Lower heart rate variability, an index of worse autonomic function, is associated with worse beta cell response to a glycemic load in vivo-The Maastricht Study.

OBJECTIVE: We investigated, using population-based data, whether worse autonomic function, estimated from lower 24-hour heart rate variability (HRV), was associated with beta cell function, assessed from beta cell response during an oral glucose tolerance test (OGTT). RESEARCH DESIGN AND METHODS: We used cross-sectional data from The Maastricht Study, a population-based cohort study (N = 2,007; age, mean ± SD:60 ± 8 years; 52% men; and 24% with type 2 diabetes). We used linear regression analyses with adjustment for potential confounders (demographic, cardiovascular, and lifestyle factors) to study the associations of time- and frequency-domain HRV (composite scores) with overall beta cell response (estimated from a composite score calculated from: C-peptidogenic index, overall insulin secretion, beta cell glucose sensitivity, beta cell potentiation factor, and beta cell rate sensitivity). In addition, we tested for interaction by sex and glucose metabolism status. RESULTS: After full adjustment, lower time- and frequency-domain HRV was significantly associated with lower overall beta cell response composite score (standardized beta, -0.055 [-0.098; -0.011] and - 0.051 [-0.095; -0.007], respectively). These associations were not modified by sex and there was no consistent pattern of interaction by glucose metabolism status. CONCLUSION: The present etiological study found that worse autonomic function, estimated from lower HRV, was associated with worse beta cell function, estimated from a composite score in a population-based sample which covered the entire spectrum of glucose metabolism. Hence, autonomic dysfunction may contribute to beta cell dysfunction and, ultimately, to the alteration of glucose metabolism status from normal glucose metabolism to prediabetes and type 2 diabetes.

Crosstalk between genetic variability of adiponectin and leptin, glucose-insulin system and subclinical atherosclerosis in patients with newly diagnosed type 2 diabetes. The Verona Newly Diagnosed Type 2 Diabetes Study 14.

AIM: To evaluate the relationship of genetic variability of adiponectin (ADIPOQ), leptin (LEP) and leptin receptor (LEPR) genes with glucose-insulin system and markers of subclinical atherosclerosis (ATS) in patients with newly diagnosed type 2 diabetes. MATERIALS AND METHODS: In 794 subjects we performed: 1) euglycemic hyperinsulinemic clamp to assess insulin sensitivity; 2) mathematical modelling of a 5h-OGTT to estimate ß-cell function; 3) resting ECG; 4) carotid artery and lower limb artery eco-doppler sonography to identify ATS; 5) genotyping of tag-SNPs within ADIPOQ, LEP and LEPR gene. RESULTS: Regression analyses showed: 1) adiponectin levels were negatively associated with BMI, waist-to-hip ratio and triglycerides and positively with HDL and insulin sensitivity (p-all<0.03); 2) leptin levels were positively associated with BMI, HDL-cholesterol and plasma triglycerides and negatively with insulin sensitivity (p-all<0.001). Two SNPs (rs1501299 and rs2241767) within ADIPOQ gene were associated with circulating levels of adiponectin. The ADIPOQ-GAACA haplotype was associated with plasma adiponectin (p=0.034; ß=-0.24), ECG abnormalities (p=0.012; OR=2.76), carotid ATS (p=0.025; OR=2.00) and peripheral limb artery ATS (p=0.032; OR=1.90). The LEP-CTA haplotype showed an association with ischemic ECG abnormalities (p=0.017; OR=2.24). Finally, LEPR-GAACGG was associated with circulating leptin (p=0.005; ß=-0.31) and worst ß-cell function (p=0.023; ß=-15.10). Omnibus haplotype analysis showed that ADIPOQ haplotypes were associated with levels of adiponectin and common carotid artery ATS, LEP with peripheral limb artery ATS, whereas LEPR haplotypes influenced circulating levels of leptin. CONCLUSIONS: Results of this study reinforce knowledge on adipokines' role in regulating glucose metabolism; in particular highlighted the potential atherogenic role of leptin and the anti atherogenic role of adiponectin.

