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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 …

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.

Microvascular complications (MC) affect CV risk and mortality in T2D. We explored the association of cumulative burden of retinopathy, nephropathy and peripheral neuropathy with mortality, CV events and ESRD in a single-centre, observational study involving 986 T2D over a 12.9±2.7 yrs follow-up. Vital status and rates of outcomes were censored on December 2017. The cohort included 491 (49.8%), 318 (32.3%), 135 (13.7%) and 42 (4.3%) people with no, 1, 2 or 3 MC. All-cause mortality (23.3%) increased from no-MC (15.3%) to 1 MC (23.3%, HR 1.60; 95%CI 1.16-2.20), 2 MC (41.5%, 3.19; 2.25-4.51) and 3 MC (59.5%, 5.32; 3.38-8.36; p Disclosure M. Garofolo: None. E. Gualdani: None. R. Giannarelli: None. D. Lucchesi: None. R. Miccoli: None. P. Francesconi: 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. G. Penno: None.

Background: Nesidioblastosis and insulinoma are disorders of the endocrine pancreas causing endogenous hyperinsulinemic hypoglycemia. Their coexistence is very unusual and treatment represents a still unresolved dilemma.Case Description: The patient was a 43-year-old Caucasian woman, with a 2-year history of repeated severe hypoglycemic events. The diagnostic work-up was strongly suggestive of insulinoma and the patient was submitted to surgical treatment carried out laparoscopically under robotic assistance. However, surgical exploration and intraoperative ultrasonography failed to detect a pancreatic tumor. Resection was therefore carried out based on the results of selective intra-arterial calcium stimulation test, following a step-up approach, eventually leading to a pancreatoduodenectomy at the splenic artery. The histopathology examination and the immunohistochemical staining were consistent with adult-onset nesidioblastosis. After surgery, the patient continued to experience hypoglycemia with futile response to medical treatments (octreotide, calcium antagonists, diazoxide, and prednisone). Following multidisciplinary evaluation and critical review of a repeat abdominal computed tomography scan, a small nodular lesion was identified in the tail of the pancreas. The nodule was enucleated laparoscopically and the pathological examination revealed an insulinoma. In spite of the insulinoma resection, glycemic values were only partially restored, with residual nocturnal hypoglycemia. Administration of uncooked cornstarch (1.25 g/kg body weight) at bedtime was associated with significant improvement of interstitial glucose levels (p < 0.0001) and reduction of nocturnal hypoglycemia episodes (p = 0.0002).Conclusions: This report describes a rare coexistence of adult-onset nesidioblastosis and insulinoma, suggesting the existence of a wide and continuous spectrum of proliferative β-cell changes. Moreover, we propose that uncooked cornstarch may offer an additional approach to alleviate the hypoglycemic episodes when surgery is impracticable/unaccepted.

Backgrounds and aims To investigate relevant indicators of quality of care in a large population-based sample of people with diabetes representative of clinical practice in Italy in 2018. Methods and results We analyzed data from 11,300,750 subjects. All administrative healthcare claims collected in 2018 were scrutinized to identify subjects with diabetes and investigate several indicators of quality of care. Subjects with diabetes were identified by anti-hyperglycemic drug prescriptions, disease-specific co-payment exemption and hospital discharge codes. Indicators of quality of care pertained to monitoring (HbA1c, creatinine, lipid profile, microalbuminuria, eye examination, ECG, ultrasonography of carotid and lower limb arteries) and diabetes treatment (anti-hyperglycemic agents in subjects with cardiovascular disease, CVD). Subjects attending and nonattending Diabetes Clinics were compared. We identified 697,208 individuals with diabetes. HbA1c was assessed at least once in the year in 62.7%, creatinine in 62.3%, total cholesterol in 59.6%, microalbuminuria in 34.3%. Frequency of eye examination was 8.2%, ECG 23.5%, carotid ultrasonography 14.3%, lower limb ultrasonography 7.6%. Among anti-hyperglycemic drugs, SGLT-2 inhibitors were prescribed to ~5% and GLP-1 receptor agonists to ~5% although the proportion of subjects with CVD was ~45%. Subjects attending Diabetes Clinics had higher figures for all these monitoring and treatment indicators. Conclusions The implementation of national and international guidelines regarding disease monitoring and treatment is far from being satisfactory, especially among subjects nonattending Diabetes Clinics. Further efforts and investments are needed for better disseminating guidelines, more efficaciously engaging healthcare professionals and more strongly empowering the healthcare system to improve diabetes care.

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.

IntroductionDiabetes is a highly prevalent disease worldwide and represents a challenge for patients and healthcare systems. This population-based study evaluated diabetes burden in Italy in 2018 by assessing all aspects of outpatient and hospital care.Research design and methodsWe investigated data of 11 300 750 residents in local health districts contributing to ARNO Diabetes Observatory (~20% of Italian inhabitants). All administrative healthcare claims were analyzed to gather information on access to medical resources. Subjects with diabetes, identified by antihyperglycemic drug prescriptions, disease-specific copayment exemption and hospital discharge codes, were compared with age, sex and residency-matched non-diabetic individuals.ResultsWe identified 697 208 subjects with ascertained diabetes, yielding a prevalence of 6.2% (6.5% in men vs 5.9% in women, p2-fold higher in subjects with diabetes, mainly driven by hospitalizations and outpatient care related to chronic complications rather than to glucose-lowering drugs, diabetes-specific devices, or metabolic monitoring.ConclusionsThe burden of diabetes in Italy is particularly heavy and, as a systemic disease, it includes all aspects of clinical medicine, with consequent high expenses in all areas of healthcare.

