient is already on therapy; x) possible LABA-LAMA dosage increase; xi) use of SABA and/or SAMA in addition to LABA+LABA; xii) use of SABA+SAMA restricted to real need; xiii) reconciliation of drugs in presence of comorbidities; xiv) check of knowledge and skills on inhalation therapy; xv) discharge bundle; xvi) use of MDI and SMI in tracheostomized patients in spontaneous and ventilated breathing.

Background: FGM is less invasive than traditional glucometer. Recent studies show benefits on glycemic control and frequency of hypoglycemia, both in type 1 and type 2 diabetes. Nonetheless, experiences on the impact of this technology in the clinical setting are still scantly reported. Aim of the Study: To verify impact of FGM on glycemic control in type 1 diabetes subjects (T1DM). Patients and Methods: From January 2017 to December 2018, 397 T1DM subjects (age 43±13 years; diabetes duration 21±13 years; MDI 81%, CSII 19%; BMI 25.4±4.8 Kg/m2; Insulin Requirements (IR) 44±21 U/day; 8 episodes of severe asymptomatic hypoglycemia in the previous 6 months; 3 ketoacidosis; Test strips: 158± 28/month) were started on FGM. A 6-month follow-up (FU) was available for 350 subjects, 204 had a 12-month FU and 39 18-month FU. Results: Out of 397 subjects, 18 discontinued (patch allergy: 4; inaccuracy: 5; switched to other devices: 3). In 6-month FU patients, HbA1c declined from 58±14 to 56±12 mmol/mol (p Conclusions and comments: In our clinical practice, FGM was associated with small but significant reduction in HbA1c (particularly for patient on MDI) and severe asymptomatic hypoglycemia. Disclosure C. Rodia: None. C. Bianchi: None. A. Bertolotto: Speaker's Bureau; Self; Abbott, Lilly Diabetes. R. Giannarelli: None. F. Campi: None. S. Del Prato: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, GlaxoSmithKline plc., Merck Sharp & Dohme Corp., Novartis Pharmaceuticals Corporation, Novo Nordisk A/S, Sanofi, Servier, Takeda Pharmaceutical Company Limited. Board Member; Self; AstraZeneca. Research Support; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc. Speaker's Bureau; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Takeda Pharmaceutical Company Limited. M. Aragona: None.

The above-referenced article contained an error in the far-right column heading in Table 2. The heading should read as follows: PPV % (TP/TP + …

Gonzalez-Clemente et al. (1) claim that a simpler though efficient assessment of cardiovascular risk in people with type 1 diabetes (T1D) is much needed. Since we showed that the estimated glucose disposal rate (eGDR) was an independent predictor of cardiovascular (CVD) and coronary artery disease (CAD) in people with T1D, they evaluated whether cutoff eGDR values could be calculated to be used in clinical practice to stratify CVD risk. They used the Steno Type 1 Risk Engine (ST1RE) (2) in 179 T1D subjects without CVD to identify 10-year risk level for a first CVD event: low (

Prediabetes (intermediate hyperglycemia) consists of two abnormalities, impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) detected by a standardized 75-gram oral glucose tolerance test (OGTT). Individuals with isolated IGT or combined IFG and IGT have increased risk for developing type 2 diabetes (T2D) and cardiovascular disease (CVD). Diagnosing prediabetes early and accurately is critical in order to refer high-risk individuals for intensive lifestyle modification. However, there is currently no international consensus for diagnosing prediabetes with HbA1c or glucose measurements based upon American Diabetes Association (ADA) and the World Health Organization (WHO) criteria that identify different populations at risk for progressing to diabetes. Various caveats affecting the accuracy of interpreting the HbA1c including genetics complicate this further. This review describes established methods for detecting glucose disorders based upon glucose and HbA1c parameters as well as novel approaches including the 1-hour plasma glucose (1-h PG), glucose challenge test (GCT), shape of the glucose curve, genetics, continuous glucose monitoring (CGM), measures of insulin secretion and sensitivity, metabolomics, and ancillary tools such as fructosamine, glycated albumin (GA), 1,5- anhydroglucitol (1,5-AG). Of the approaches considered, the 1-h PG has considerable potential as a biomarker for detecting glucose disorders if confirmed by additional data including health economic analysis. Whether the 1-h OGTT is superior to genetics and omics in providing greater precision for individualized treatment requires further investigation. These methods will need to demonstrate substantially superiority to simpler tools for detecting glucose disorders to justify their cost and complexity.