Insulin resistance and beta-cell dysfunction in newly diagnosed type 2 diabetes: Expression, aggregation and predominance. Verona Newly Diagnosed Type 2 Diabetes Study 10.

AIMS: We investigated quantitative expression, mutual aggregation and relation with hyperglycemia of insulin resistance (IR) and beta-cell dysfunction (BCD) in newly diagnosed type 2 diabetes. METHODS: We assessed IR with euglycemic hyperinsulinemic clamp and BCD with modelled glucose/C-peptide response to oral glucose in 729 mostly drug-naïve patients. We measured glycated hemoglobin, pre-prandial, post-prandial and meal-related excursion of blood glucose. RESULTS: IR was found in 87.8% [95% confidence intervals 85.4-90.2] and BCD in 90.0% [87.8-92.2] of subjects, ranging from mild to moderate or severe. Approximately 20% of subjects had solely one defect: BCD 10.8% [8.6-13.1] or IR 8.6% [6.6-10.7]. Insulin resistance and BCD aggregated in most subjects (79.1% [76.2-82.1]). We arbitrarily set nine possible combinations of mild, moderate or severe IR and mild, moderate or severe BCD, finding that each had a similar frequency (∼10%). In multiple regression analyses parameters of glucose control were related more strongly with BCD than with IR. CONCLUSIONS: In newly-diagnosed type 2 diabetes, IR and BCD are very common with a wide range of expression but no specific pattern of aggregation. Beta-cell dysfunction is likely to play a greater quantitative role than IR in causing/sustaining hyperglycemia in newly-diagnosed type 2 diabetes.

Growing up with type 1 diabetes mellitus: Data from the Verona Diabetes Transition Project.

AIM: Transition from paediatric to adult care is a critical step in life of emerging adults with type 1 diabetes. We assessed, according to indicators established by panel of experts, clinical, socio-demographic and psychosocial factors in young adults with type 1 diabetes throughout structured transition to investigate the associations, if any, with HbA1c value at time of transition. METHODS: The "Verona Diabetes Transition Project" started in January 2009: a structured transition program, shared between paediatric and adult clinic, was organised with a multi-disciplinary team. All young adults underwent a semi-structured interview by a psychologist, before transition. Minimum age for transition was 18 years. RESULTS: 222 (M/F = 113/109) young adults moved to adult care from January 2009 to March 2020. The mean time between the last paediatric visit and the first adult visit ranged from 13.6 ± 6.1 months at the beginning of the project to 3.6 ± 11.5 months over the following years. At first adult clinic attendance, women showed higher HbA1c values (70 ± 11 mmol/mol vs. 65 ± 7 mmol/mol or 8.57% ± 1.51% vs. 8.14% ± 0.98%, p = 0.01), higher frequency of disorders of eating behaviours (15.6% vs. 0%, p < 0.001) and poor diabetes acceptance (23.9% vs. 9.7%, p < 0.001) than men. Mediation analyses showed a significant mediating role of glucose control 2 years before transition in the relationship between poor diabetes acceptance and glucose control at transition. CONCLUSIONS: This study demonstrated a delay reduction in establishing care with an adult provider and suggested the potential role of low diabetes acceptance on glycemic control at transition. Further studies are needed to confirm and expand these data.

SARS-CoV-2 and COVID-19 in diabetes mellitus. Population-based study on ascertained infections, hospital admissions and mortality in an Italian region with ∼5 million inhabitants and ∼250,000 diabetic people.