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

Estimated Glucose Disposal Rate (eGDR), a validated tool to estimate insulin sensitivity (IS) in T1DM [eGDR = 21.158 - (0.09 x WC, cm) - (3.47 x hypertension, yes = 1) - (0.551 x HbA1c, %)], has been associated to all-cause death. The relationship between eGDR and major vascular (CV) events was evaluated in 736 T1DM enrolled in an observational, single-centre study over a 10-year follow-up. Incidence of CV and coronary events were obtained by interrogating hospital discharge registers. Mean eGDR was 7.51±2.26 (M±SD) mg/kg/min (median 8.26; IQR 5.53-9.29). According to the “Swedish National Diabetes Register,” eGDR was stratified in: C1: ≥8.0 (N. 399, 54.2%, ref); C2: 6.0-7.99 (N. 121, 16.4%); C3: 4.0-5.99 (N. 144, 19.6%) and C4: Disclosure M. Garofolo: None. E. Gualdani: None. R. Giannarelli: None. M. Aragona: None. F. Campi: None. D. Lucchesi: None. G. Daniele: None. R. Miccoli: None. P. Francesconi: 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. G. Penno: None.

We report results from the clinical use of IDegLira compared to basal-bolus (BB) insulin regimen in T2DM patients admitted to our department because of DFU and CLI. We retrospectively identified 44 consecutive T2DM patients admitted to our diabetes ward because of DFU (M/F: 24/20; age: 67.3±9.5 years; BMI: 30.6±5.2 Kg/m2; diabetes duration (DD): 23.5±9.9 years; HbA1c 71.7±24.5 mmol/mol). During hospitalization, 28 patients (Group A: M/F: 15/13; age: 65.7±8.9 years; BMI: 32.6±4.8 Kg/m2; DD: 21.1±9.9 years; HbA1c 76.1±25.2 mmol/mol) previously on BB (63.7±33.9 U/day), were started on IDegLira (IDeg 22.8±7.8 U/day, liraglutide 0.82±0.3 mg/day) while the remaining 16 (Group B; M/F: 9/7; age: 70.4±10.1 years; BMI: 30.3±2.2 Kg/m2; DD: 27±9.2 years; HbA1c 63.9±22.0 mmol/mol; all p=NS vs. Group A) continued BB (43±18 U/day), allowing comparison over a mean follow-up period of 3 months. Patients were comparable with respect to distal lesions, pain-relieving, antibiotic therapies, revascularization procedures and surgical treatments performed. In Group A, BMI, HbA1c and LDL-C improved significantly (26.4±10.1 Kg/m2; 54±11 mmol/mol; 61.5±32 mg/dl; p Disclosure P. Falcetta: None. F.S. Indovina: None. R. Giannarelli: None. A. Piaggesi: None. G. Penno: None. R. Miccoli: 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. A. Coppelli: None.

Gestational diabetes (GDM) enhances the risk of type 2 diabetes (T2D) with 20-50% of women progressing to T2D within 10-years after pregnancy. Preventative strategies, including use of pharmacologic agents, are worth considering. We assessed, in a randomized double-blind study, the effect of 16-week therapy with sitagliptin (SITA, 100 mg qd), metformin (MET, 850 mg bid), and SITA+MET (50+850 mg bid) on beta-cell function and insulin sensitivity in women (n=40, age 30-49 y) with recent GDM and impaired glucose regulation (IGR: IFG and/or IGT). A 75gr OGTT and +125 mg/dl hyperglycemic clamp followed by 5 gr i.v. L-arginine were performed at baseline and study-end. Baseline characteristics were comparable in the 3 groups. At week 16, BMI declined in all groups (-1.2±0.2 Kg/m2; p Disclosure S. Barone: None. A. Dardano: None. A. Tura: None. J.J. Kurumthodathu: None. A. Bertolotto: Speaker's Bureau; Self; Abbott, Lilly Diabetes. C. Bianchi: None. L. Giusti: None. E. Lacaria: None. M. Romano: None. R. Miccoli: None. G. Penno: 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. G. Daniele: None.

Metabolic Syndrome (MetS) is associated with CV events in T2DM. We assessed over a 13-years follow-up the association between a “MetS severity score”, derived from WC, sBP, HDL and triglycerides (courtesy Dr. Mark DeBoer) and both all-cause death and incident CV events in 986 T2DM. Compared to lowest quartile, Q2-4 showed a steeply worsening CV risk profile. A total of 230 deaths occurred over 12.9±2.7 years (23.3%; 18.0 x 1000 PYs). Death rate was J-shaped: Q1 22.4%; Q2 18.2%; Q3 25.9% and Q4 26.8% (p=0.090). Electing arbitrarily Q2 as reference, and after adjustment for confounders and, finally, for parameters of MetS score, HRs (95% CI) vs. Q2 for death were: Q1 1.46 (0.97-2.19; p=0.070), Q3 1.61 (1.09-2.38; p=0.016) and Q4 1.82 (1.20-2.75, p=0.005). Over 11.3±4.4 years, 276 major CV events occurred in 972 T2DM (28.4%; 25.2 x 1000 PYs); adjusted HRs vs. Q1 were: Q2 1.34 (0.93-1.93; p=0.117), Q3 1.99 (1.40-2.82, p Disclosure M. Garofolo: None. E. Gualdani: None. D. Lucchesi: None. L. Giusti: None. V. Sancho-Bornez: None. G. Daniele: None. R. Miccoli: None. P. Francesconi: None. G. Penno: 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.