AIM To investigate the effect of sitagliptin (SITA) and metformin (MET) monotherapy as well as in combination (MET+SITA) on beta-cell function and insulin sensitivity in women with recent gestational diabetes (GDM) and impaired glucose regulation (IGR: impaired fasting glucose and/or impaired glucose tolerance). MATERIAL AND METHODS Forty women were randomly assigned to receive SITA (100 mg qd), MET (850 mg bid) or MET+SITA (50 + 850 mg bid) for 16 weeks. A 75 g oral glucose tolerance test (OGTT) and +125 mg/dL hyperglycaemic clamp followed by 5 g i.v. L-arginine were performed at baseline and end of study. The primary outcome of the study was the mean change in arginine-stimulated insulin secretion rate during the hyperglycaemic clamp test from baseline to 16-week therapy. RESULTS At week 16, body mass index declined in all groups (-1.2 ± 0.2 kg/m2 ; P

Large cardiovascular outcome trials (CVOTs) have lent support to a cardiovascular protection with the use of SGLT2-inhibitors (SGLT2is) and GLP1-Receptor Agonists (GLP1-RAs) in subjects with type 2 diabetes. These two classes of novel glucose lowering agents have been shown to have a similar effect on the risk reduction of Major Adverse Cardiovascular Events (MACE: nonfatal myocardial infarction, nonfatal stroke, cardiovascular mortality). Nonetheless, they may not be simply interchangeable. Rather, careful evaluation of all the results of CVOTs leads identification of different effects that may allow profiling of the ideal individuals with T2DM who may benefit most from the use of one or the other class of agents. These differences include effect on heart failure, stroke and diabetic kidney disease that have prompt recent guidelines and recommendation for the treatment of type 2 diabetes to suggest the preferential use of SGLT2is in those with evidence of heart failure and impaired kidney function, while both SGLT2i and GLP1-RAs with proven effect could be use in those with prevalent atherosclerotic cardiovascular disease. This review discusses all these elements of differentiation along with others that in the future may help establishing the best cardiorenal benefit for individuals with T2DM.

Background Alcohol abuse is a health concern worldwide. Studies have associated alcohol abuse with cardiovascular impairments. In this study, we investigated differences in the effects of chronic alcohol vapor exposure on cardiovascular function between male and female rats by using the alcohol vapor chamber method to induce alcohol addiction-like behaviors in rats. Methods We exposed male and female Long-Evans rats to alcohol vapor for 14 hours, followed by ethanol withdrawal for 10 hours, for 30 consecutive days or room air (control groups). The animals underwent preparation for the surgical implantation of cannulas into femoral vessels, for allowing the assessment of the basal arterial pressure and heart rate values, baroreflex function, and autonomic activity. Results Female control rats showed higher basal heart rate compared to male control rats. Chronic alcohol vapor inhalation reduced basal heart rate in females, but not in males; this effect was followed by an increase in the parasympathetic tone of the heart. Further, female rats subjected to alcohol vapor showed an increase in the baroreflex activity. Conclusions These findings suggest that females are more sensitive to chronic alcohol vapor exposure than males because they had a reduction in basal heart rate and changes in the baroreflex activity.

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.

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.We analyzed data of 1198 pregnant women, who underwent selective screening for GDM. Data on pregnancy outcomes was collected from hospital discharge records.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 age37 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.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.

The aim of this work was to present a novel minimally invasive surgical stabilization technique for canine atlanto-occipital dislocation and to report the associated magnetic resonance imaging (MRI) findings. All 5 dogs in this case series underwent 1.5 T MRI of the head and neck and 3 underwent both MRI and computed tomography (CT). Atlanto-occipital dislocations were diagnosed based on the increased joint space between the occipital condyles and the atlas on MRI. Surgery was performed immediately with a never previously described fixation technique based on an external ligature. The stabilization was performed via 4 holes drilled in the zygomatic processes and in the atlas wings on each side. A nylon monofilament of 1 mm diameter was inserted in the 4 holes, and an O-shaped ligature was carried out externally to the skin through the ipsilateral zygomatic arch. Ligatures were removed within 2 months. At the postsurgical follow-up examination, 14 days after surgery, all dogs were found to be ambulatory. Atlanto-occipital stability was assessed by clinical examination with an average of 24 months of follow-up. The positive outcomes in this case series suggest that atlanto-occipital dislocation may be surgically treated with this novel technique, irrespective of the severity of the clinical presentation and associated lesions observed on MRI.