BACKGROUND AND AIMS: Diabetes conveys an increased risk of infectious diseases and related mortality. We investigated risk of ascertained SARS-CoV-2 infection in diabetes subjects from the Veneto Region, Northeastern Italy, as well as the risk of being admitted to hospital or intensive care unit (ICU), or mortality for COVID-19. METHODS AND RESULTS: Diabetic subjects were identified by linkage of multiple health archives. The rest of the population served as reference. Information on ascertained infection by SARS-CoV-2, admission to hospital, admission to ICU and mortality in the period from February 21 to July 31, 2020 were retrieved from the regional registry of COVID-19. Subjects with ascertained diabetes were 269,830 (55.2% men; median age 72 years). Reference subjects were 4,681,239 (men 48.6%, median age 46 years). Ratios of age- and gender-standardized rates (RR) [95% CI] for ascertained infection, admission to hospital, admission to ICU and disease-related death in diabetic subjects were 1.31 [1.19-1.45], 2.11 [1.83-2.44], 2.45 [1.96-3.07], 1.87 [1.68-2.09], all p < 0.001. The highest RR of ascertained infection was observed in diabetic men aged 20-39 years: 1.90 [1.04-3.21]. The highest RR of ICU admission and death were observed in diabetic men aged 40-59 years: 3.47 [2.00-5.70] and 5.54 [2.23-12.1], respectively. CONCLUSIONS: These data, observed in a large population of ∼5 million people of whom ∼250,000 with diabetes, show that diabetes not only conveys a poorer outcome in COVID-19 but also confers an increased risk of ascertained infection from SARS-CoV-2. Men of young or mature age have the highest relative risks.

Central role of the ß-cell in driving regression of diabetes after liver transplantation in cirrhotic patients.

BACKGROUND & AIMS: Diabetes occurring as a direct consequence of loss of liver function is usually characterized by non-diabetic fasting plasma glucose (FPG) and haemoglobin A1c (HbA1c) levels and should regress after orthotopic liver transplantation (OLT). This observational, longitudinal study investigated the relationship between the time-courses of changes in all 3 direct determinants of glucose regulation, i.e., ß-cell function, insulin clearance and insulin sensitivity, and diabetes regression after OLT. METHODS: Eighty cirrhotic patients with non-diabetic FPG and HbA1c levels underwent an extended oral glucose tolerance test (OGTT) before and 3, 6, 12 and 24 months after OLT. The OGTT data were analysed with a mathematical model to estimate derivative control (DC) and proportional control (PC) of ß-cell function and insulin clearance (which determine insulin bioavailability), and with the Oral Glucose Insulin Sensitivity (OGIS)-2 h index to estimate insulin sensitivity. RESULTS: At baseline, 36 patients were diabetic (45%) and 44 were non-diabetic (55%). Over the 2-year follow-up, 23 diabetic patients (63.9%) regressed to non-diabetic glucose regulation, whereas 13 did not (36.1%); moreover, 4 non-diabetic individuals progressed to diabetes (9.1%), whereas 40 did not (90.9%). Both DC and PC increased in regressors (from month 3 and 24, respectively) and decreased in progressors, whereas they remained stable in non-regressors and only PC decreased in non-progressors. Insulin clearance increased in all groups, apart from progressors. Likewise, OGIS-2 h improved at month 3 in all groups, but thereafter it continued to improve only in regressors, whereas it returned to baseline values in the other groups. CONCLUSIONS: Increased insulin bioavailability driven by improved ß-cell function plays a central role in favouring diabetes regression after OLT, in the presence of a sustained improvement of insulin sensitivity. LAY SUMMARY: Diabetes occurring in cirrhosis as a direct consequence of loss of liver function should regress after transplantation of a new functioning liver, though the pathophysiological mechanisms are unclear. This is the first study evaluating the contribution of all 3 direct determinants of insulin-dependent glucose regulation using a sophisticated mathematical model. Results show that ß-cell function is the key process governing favourable or detrimental changes in glucose regulation in cirrhotic patients undergoing transplantation, pointing to the need to develop therapies to sustain ß-cell function in these individuals. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02038517.

Contribution of ß-cell dysfunction and insulin resistance to cirrhosis-associated diabetes: Role of severity of liver disease.