BackgroundMicrovascular complications (MC) have been claimed to increase the risk for cardiovascular disease in diabetic subjects. However, the effect of MC burden on the risk of major vascular outcomes and all-cause mortality in type 1 diabetes is still poorly explored. We evaluated the relationship between microvascular complications burden and incidence of major cardiovascular events and all-cause mortality in subjects with type 1 diabetes.MethodsWe recruited 774 participants with type 1 diabetes in a single-center observational study over a follow-up of 10.8 ± 2.5 years. Hazard ratios (HR) for cardiovascular outcomes and all-cause death associated with microvascular complications were determined by unadjusted and adjusted Cox regression analysis.ResultsOut of 774 individuals, 54.9% had no-MC, 32.3% 1 MC, 9.7% 2 MC and 3.1% 3 MC. A total of 54 deaths (7.0%) occurred. Death rate increased from no-MC 2.1% (Ref) to 1 MC 7.2% (HR 3.54 [95% CI 1.59–7.87]), 2 MC 14.7% (HR 6.41 [95% CI 2.65–15.49]) and 3 MC 66.7% (HR 41.73 [95% CI 18.42–94.57], p ConclusionsIn type 1 diabetes, microvascular complications burden increases in an independent dose-dependent manner the risk of major cardiovascular outcomes and all-cause mortality. The presence and number of microvascular complications should be considered in stratifying overall cardiovascular risk in type 1 diabetes.

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 (

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.

Metabolic Syndrome (MetS) is identified by dichotomous criteria thus masking MetS-related risk exists as a continuum. We assessed the association of a “MetS severity score” (MSs; courtesy Dr. M. DeBoer) with all-cause death in 774 T1D (age 40.2±11.7; DD 19.4±12.2 years; HbA1c 7.8±1.2%) over a 10.6±2.5 year follow-up. MSs was derived from WC, sBP, HDL and triglycerides (no glucose). Mean MSs was -0.5046±0.6717 (median -0.5820; IQR -0.9556 to -0.1529). MSs was stratified by quartiles. Compared to Q1, Q2-4 had a worse CV risk profile with increasing age, BMI, dBP, fasting glucose, HbA1c, total-, LDL- and nonHDL-Ch, uric acid and fibrinogen (p Disclosure G. Penno: None. M. Garofolo: None. R. Giannarelli: None. F. Campi: None. D. Lucchesi: None. L. Giusti: None. V. Sancho-Bornez: None. A. Dardano: None. G. Daniele: None. R. Miccoli: 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. Speaker's Bureau; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Novartis Pharmaceuticals Corporation, Takeda Pharmaceuticals U.S.A., Inc.. Advisory Panel; Self; Janssen Biotech, Inc., Abbott.

Insulin resistance (IR) was described in type 1 diabetes (T1D) and is related to higher risk of complications. The association of estimated Glucose Disposal Rate (eGDR), a proxy of IR, to all-cause mortality was assessed in 774 T1D (age 40.2±11.7; DD 19.4±12.2 years; HbA1c 7.8±1.2%) in a follow-up of 10.6±2.5 years. Mean eGDR was 7.52±2.28 mg/kg/min (median 8.29; IQR 5.54-9.31). In agreement with the “Swedish National Diabetes Register” eGDR was stratified in 4 categories: C1: ≥8.0 (n. 424, 54.8%); C2: 6.0-7.99 (n. 125, 16.1%); C3: 4.0-5.99 (n. 149, 19.3%) and C4: Disclosure M. Garofolo: None. A. Bertolotto: None. F. Campi: None. D. Lucchesi: None. L. Giusti: None. V. Sancho-Bornez: None. A. Dardano: 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. Speaker's Bureau; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Novartis Pharmaceuticals Corporation, Takeda Pharmaceuticals U.S.A., Inc.. Advisory Panel; Self; Janssen Biotech, Inc., Abbott.

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. Speaker's Bureau; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Novartis Pharmaceuticals Corporation, Takeda Pharmaceuticals U.S.A., Inc.. Advisory Panel; Self; Janssen Biotech, Inc., Abbott.

Background and Aim: Obesity adversely affects brain function, but the effect of bariatric surgery on cognitive function is still poorly evaluated. We assessed metabolic parameters and cognitive function in obese patients before and after bariatric surgery (RYGB). Methods: A 75g OGTT was performed in 10 nondiabetic obese patients (BMI 46.0±5.4 kg/m2; age 43.6±10.5 years; HbA1c 43.3±4.6 mmol/mol) before and 6-months after RYGB for measurements of metabolic parameters. Mini Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) were administered; neuronal plasticity (NP) of the visual cortex was measured as change in ocular dominance after 120 min monocular deprivation. No subject with drugs or alcohol abuse, psychiatric illness, head injury, brain tumor, dementia, epilepsy, learning disorder, developmental disability, and impaired sensory function were included. Results: At baseline median MMSE score was 28.5 (range 25-30) and median MoCA score 26.5 (range 21-30), indicating early cognitive abnormalities (MoCA Conclusion: Morbid obese subjects have subclinical cognitive impairments and brain plasticity alterations that significantly improve after RYGB. While no correlation was found between metabolic and hormonal changes, NP was positively associated with MoCA score. Disclosure A. Dardano: None. G. Daniele: None. C. Lunghi: None. A. Ciccarone: None. F. Santini: None. G. Ceccarini: None. C. Moretto: None. G. Penno: None. R. Miccoli: None. M. Morrone: 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. Speaker's Bureau; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Novartis Pharmaceuticals Corporation, Takeda Pharmaceuticals U.S.A., Inc.. Advisory Panel; Self; Janssen Biotech, Inc., Abbott.