The mechanisms responsible for contribution of variants in the gene TFC7L2 to the risk for type 2 diabetes (T2DM) remains far from being completely understood, and available studies have generated nonunivocal results.We investigated the postprandial glucose metabolism in subjects at risk for T2DM carrying the TCF7L2 risk allele.Twenty-three subjects carrying the risk-conferring TCF7L2 genotypes (11 TT and 12 CT at rs7901346) and 13 subjects with wild-type genotype (CC) underwent a standard mixed-meal test (MMT) in combination with stable isotope tracers.We evaluated endogenous and exogenous glucose fluxes and hormonal responses.Fasting plasma glucose, insulin, C-peptide, glycated hemoglobin, endogenous glucose production, and plasma glucose clearance were similar in the three groups, whereas plasma glucagon levels were lower in both CT and TT than in CC (64 ± 20, 63 ± 18 and 90 ± 29 pg/mL, respectively; both P = .01). In response to the MMT, TT subjects had lower plasma glucose levels than CC subjects [mean area under the time-concentration curve (AUC) 6.1 ± 3.9 vs 7.1 ± 12.0 mmol/L, P = .04] and lower insulin secretion rate (mean AUC 385 ± 95 vs 530 ± 159 pmol/m(2) · min, P = .02). Initial (0-60 min) rate of appearance (Ra) of oral glucose was lower in TT compared with CT/CC (AUC 2.7 ± 1.1 vs 3.8 ± 1.2 μmol/kg · min, P = .02) with no difference among the three groups in endogenous glucose production. The AUC0-60min for Ra of exogenous glucose (Raex) was positively correlated with the plasma glucose AUC0-60min. Total Raex AUC0-120min was correlated with total AUC0-120min of plasma glucose (r = 0.45, P.01). Plasma glucagon-like peptide-1 and glucose-dependent insulinotropic peptide levels in response to the MMT were not affected by genotype.In subjects at risk for T2DM, the TCF7L2 polymorphisms were associated with reduced Raex into systemic circulation, causing reduced postprandial blood glucose increase and, in turn, lower insulin secretion rate with no impairment in β-cell function. The reduced Raex is likely due to greater glucose retention in the splanchnic area.

Background Hypoglycaemia is a major burden of the pharmacological therapy of diabetes and is associated with increased morbidity, mortality and treatment costs. Methods We screened all admissions to the emergency room of the Pisa University Hospital from 1 January 2009 to 31 December 2013, selecting individuals with a discharge diagnosis of hypoglycaemia. We retrieved 500 admissions involving adult diabetic patients: age 71 ± 16 years; M/F 50.2/49.8%; 70.2% type 2 diabetes (T2DM). Results Among T2DM, 42.2% were on insulin, 10.8% on insulin plus oral anti-diabetes drugs and 38.2% on oral anti-diabetes drugs alone (92% sulphonylureas/glinides ± insulin-sensitizers). Glibenclamide was the most frequently used sulphonylurea (69%). Individuals treated with oral anti-diabetes drugs were older than those on insulin (79 ± 11 versus 74 ± 12 years; p

An altered metabolism is involved in the development of clear cell - renal cell carcinoma (ccRCC), and in this tumor many altered genes play a fundamental role in controlling cell metabolic activities. We delineated a large-scale metabolomic profile of human ccRCC, and integrated it with transcriptomic data to connect the variations in cancer metabolism with gene expression changes. Moreover, to better analyze the specific contribution of metabolic gene alterations potentially associated with tumorigenesis and tumor progression, we evaluated the transcription profile of primary renal tumor cells. Untargeted metabolomic analysis revealed a signature of an increased glucose uptake and utilization in ccRCC. In addition, metabolites related to pentose phosphate pathway were also altered in the tumor samples in association with changes in Krebs cycle intermediates and related metabolites. We identified NADH dehydrogenase (ubiquinone) 1 alpha subcomplex 4-like 2 (NDUFA4L2) as the most highly expressed gene in renal cancer cells and evaluated its role in sustaining angiogenesis, chemoresistance, and mitochondrial dysfunction. Finally, we showed that silencing of NDUFA4L2 affects cell viability, increases mitochondrial mass, and induces ROS generation in hypoxia.