BACKGROUND & AIMS: This study evaluated the contribution of ß-cell dysfunction and insulin resistance to cirrhosis-associated diabetes. METHODS: One-hundred and sixty cirrhotic patients with normal fasting plasma glucose (FPG), three with impaired fasting glucose and seven with untreated diabetes mellitus (DM) underwent an extended oral glucose tolerance test (OGTT). The OGTT data were analyzed with a Minimal Model to estimate dynamic (derivative) control (DC) and static (proportional) control (PC) of ß-cell function, and with the Oral Glucose Insulin Sensitivity (OGIS)-2h index to estimate insulin sensitivity. RESULTS: Twenty-six patients (15.6%) had normal glucose tolerance (NGT), 60 (35.8%) had impaired glucose tolerance (IGT), and 84 (48.6%) had DM. DC was significantly reduced in DM vs. NGT and IGT patients. PC was significantly impaired in DM and IGT vs. NGT patients and in DM vs. IGT subjects. The OGIS-2h index was significantly reduced to a similar extent in DM and IGT vs. NGT patients. Patients with Child-Pugh class B and C cirrhosis had reduced DC and PC, but not OGIS-2h values, as compared with subjects in class A. Moreover, Child-Pugh class/score was an independent predictor of ß-cell function even after adjustment for glucose tolerance. CONCLUSIONS: Abnormalities of glucose tolerance occur frequently in cirrhosis even in patients with normal FPG, thereby supporting the importance of performing an OGTT. Transition from IGT to DM is driven primarily by ß-cell dysfunction. Insulin secretion worsens in parallel with the severity of liver disease, thus suggesting a detrimental effect of liver failure on pancreatic islets on its own.

G Protein-Coupled Receptors and the Rise of Type 2 Diabetes in Children.

The human genome counts hundreds of GPCRs specialized to sense thousands of different extracellular cues, including light, odorants and nutrients in addition to hormones. Primordial GPCRs were likely glucose transporters that became sensors to monitor the abundance of nutrients and direct the cell to switch from aerobic metabolism to fermentation. Human ß cells express multiple GPCRs that contribute to regulate glucose homeostasis, cooperating with many others expressed by a variety of cell types and tissues. These GPCRs are intensely studied as pharmacological targets to treat type 2 diabetes in adults. The dramatic rise of type 2 diabetes incidence in pediatric age is likely correlated to the rapidly evolving lifestyle of children and adolescents of the new century. Current pharmacological treatments are based on therapies designed for adults, while youth and puberty are characterized by a different hormonal balance related to glucose metabolism. This review focuses on GPCRs functional traits that are relevant for ß cells function, with an emphasis on aspects that could help to differentiate new treatments specifically addressed to young type 2 diabetes patients.

Assessing attitudes towards insulin pump therapy in adults with type 1 diabetes: Italian validation of the Insulin Pump Attitudes Questionnaire (IT-IPA questionnaire).

AIMS: The aim of the study was to adapt the German version of the insulin pump therapy (IPA) questionnaire to Italian (IT-IPA) and to evaluate its psychometric properties in adults with type 1 diabetes. METHODS: We conducted a cross-sectional study, data were collected through an online survey. In addition to IT-IPA, questionnaires evaluating depression, anxiety, diabetes distress, self-efficacy, and treatment satisfaction were administered. The six factors identified in the IPA German version were assessed using confirmatory factor analysis; psychometric testing included construct validity and internal consistency. RESULTS: The online survey was compiled by 182 individuals with type 1 diabetes: 45.6% continuous subcutaneous insulin infusion (CSII) users and 54.4% multiple daily insulin injection users. The six-factor model had a very good fit in our sample. The internal consistency was acceptable (Cronbach's α = 0.75; 95% IC [0.65-0.81]). Diabetes treatment satisfaction was positively correlated with a positive attitude towards CSII therapy (Spearman's rho = 0.31; p < 0.01), less Technology Dependency, higher Ease of Use, and less Impaired Body Image. Furthermore, less Technology Dependency was associated with lower diabetes distress and depressive symptoms. CONCLUSIONS: The IT-IPA is a valid and reliable questionnaire evaluating attitudes towards insulin pump therapy. The questionnaire can be used for clinical practice during consultations for shared decision-making to CSII therapy.

Effects of Semaglutide on Glycemic Control and Weight Loss in a Patient with Prader-Willi Syndrome: A Case Report.