L’ipoglicemia iperinsulinemica (HH) è una rara condizione caratterizzata da inappropriata secrezione di insulina rispetto ai valori di glicemia. In condizioni fisiologiche, le cellule beta secernono insulina per mantenere la glicemia nel range di 3,3-5,6 mmol/l (1). Nell’ipoglicemia iper-insulinemica, la fine regolazione della secrezione di insulina è perturbata e l’insulina continua a essere secreta in presenza di ipoglicemia (2). L’HH può riconoscere cause genetiche (congenite) o non genetiche. Tra le prime, sono stati descritti difetti in diversi geni tra cui ABCC8, KCN11, GCK, SCHAD, GLUD1, SLC16A1, HNF1A, HNF4A e UCP2. In questo case report, verrà descritto un raro e insolito caso di ipoglicemia iperinsulinemica in età adulta dovuto a nesidioblastosi e insulinoma.

Background High-density lipoproteins (HDLs) can exert anti-atherogenic effects. On top of removing excess cholesterol through reverse cholesterol transport, HDLs play beneficial actions on endothelial function and integrity. In particular, HDLs are strong determinant of endothelial progenitor cells (EPCs) number and function. To gain further insights into such an effect we characterized in vitro functionality of circulating “early” EPCs obtained from 60 type 2 diabetes individuals with low HDL-cholesterol (HDL-C) and 59 with high HDL-C levels. Methods After an overnight fast, venous blood was drawn in EDTA tubes and processed within 2-h from sampling. Peripheral blood mononuclear cells were isolated and plated on fibronectin coated culture dishes; after 3 days culture, adherent cells positive for Dil-ac-LDL/Lectin dual fluorescent staining were identified as monocytic angiogenic cells (MACs). After 5–7 days culture in EBM-2 medium, adherent cells were evaluated for viability/proliferation (MTT assay), senescence (beta-galactosidase activity detection), migration (modified Boyden chamber using VEGF as chemoattractant), adhesion capacity (on fibronectin-coated culture dishes) and ROS production (ROS-sensitive fluorescent probe CM-H2DCFDA). Results MACs obtained from diabetic individuals with high HDL-C had 23% higher viability compared to low HDL-C (111.6 ± 32.7% vs. 90.5 ± 28.6% optical density; p = 0.002). H2O2 exposure impaired MACs viability to a similar extent in both groups (109.2 ± 31.7% vs. 74.5 ± 40.8% in high HDL-C, p

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 and aims An intra-islet incretin system has been recently suggested to operate through modulation of the expression and activity of proconvertase 1/3 and 2 (PC1/3, PC2) in pancreatic alpha-cell accounting for local release of GLP-1. Little is known, whether this alpha-cell activity can be affected by the metabolic alterations occurring in type 2 diabetes, such as hyperglycemia, hyperlipidemia or hyperglucagonemia. Materials and methods AlphaTC1/6 cells from a mice pancreatic cell line were incubated in the presence of two glucose (G) concentration (5.5 and 16.7 mM) for 16 h with or without free fatty acid, IL6 or glucagon. GLP-1 secretion was measured by ELISA and expression of PC1/3 and PC2 by RT-PCR and western blot; cell viability was determined by MTT method, Reactive Oxygen Species generation (ROS) by H2DCFDA fluorescence and apoptosis by Annexin staining and Propidium Iodine (PI) fluorescence. Results Upon 16.7G incubation, GLP-1 secretion (total and active) was significantly increased in parallel with a significant increment in PC1/3 expression, a slight increase in cell viability and ROS generation and by a decrement in PC2 expression with no change in cell apoptosis. When cells were incubated at 5.5mM glucose with FFA, also an increment in GLP-1 secretion and PC1/3 expression was observed together an increment in ROS generation, a decrement in cell viability, and a modest increment in apoptosis. When incubated with 16.7mM glucose with FFA, the increment in GLP-1 secretion was reduced to basal, accompanied by an increment in apoptosis and ROS generation. This was also observed with IL-6, but in this case, no modification in ROS generation or apoptosis was observed when compared to 16.7mM glucose. The presence of glucagon did not modify any of the parameters studied. Conclusion These data suggest that under hyperglycemic, hyperlipidemia or inflammatory conditions, alpha cells can increase expression PC1/3 and activate GLP-1 secretion, which may contribute protecting both alpha and beta-cells from glucose and lipotoxicity, while this effect seems to be lost in the presence of both pathophysiological conditions.