Atlanto-axial (AA) instability due to ligament insufficiency is a common cause of cervical spinal cord compression in toy breeds. However, in some dogs a difference in size between the atlas and the axis leads to joint incongruence that exacerbates AA subluxation and makes surgical treatment challenging. Twelve dogs with AA instability with incongruence were enrolled in a single institution prospective observational study. Computed tomography (CT) and magnetic resonance imaging (MRI) of the AA joint were compared to a retrospectively reviewed control group. A novel surgical approach consisting of a dorsal internal fixation technique was performed in six dogs. For affected dogs, the mean normalised difference between the dorso-ventral atlas canal and the dorso-ventral axis canal was 29.67% (median of 35.07%, standard deviation 25.64%), while in normal dogs a mean difference of 4.67% (median of 3.95%, standard deviation 5.21%) was observed. On MRI, 12/12 affected dogs had spinal cord compression, which was classified as reducible (3/12), partially reducible (6/12) and non-reducible (3/12). In surgically operated dogs, follow-up CT showed a partial or complete reduction of the previous spinal cord compression with a consistent amelioration or resolution of the presenting complaints. The proposed surgical technique was safe and effective in dogs with partially or completely reducible spinal cord compression.

Obesity, physical inactivity and unhealthy diet are common risk factors in men and women for the development of diabetes. Yet some physiological and pathological conditions are unique to the women and these conditions can increase their risk of developing diabetes and its complications. In particular, the metabolic status during pregnancy may have important implications on their own well being as well as the one of their children. Therefore, it is necessary that these feature conditions become the object of screenings in order to identify women at high risk and implement effective preventative maneuvers. Though the quality and intensity of diabetes care in women does not appear to be inferior to that of men, their therapeutic response remains limited. Better understanding of gender-related pathophysiological, diagnostic, and therapeutic responses is needed in order to design specific approaches to improve outcomes in women. Women must consider the opportunity to change their eating habits and lifestyle in general, in an attempt to preserve themselves and their family.

In 2011, the Italian National Health System guidelines introduced a selective screening for gestational diabetes (GDM) based on risk factors, recommending early evaluation in high risk women. The present study examined to which extent guidelines are applied, and analyzed the effectiveness of GDM diagnosis according to risk profile.We analyzed 1338 pregnant women, consecutively screened for GDM with a 75 g OGTT between January 2013 and December 2015, according to national guidelines. Diagnosis of GDM was based on IADPSG/WHO 2013 criteria. As many as 14.4% of screened women was at high risk, 64% at medium, 21.6% did not have any risk factor. Only 50% of high-risk women were appropriately screened at 16th-18th gestational weeks; 28% of them repeated the OGTT due to NGT. The overall prevalence of GDM was 39.9%, higher in high risk women (67% vs. 40% medium risk vs. 22% low risk; p 0.0001). An early GDM diagnosis was performed in 40.7% of high-risk women. In low risk women, gestational weight gain at the screening time was independently associated with GDM.The recommendations for the screening of GDM are still insufficiently implemented, especially for early evaluation in high risk women. Considering the high proportion of early GDM diagnosis, the poor adherence to screening recommendation may result in late diagnosis of GDM. Finally, our finding of a 22% prevalence of GDM among low risk women suggests the need to consider additional risk factors, such as excessive weight gain during pregnancy.

Despite the considerable burden of disease associated with type 2 diabetes mellitus (T2DM), most patients are not at, or are unable to achieve, recommended glycemic targets. This is partly because of the relentless progressive nature of the disease, but it may also be attributable to the current diabetes treatment paradigm. The recommended stepwise approach may lead to frequent early treatment failure with prolonged periods of elevated glucose as a consequence of clinical inertia and delays in achieving optimal glycemic control. Thus, it is most appropriate to consider the current treatment paradigm for T2DM in the context of a more aggressive initial therapy with early combination therapy. Current guidelines advise that initial combination therapy should be used for patients presenting with elevated glycated hemoglobin (HbA1c). However, several studies and recent meta-analyses suggest a potential benefit from initial combination therapy on glycemic outcomes in diabetes compared with metformin monotherapy across a wide range of baseline HbA1c levels. Indeed, combination therapy can increase the number of patients achieving glycemic goals, and the newer glucose-lowering agents may reduce the risk of hypoglycemia and body weight gain. Moreover, our improving understanding of the complex pathophysiology of T2DM and the availability of treatments tackling specific mechanisms contributing to hyperglycemia should lead to more pathophysiologically sound combination therapy. We discuss the rationale behind and evidence for early combination therapy as well as what is needed in the future to better understand its potential.

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.