BACKGROUND: Prader-Willi syndrome is the most frequent genetic cause of obesity and is often complicated by glucose metabolism alterations. Conventional therapies prescribed for type 2 diabetes frequently failed to achieve adequate glycemic control in patients with Prader-Willi syndrome. Beneficial effects of glucagon like peptide-1 receptor agonists exenatide and liraglutide have been reported for the management of type 2 diabetes in Prader-Willi syndrome, but no data are currently available in this population on the use of semaglutide. CASE PRESENTATION: We report for the first time the use of semaglutide 1 mg per week in a 33-yearold man with Prader-Will syndrome complicated by poorly controlled diabetes and severe obesity. After 12 months of semaglutide treatment, we observed an important reduction in glycated hemoglobin levels (11.1% to 7.2%) and body weight (99.5 kg to 94.3 kg), with a notable decrease in fat mass and insulin requirements. Interestingly, our patient had already tried liraglutide therapy in adjunction to metformin and insulin therapy, reporting no substantial efficacy. CONCLUSION: The beneficial effects of semaglutide on glycemic control and weight reduction provide a promising treatment for diabetes and obesity in Prader-Willi syndrome, even where other glucagons like peptide-1 receptor agonists have failed. Further studies are required to confirm the efficacy and safety of semaglutide in patients with Prader-Willi syndrome.

Markers of subclinical vascular damage in young adults with type 1 diabetes mellitus: the role of central blood pressure.

INTRODUCTION: Type 1 diabetes mellitus (T1D) is a chronic disease leading to cardiovascular complications that can be diagnosed early as subclinical vascular damage. To prevent such damage, it is important to increase knowledge of the effects of the different cardiovascular risk factors in patients with T1D. The aim of our study was to assess possible associations between markers of subclinical arterial damage and traditional cardiovascular risk factors, with a special focus on peripheral blood pressure and central blood pressure (cBP), in a sample of young adults with T1D. PATIENTS AND METHODS: The study included 172 T1D patients (mean age 24.7 ±â€Š8.7 years, duration of T1D 13.5 ±â€Š9.6 years). Pulse wave velocity (PWV), pulse wave analysis and cBP were assessed by tonometry (SphygmoCor Xcel). Carotid intima-media thickness (cIMT) and carotid distensibility coefficient (cDC) were assessed by high-resolution echo-Doppler analysis and further examined with dedicated hardware. RESULTS: Seventeen patients (10.1%) were classified as hypertensive by office peripheral blood pressure, and 48 patients (27.9%) were classified as hypertensive by cBP. One hundred sixteen patients (68.8%) had cDC under the range of normality, one patient had a PWV (0.6%) above 10 m/s, and no patients had a cIMT above 0.9 mm. In multivariable analysis, central SBP, but not metabolic parameters, remained associated with all the markers of subclinical arterial damage [cIMT ( ß â€Š= 0.288 ±â€Š0.001; P  < 0.001), PWV ( ß â€Š= 0.374 ±â€Š0.007; P  < 0.001), cDC ( ß â€Š= -0.149 ±â€Š0.055; P  = 0.029)]. CONCLUSION: The independent association between cBP and markers of subclinical vascular damage underlines the importance of haemodynamic factors in the development of early signs of macrovascular disease in T1D patients. Further studies are warranted to better define the role of cBP to stratify cardiovascular risk, to individualize the need for follow-up and to tailor preventive strategies in T1D patients.

Impact of CFTR Modulators on Beta-Cell Function in Children and Young Adults with Cystic Fibrosis.