Aims: To assess whereas prevalence, treatment and direct costs of drug-treated dia-betes were similar in migrants and in people of Italian citizenship under the universalistic Italian health care system. Methods and results: Drug-treated diabetic individuals were identified in the population-based multiregional ARNO Observatory on the basis of 2010 prescriptions. Migrants were identified by the country-of-birth code on the fiscal identification code. Diabetes prevalence was calculated for Italians (n Z 7,328,383) and migrants (n Z 527,965). To assess the odds of migrants of having diabetes compared to Italians, we individually matched all migrants to Italians for major con-founders (age, sex and place of residence). Finally, all migrants with diabetes were individually matched for confounders to Italians with diabetes to compare prescriptions, hospitalization rates, services use and direct costs for the National Health System. We identified 368,797 sub-jects with diabetes among Italians and 10,336 among migrants, giving prevalence of 5.03% and 1.96%, respectively. Migrants with diabetes were younger than Italians (52 13 years vs. 68 14 years, P < 0.001); after matching, their risk of disease was higher (odds ratio, 1.55, 95% confidence interval, 1.50e1.60). The total cost was 27% lower in migrants, due to lower cost of drugs (29%), hospital admission (27%) and health services (22%). The number of packages/treated person-year of all glucose-lowering drugs was also lower in migrants (15%) (P < 0.001). Conclusions: Compared to subjects of Italian ancestry, migrants to Italy show a higher risk of diabetes but less intense treatment. Inequalities in health care use are likely and are maintained also in a universalistic system.

OBJECTIVE To evaluate the feasibility and effectiveness of an intensive, multifactorial cardiovascular risk reduction intervention in a clinic-based setting. RESEARCH DESIGN AND METHODS The study was a pragmatic, cluster randomized trial, with the diabetes clinic as the unit of randomization. Clinics were randomly assigned to either continue their usual care (n = 5) or to apply an intensive intervention aimed at the optimal control of cardiovascular disease (CVD) risk factors and hyperglycemia (n = 4). To account for clustering, mixed model regression techniques were used to compare differences in CVD risk factors and HbA1c. Analyses were performed both by intent to treat and as treated per protocol. RESULTS Nine clinics completed the study; 1,461 patients with type 2 diabetes and no previous cardiovascular events were enrolled. After 2 years, participants in the interventional group had significantly lower BMI, HbA1c, LDL cholesterol, and triglyceride levels and significantly higher HDL cholesterol level than did the usual care group. The proportion of patients reaching the treatment goals was systematically higher in the interventional clinics (35% vs. 24% for LDL cholesterol, P = 0.1299; 93% vs. 82% for HDL cholesterol, P = 0.0005; 80% vs. 64% for triglycerides, P = 0.0002; 39% vs. 22% for HbA1c, P = 0.0259; 13% vs. 5% for blood pressure, P = 0.1638). The analysis as treated per protocol confirmed these findings, showing larger and always significant differences between the study arms for all targets. CONCLUSIONS A multifactorial intensive intervention in type 2 diabetes is feasible and effective in clinical practice and it is associated with significant and durable improvement in HbA1c and CVD risk profile.

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.

To assess temporal trend in incidence (2003-12) and prevalence (2002-12) of type 1 diabetes in children and young adults, direct costs and selected indicators of quality of care under the coverage of the universalistic Italian National Health System (NHS).The ARNO Observatory, a healthcare monitoring system based on administrative data, identified a population-based multiregional cohort of subjects aged 0-29 years. Type 1 diabetes was defined by at least two prescriptions of insulin over 12 months and continuous insulin-treatment in the following year. Indicators of quality of care and directs costs were assessed in persons with diabetes and in people without diabetes, individually matched for age, gender and health unit (1:4 ratio). We identified 2357 incident cases of type 1 diabetes aged 0-29 years (completeness of ascertainment, 99%). Incidence rates were similar in ages 0-14 (15.8, 95% CI 14.9-16.8) and 15-29 years (16.3, 15.4-17.2), with no significant trend. Prevalence increased from 137 to 166.9/100,000, particularly in the age 15-29 years. Direct costs accounted for € 2117 in persons with diabetes and € 292 in control individuals. A statistically significant decreasing trend in hospitalization for acute complications was evident (p 0.001), which was almost completely due to ketoacidosis. People with at least one HbA1c measurement over the year were 48.5%.We showed high incidence and increasing prevalence of type 1 diabetes in young adults in Italy, which impact on direct costs under the universalistic coverage of the NHS.

Background and aims In the present population-based study, we aimed to describe the per patient annual healthcare cost of people with diabetes in 2007–2012, to assess the relative burden of diabetes complications and other potential determinants on healthcare costs in the 2012 cohort, and to describe and analyse the determinants of the cost of incident cases diagnosed in 2012. Methods and results We analysed data from a retrospective cohort of residents in four Italian areas that were served by Local Health Units participating in the ARNO Observatory. Per patient annual healthcare costs (Euros) were estimated as the sum of all the resources supplied during that year (drugs, outpatient care, and hospitalisations). The mean per patient annual healthcare cost increased from €2752 in 2007 to €3191 in 2010, before decreasing to €2791 in 2012. The largest component of these costs was represented by hospitalisations (around €1550, on average; 51.7% of total cost), followed by outpatient care (€422; 14.6%) and drugs (€973; 33.7%). In 2012, the most relevant cost determinants were chronic diabetes complications, with an additional cost due to nephropathy/end stage renal disease (€4683), amputations (€5042), lower extremity revascularization (€4808), and cerebrovascular diseases (€3861). Costs associated with incidence cases were higher than those associated with prevalent. Conclusion The present study provides evidence on the excess of healthcare costs due to diabetes complications in both prevalent and incident cases.