Objective: To compare magnetic resonance imaging (MRI) and spectroscopy (MRS) findings in dogs affected by persistent hepatic encephalopathy (HE) before and after treatment and assess any correlation between plasma ammonia levels and metabolite concentrations.Methods: In dogs with persistent HE, plasma ammonia measurement, brain MRI and single voxel MRS were performed before and 4 months after treatment. The concentrations of N-acetyl aspartate, (NAA) glutamate-glutamine complex (Glx), creatine (Cr), choline (Cho) and myo-inositol (mI) as well as the MRI findings werecompared and the correlation with plasma ammonia concentration was evaluated. Statistical analysis included Shapiro Wilk test, Student t-test and linear-fit regression.Results: Twenty dogs were enrolled. Initial MRI and MRS showed alterations in 18/20 and 20/20 dogs respectively. The MRI findings were normalized in dogs aged less than 3 years. Comparing post-treatment metabolite concentrations with the control group, no statistically significant differences were evident for dogs aged less than 3 years, whereas dogs aged more than 5 years showed a persistent but not significant reduction in NAA and mI, with a statistically significant increase in Glx. In dogs younger than 3 years, but not in dogs older than 5 years, a positive correlation was detected between plasma ammonia levels and Glx (r=0.80, p=0.041) and a negative correlation between ammonia level and NAA (r=-0.96, p=0.03) and between NAA and Glx (r=-0.87, p=0.037). No correlation was observed for Cr, Cho and mI.Conclusion: In young dogs MRI and MRS findings of persistent HE can normalize after effective treatment whereas abnormalities are still detected in older dogs. MRI and MRS could therefore be useful in the short-term treatment response evaluation of persistent canine HE.

© Bianchi et al. Clear cell renal cell carcinoma (ccRCC) has a poor prognosis despite novel biological targeted therapies. Tumor aggressiveness and poor survival may correlate with tumor grade at diagnosis and with complex metabolic alterations, also involving glucose and lipid metabolism. However, currently no grade-specific metabolic therapy addresses these alterations. Here we used primary cell cultures from ccRCC of low- and high-grade to investigate the effect on energy state and reduced pyridine nucleotide level, and on viability and proliferation, of specific inhibition of glycolysis with 2-deoxy-D-glucose (2DG), or fatty acid oxidation with Etomoxir. Our primary cultures retained the tissue grade-dependent modulation of lipid and glycogen storage and aerobic glycolysis (Warburg effect). 2DG affected lactate production, energy state and reduced pyridine nucleotide level in high-grade ccRCC cultures, but the energy state only in low-grade. Rather, Etomoxir affected energy state in high-grade and reduced pyridine nucleotide level in low-grade cultures. Energy state and reduced pyridine nucleotide level were evaluated by ATP and reduced 3-(4,5-dimethylthiazol-2-yl)-2,5- diphenyltetrazolium (MTT) dye quantification, respectively. 2DG treatment impaired cell proliferation and viability of low-grade ccRCC and normal cortex cultures, whereas Etomoxir showed a cytostatic and cytotoxic effect only in high-grade ccRCC cultures. Our data indicate that in ccRCC the Warburg effect is a grade-dependent feature, and fatty acid oxidation can be activated for different grade-dependent metabolic needs. A possible grade-dependent metabolic therapeutic approach in ccRCC is also highlighted.

OBJECTIVE To ascertain to which extent the use of HbA1c and oral glucose tolerance test (OGTT) for diagnosis of glucose tolerance could identify individuals with different pathogenetic mechanisms and cardiovascular risk profile. RESEARCH DESIGN AND METHODS A total of 844 subjects (44% men; age 49.5 ± 11 years; BMI 29 ± 5 kg/m2) participated in this study. Parameters of β-cell function were derived from deconvolution of the plasma C-peptide concentration after a 75-g OGTT and insulin sensitivity assessed by homeostasis model assessment of insulin resistance (IR). Cardiovascular risk profile was based on determination of plasma lipids and measurements of body weight, waist circumference, and blood pressure. Glucose regulation categories by OGTT and HbA1c were compared with respect to insulin action, insulin secretion, and cardiovascular risk profile. RESULTS OGTT results showed 42% of the subjects had prediabetes and 15% had type 2 diabetes mellitus (T2DM), whereas the corresponding figures based on HbA1c were 38 and 11%, with a respective concordance rate of 54 and 44%. Subjects meeting both diagnostic criteria for prediabetes presented greater IR and impairment of insulin secretion and had a worse cardiovascular risk profile than those with normal glucose tolerance at both diagnostic methods. In a logistic regression analyses adjusted for age, sex, and BMI, prediabetic subjects, and even more T2DM subjects by OGTT, had greater chance to have IR and impaired insulin secretion. CONCLUSIONS HbA1c identifies a smaller proportion of prediabetic individuals and even a smaller proportion of T2DM individuals than OGTT, with no difference in IR, insulin secretion, and cardiovascular risk profile. Subjects fulfilling both diagnostic methods for prediabetes or T2DM are characterized by a worse metabolic profile.