Type 2 diabetes is a chronic and progressive condition associated with the risk of invalidating micro- and macrovascular complications. Hyperglycemia is the hallmark of the condition and, despite much discussion, glycemic control remains a main goal of treatment in the attempt to prevent chronic complications. A beneficial effect of glycemic control was initially supported by the UK Diabetes Prospective Study showing that intensive treatment, compared with conventional therapy, resulted in an average HbA1c level of 7% and was associated with a 24% relative risk reduction of any diabetes-related end point and a 37% reduction in the risk of microvascular disease. Moreover, a nonsignificant 16% reduction ( P = 0.052) in the risk of acute myocardial infarction was reported (1). Similar results were confirmed in the Kumamoto study (2), whereas the results of more recent intervention trials remain questionable. In the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) study (3), a lower mean HbA1c level was achieved in the intensive-control group than in the standard-control group (6.6 vs. 7.3%). Intensive control reduced the incidence of combined major macro- and microvascular events (hazard ratio [HR] 0.90; 95% CI 0.82–0.98; P = 0.01), as well as that of major microvascular events (HR 0.86; 0.77–0.97; P = 0.01). However, there was no significant effect of glucose control on major macrovascular events, death from cardiovascular causes, or death from any cause. In the Veteran Administration Diabetes Trial (VADT) (4), median HbA1c levels were 8.4% in the standard therapy group and 6.9% in the intensive therapy group. There was no significant difference between the two groups in the rate of cardiovascular events or in the rate of death from any cause (HR 1.07; 0.81–1.42; P = 0.62). No differences between the two groups were observed for microvascular …

Athough type 2 diabetes is a heterogeneous condition encompassing multiple metabolic and vascular alterations, it can be easily described as a disease characterized by chronic hyperglycemia and increased cardiovascular (CV) risk. Hyperglycemia is the diagnostic criterion for diabetes, the target for antidiabetic therapy, and, together with A1C, the marker of glycemic control. Progressive worsening of glycemic control has been described in type 2 diabetic patients irrespective of initial form of treatment, leading the U.K. Prospective Diabetes Study (UKPDS) investigators to describe such changes as the “natural history” of the disease (1). Still, maintaining good glycemic control is crucial, since it is associated with marked reduction in the risk of developing retinopathy, nephropathy, and neuropathy in both type 1 (2) and type 2 diabetic patients (1). But it is CV disease that worsens long-term prognosis in type 2 diabetes (3), to the point that diabetes has been proposed as a CV risk equivalent owed to the observation that 10-year risk for major coronary events approximates the risk in CHD in patients without diabetes with previous CV events (4), increased case fatality rate after myocardial infarction, and worse overall prognosis after CHD (5). In diabetic patients, even after correction for known CV risk factors, the incidence of myocardial infarction or stroke is two- to threefold higher than in the nondiabetic population, with a twofold increase in risk of death (6), suggesting that some feature of diabetes must confer excessive propensity toward CV disease. Can this feature be hyperglycemia? No better issue can be chosen for debate. From an epidemiological point of view, there is evidence that the risk of CV mortality increases with the increase of plasma glucose concentrations (7) and A1C values (8). Moreover, multiple atherogenic mechanisms have been identified that can be activated by hyperglycemia (9). In spite of evident …

Cardiovascular disease accounts for a great majority of deaths in patients with type 2 diabetes. According to the World Health Organization, the prevalence of cardiovascular disease in diabetic patients ranges from 26 to 36%. Fatality rate after myocardial infarction is greater in diabetic patients, and overall prognosis after coronary heart disease is worse. Based on these observations, it has been proposed that diabetes should be considered as a coronary heart disease risk equivalent. If that is the case, prevention of diabetes and early intervention should be pursued. This view is supported by the notion that cardiovascular risk is already increased in people with impaired glucose tolerance. Moreover, higher-than-optimum blood glucose is a major cause of cardiovascular mortality in most world regions of the world. Whether dysglycemia is a marker for a more complex metabolic condition or may directly contribute to excess cardiovascular risk is still a matter of debate. However, experimental work has shown how increased glucose level can trigger multiple mechanisms of susceptibility to atherosclerosis, and diabetes prevention trials have indicated that along with reduction of the rate of conversion toward diabetes, significant improvement in cardiovascular risk factors occurs. Moreover, in the STOP-NIDDM trial, targeting postprandial glucose was associated with reduction in new cases of hypertension, myocardial infarction, and any cardiovascular events. In conclusion, dysglycemia should be included in the list of established cardiovascular risk factors and early treatment introduced in the attempt to improve cardiovascular morbidity and mortality.

Background: Early identification of impairment in renal function is crucial in diabetic patients. Serum cystatin C may be the most sensitive indicator of glomerular filtration rate (GFR) in the clinical setting. Methods: We compared cystatin C with creatinine, the Cockcroft-Gault (C-G) formula, and the Modification of Diet in Renal Disease (MDRD) study equation for the assessment of early decreased renal function in 288 diabetic patients (125 type 1, 163 type 2) with renal impairment [GFR: 4–222 mL · min−1 · (1.73 m2)−1]. Relationships of cystatin C, creatinine, and iohexol clearance were linearized by plotting their reciprocals in a simple regression model. Diagnostic efficiency was calculated from ROC curves. Results: In this study population, cystatin C (P = 0.0013) was better correlated with GFR (r = 0.857) than were creatinine (r = 0.772), C-G (r = 0.750), and MDRD (r = 0.806), a result replicated in patients with normal renal function (P = 0.023, type 1; P = 0.011, type 2), but not in those with decreased GFR. Mean cystatin C concentrations showed step-by-step statistically significant increases as GFR decreased, allowing very early detection of reduction in renal function. At 90 mL · min−1 · (1.73 m2)−1 and 75 mL · min−1 · (1.73 m2)−1 cut-points, diagnostic efficiencies of cystatin C (89% and 92%) were better than those of the other variables (79%–82% and 85%–86%, respectively; P = 0.01). Conclusions: All data supported the value of serum cystatin C compared with conventional estimates based on serum creatinine measurement for detecting very early reduction of renal function. Use of cystatin C to measure renal function will optimize early detection, prevention, and treatment strategies for diabetic nephropathy.