Reducing the burden of long-term complications in type 2 diabetic patients remains a major task, and represents a huge challenge. Whilst tight glycemic control has been shown to reduce the risk of microvascular complications, controversy remains regarding the benefit of intensive treatment in relation to the prevention of cardiovascular events. Recent large trials (including ACCORD, ADVANCE, and VADT) were unable to show a significant impact of glycemic control on cardiovascular events. Also, it has been argued that these trials included patients with a long duration of the disease, and with previous unsatisfactory glycemic control. Chronic exposure to hyperglycemia may cause a kind of negative metabolic memory, and thereby reduce the potential impact of good glycemic control. This concept has been corroborated by the UKPDS which recruited only subjects with newly diagnosed diabetes and without prior cardiovascular events. In these patients, early achievement of glycemic control translated into a long-term reduction of the risk of micro- and macrovascular complications. This observation prompted the UKPDS investigators to propose a positive "glycemic legacy", supporting the need for early and appropriate treatment of hyperglycemia and associated metabolic disturbances. This should be feasible now through the selection of individual targets and personalized pharmacologic treatments. In doing so, the potential risks of intensive treatment might then be avoided.

Epidemiologic data support the hypothesis of a direct and independent relationship between hyperglycemia and cardiovascular disease. The lack of a clear-cut threshold value in diabetic patients, and the persistence of the relationship in nondiabetic population as well, suggest that glycemia is a continuous variable, similarly to other cardiovascular risk factors. Moreover, increased plasma glucose levels contribute to cardiovascular risk by activating multiple atherogenic mechanisms. In spite of evident plausibility for hyperglycemia as a cardiovascular risk factor per se, intervention data remain controversial. Results of recent large-scale intervention trials, such as ACCORD, ADVANCE, and VADT, seem to undermine the concept that tight glycemic control confers some protection against cardiovascular disease in patients with type 2 diabetes, while maintenance of near-normal glycemic control from earlier stage of the disease and during acute coronary events seems to be more beneficial. However, individualized therapies remain the cornerstone of strategies aimed to reduce cardiovascular risk associated to hyperglycemia.

Background To test the association between gamma-glutamyltransferase level and glucose regulation. Methods We performed a cross-sectional analysis of 500 subjects [199 men/301 women, age 47 ± 11 years, body mass index (BMI) 28.6 ± 5.5 kg/m2] referred to Diabetes Clinics because of potential risk of type 2 diabetes mellitus (T2DM). Results The prevalence of all glucose intolerance categories was higher in the top quartile of gamma-glutamyltransferase than in the first. Subjects with normal glucose tolerance showed lower gamma-glutamyltransferase levels compared with those with impaired glucose tolerance (IGT), impaired fasting glucose (IFG)+ IGT and T2DM (ANOVA, p < 0.0001), but not those with IFG. Homeostasis model assessment-insulin resistance (HOMA-IR) increased with increasing levels of gamma-glutamyltransferase, while the insulinogenic index/HOMA-IR ratio decreased. In an age- and sex-adjusted analysis, the top gamma-glutamyltransferase quartile was independently associated with IFG + IGT [odds ratio (OR) 2.41; 95% confidence interval (CI): 1.13–5.15] and T2DM (OR 2.77; 95% CI: 1.47–5.22). After further adjustment for BMI, alcohol intake, family history of diabetes, cigarette smoking and physical activity, the top quartile of gamma-glutamyltransferase remained an independent predictor of IFG + IGT (OR 2.62; 95% CI: 1.13–6.07) and T2DM (OR 2.39; 95% CI: 1.20–4.76). Only when transaminases and HOMA-IR have been added to the model, the top quartile of gamma-glutamyltransferase resulted no more independently associated to IFG + IGT or T2DM. Conclusions Gamma-glutamyltransferase is closely related to insulin resistance, reduced beta-cell function and deterioration of glucose tolerance. Copyright © 2010 John Wiley & Sons, Ltd.