Low insulin sensitivity and a selective loss of acute insulin release identify those individuals at the highest risk of developing type 2 diabetes. Normally, the rapid release of insulin after the ingestion of a meal is critical for post-prandial glucose regulation as first-phase insulin modulates suppression of endogenous glucose production and, therefore, limits meal-related plasma glucose excursions. The loss of first-phase insulin secretion contributes to the development of glucose intolerance. Indeed, postprandial hyperglycaemia represents the first and more evident perturbation of glucose homeostasis in about 60% of newly diagnosed type 2 diabetic patients. In these individuals, restoration of first-phase insulin secretion may result in more efficient inhibition of hepatic glucose production and improved glucose tolerance. In the light of these considerations, therapeutic intervention either alone or in combination with improvement of insulin resistance should be considered early in the course of the disease to prevent excessively rapid deterioration of glycaemic control.

Hyperglycemia is associated with a higher carotid intima-media thickness (IMT); however, it is not established whether this increase reflects early atherosclerotic changes or adaptive remodeling responding to hyperglycemia-induced alteration in mechanical properties of the arterial wall.The aims of this study were to compare carotid geometry and circumferential wall stress between patients with type 2 diabetes mellitus (T2DM) and healthy controls and to evaluate the associations between chronic glucose exposure and measures of arterial structure and function.This was a case-control and cross-sectional study within institutional practice.PARTICIPANTS included 133 T2DM patients free of cardiovascular complications and 133 healthy controls with normal glucose metabolism, matched for sex, age, and body mass index.Common carotid artery (CCA) IMT, luminal diameter, wave speed, and local pulse pressure (PP) were evaluated.As compared with controls, T2DM patients had higher (P.0001) CCA IMT (640 ± 81 vs 709 ± 118 μm), luminal diameter (6.12 ± 0.67 vs 6.69 ± 0.56 mm), and brachial PP (47 ± 7 vs 57 ± 12 mm Hg), whereas luminal radius to IMT ratio (4.8 ± 0.7 vs 4.8 ± 0.8, P = .57) and circumferential wall stress (49.0 ± 8.3 vs 50.6 ± 10.3 kPa, P = .26) were comparable between the 2 groups. In T2DM patients, glycosylated hemoglobin was independently related to CCA wave speed and local PP, but not to IMT that was determined by age, local PP, and luminal diameter.This study suggests that the increase in IMT associated with a higher glucose exposure might reflect adaptive remodeling counteracting an increase in pulsatile strain and preventing increase in circumferential wall stress caused by luminal enlargement of stiff arteries.

Type 2 diabetes mellitus (T2DM) is one of the most common chronic disorders in older adults and the number of elderly diabetic subjects is growing worldwide. Nonetheless, the diagnosis of T2DM in elderly population is often missed or delayed until an acute metabolic emergency occurs. Accumulating evidence suggests that both aging and environmental factors contribute to the high prevalence of diabetes in the elderly. Clinical management of T2DM in elderly subjects presents unique challenges because of the multifaceted geriatric scenario. Diabetes significantly lowers the chances of “successful” aging, notably it increases functional limitations and impairs quality of life. In this regard, older diabetic patients have a high burden of comorbidities, diabetes-related complications, physical disability, cognitive impairment and malnutrition, and they are more susceptible to the complications of dysglycemia and polypharmacy. Several national and international organizations have delivered guidelines to implement optimal therapy in older diabetic patients based on individualized treatment goals. This means appreciation of the heterogeneity of the disease as generated by life expectancy, functional reserve, social support, as well as personal preference. This paper will review current treatments for achieving glycemic targets in elderly diabetic patients, and discuss the potential role of emerging treatments in this patient population.

The Emerging Risk Factors Collaboration (1) has recently confirmed that type 2 diabetes remains associated with substantial premature mortality. Compared with nondiabetic individuals, those with diabetes have a hazard ratio (HR) of 1.80 (95% CI 1.71–1.90) for death from any cause, 1.25 (1.19–1.31) for death from cancer, 2.32 (2.11–2.56) for death from vascular causes, and 1.73 (1.62–1.85) for death from other causes. As is apparent, the greater risk is owing to cardiovascular (CV) disease, which accounts for >60% of the years of life lost because of diabetes. Although this increase in CV risk is largely attributable to the coexistence of multiple metabolic and hemodynamic disorders, elevation of plasma glucose levels remains strongly associated with increased CV morbidity and mortality (2–4). In support of a potential direct effect of plasma glucose elevation is the association between fasting plasma glucose levels >100 mg/dL (5.6 mmol/L) and vascular death (1). Since this a near-linear association (1,5) it has been postulated that reduction of plasma glucose levels should exert a positive impact on CV morbidity and mortality. In the UK Prospective Diabetes Study (UKPDS), improvement of glycemic control was associated with a 16% reduction in the risk of myocardial infarction without achieving statistical significance ( P < 0.052) (6). Glycemic control in that seminal trial was, however, relatively unsuccessful. Though intensively treated patients achieved an average A1C of 7%, a progressive worsening in glycemic control occurred after the initial improvement. A more aggressive and successful approach was adopted in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) (7) and Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE) (8) trials and Veterans Affairs Diabetes Trial (VADT) (9). In all these three large studies, glycemic control was achieved (A1C 6.5–7.0%) and maintained over a substantial period of …

We investigated cross-sectionally whether the type 2 diabetes (T2DM) risk alleles of rs1801282 (PPARG2) and rs4607103 (ADAMTS9) were associated with T2DM and/or insulin sensitivity (IS) and beta cell function (βF) in Italians without and with newly diagnosed T2DM. In 676 nondiabetic subjects (336 NGR and 340 IGR) from the GENFIEV study and in 597 patients from the Verona Newly Diagnosed Type 2 Diabetes Study (VNDS), we (1) genotyped rs1801282 and rs4607103, (2) assessed βF by C-peptide/glucose modeling after OGTT, and (3) assessed IS by HOMA-IR in both studies and by euglycemic insulin clamp in VNDS only. Logistic, linear, and two-stage least squares regression analyses were used to test (a) genetic associations with T2DM and with pathophysiological phenotypes, (b) causal relationships of the latter ones with T2DM by a Mendelian randomization design. Both SNPs were associated with T2DM. The rs4607103 risk allele was associated to impaired βF (p

OBJECTIVE The incretin hormone GIP (glucose-dependent insulinotropic polypeptide) promotes pancreatic β-cell function by potentiating insulin secretion and β-cell proliferation. Recently, a combined analysis of several genome-wide association studies (Meta-analysis of Glucose and Insulin-Related Traits Consortium [MAGIC]) showed association to postprandial insulin at the GIP receptor (GIPR) locus. Here we explored mechanisms that could explain the protective effects of GIP on islet function. RESEARCH DESIGN AND METHODS Associations of GIPR rs10423928 with metabolic and anthropometric phenotypes in both nondiabetic (N = 53,730) and type 2 diabetic individuals (N = 2,731) were explored by combining data from 11 studies. Insulin secretion was measured both in vivo in nondiabetic subjects and in vitro in islets from cadaver donors. Insulin secretion was also measured in response to exogenous GIP. The in vitro measurements included protein and gene expression as well as measurements of β-cell viability and proliferation. RESULTS The A allele of GIPR rs10423928 was associated with impaired glucose- and GIP-stimulated insulin secretion and a decrease in BMI, lean body mass, and waist circumference. The decrease in BMI almost completely neutralized the effect of impaired insulin secretion on risk of type 2 diabetes. Expression of GIPR mRNA was decreased in human islets from carriers of the A allele or patients with type 2 diabetes. GIP stimulated osteopontin (OPN) mRNA and protein expression. OPN expression was lower in carriers of the A allele. Both GIP and OPN prevented cytokine-induced reduction in cell viability (apoptosis). In addition, OPN stimulated cell proliferation in insulin-secreting cells. CONCLUSIONS These findings support β-cell proliferative and antiapoptotic roles for GIP in addition to its action as an incretin hormone. Identification of a link between GIP and OPN may shed new light on the role of GIP in preservation of functional β-cell mass in humans.

Cardiovascular diseases still represent the leading cause of mortality and hospitalization, worldwide. As a consequence of the marked demographic changes observed in the general population, the improved survival rate after an acute cardiovascular event and the progressive rise of costs (mostly due to technological and pharmacological innovations), the estimated burden of cardiovascular diseases will be soon become insurmountable for national healthcare systems. In this view, an integrated approach aimed at improving strategies for cardiovascular disease prevention and, thus, limiting the negative outcomes, would probably be successful. Such an approach may not only achieve long-term benefits, but even significant advantages in the short to medium term, mostly in asymptomatic high-risk individuals. Indeed, this latter population of asymptomatic high-risk individuals would mostly benefit from extensive application and improvement of strategies for cardiovascular disease prevention with a favourable cost-benefit ratio. The Italian Society for Cardiovascular Disease Prevention — Societa Italiana per la Prevenzione Cardiovascolare (SIPREC) — has recognized this strategic aim, focusing a significant part of its institutional actions on the effort for providing educational supports and consensus documents, which represent an overview of the scientific knowledge and personal clinical expertise by national and international key opinion leaders. Expert committees periodically generate ‘state-of-the-art’ documents on specific scientific topics with relevant socioeconomic implications and large clinical impact. The present article is dedicated to healthcare professionals, is based on the available evidence, and provides information on diagnostic algorithms and therapeutic options on abnormal glucose regulation (or dysglycaemia). The relationship between abnormalities in glucose metabolism and cardiovascular complications represents an important and relatively early target for cardiovascular disease prevention. SIPREC identified, even in this clinical setting, a group of scientific experts in order to form a multidisciplinary ‘task force’. This group has been asked to explain in a short, simple and effective fashion the epidemiological impact and the pathophysiological nature of the problem, its clinical features, potential diagnostic algorithms and therapeutic options, and its influence on the clinical practice of both specialist physicians and general practitioners. This work provides the background for discussing novel future strategies for cardiovascular prevention. It is also aimed at highlighting the importance of an emerging marker of cardiovascular risk, which is often not recognized and underestimated.