BACKGROUND: To date, no consistent data are available on the possible impact of CFTR modulators on glucose metabolism. The aim of this study was to test the hypothesis that treatment with CFTR modulators is associated with an improvement in the key direct determinants of glucose regulation in children and young adults affected by Cystic Fibrosis (CF). METHODS: In this study, 21 CF patients aged 10-25 underwent oral glucose tolerance test (OGTT) before and after 12-18 months of treatment with Lumacaftor/Ivacaftor or Elexacaftor-Ivacaftor-Tezacaftor. ß-cell function (i.e., first and second phase of insulin secretion measured as derivative and proportional control, respectively) and insulin clearance were estimated by OGTT mathematical modelling. Insulin sensitivity was estimated by the Oral Glucose Sensitivity Index (OGIS). The dynamic interplay between ß-cell function, insulin clearance and insulin sensitivity was analysed by vector plots of glucose-stimulated insulin bioavailability vs. insulin sensitivity. RESULTS: No changes in glucose tolerance occurred after either treatment, whereas a significant improvement in pulmonary function and chronic bacterial infection was observed. Beta cell function and insulin clearance did not change in both treatment groups. Insulin sensitivity worsened in the Lumacaftor/Ivacaftor group. The analysis of vector plots confirmed that glucose regulation was stable in both groups. CONCLUSIONS: Treatment of CF patients with CFTR modulators does not significantly ameliorate glucose homeostasis and/or any of its direct determinants.

Glucose Tolerance Stages in Cystic Fibrosis Are Identified by a Unique Pattern of Defects of Beta-Cell Function.

OBJECTIVE: We aimed to assess the order of severity of the defects of 3 direct determinants of glucose regulation-beta-cell function, insulin clearance, and insulin sensitivity-in patients with cystic fibrosis (CF), categorized according their glucose tolerance status, including early elevation of mid-level oral glucose tolerance test (OGTT) glucose values (>140 and <200 mg/dL), referred to as AGT140. METHODS: A total of 232 CF patients aged 10 to 25 years underwent OGTT. Beta-cell function and insulin clearance were estimated by OGTT mathematical modeling and OGTT-derived biomarkers of insulin secretion and sensitivity were calculated. The association between glucometabolic variables and 5 glucose tolerance stages (normal glucose tolerance [NGT], AGT140, indeterminate glucose tolerance [INDET], impaired glucose tolerance [IGT], cystic fibrosis-related diabetes CFRD]) was assessed with a general linear model. RESULTS: Beta-cell function and insulin sensitivity progressively worsened across glucose tolerance stages (P < 0.001), with AGT140 patients significantly differing from NGT (all P < 0.01). AGT140 and INDET showed a degree of beta-cell dysfunction similar to IGT and CFRD, respectively (all P < 0.01). Insulin clearance was not significantly associated with glucose tolerance stages (P = 0.162). Each stage of glucose tolerance was uniquely identified by a specific combination of defects of the direct determinants of glucose regulation. CONCLUSIONS: In CF patients, each of the 5 glucose tolerance stages shows a unique pattern of defects of the direct determinants of glucose regulation, with AGT140 patients significantly differing from NGT and being similar to IGT. These findings suggest that AGT140 should be recognized as a distinct glucose tolerance stage and that reconsideration of the grade of glucometabolic deterioration across glucose tolerance stages in CF is warranted.

Glomerular filtration rate decline in T2DM following diagnosis. The Verona newly diagnosed diabetes study-12.

AIMS: Nephropathy is a complication of type 2 diabetes, with increased albuminuria and reduced glomerular filtration rate (GFR) as biomarkers. Rates of progression to end-stage-renal disease are variable among patients. In this study we have examined the GFR decline in newly diagnosed T2DM. METHODS: A cohort of 410 patients with newly diagnosed T2DM and with at least four serum creatinine during the follow-up period were recruited. A linear model was used to calculate the decline in eGFR. A multivariable logistic model was used to identify independent predictors of rapid eGFR decline. RESULTS: Average follow-up was 12.4 years. The eGFR change was -0.80 ±â€¯2.23 ml/min/1.73 m2 per year. Patients were arbitrarily stratified into rapid decliners (≤-3.0 ml/min/1.73 m2 per year), moderate decliners (-2.9/-1 ml/min/1.73 m2 per year) and slow/no decliners (>-1.0 ml/min/1.73 m2 per year). Subjects in the 3 categories were 11.4%, 27.3%, and 61.3%, respectively. Albuminuria was the stronger predictor of rapid eGFR decline. CONCLUSIONS: A rapid decline in eGFR occurs in approximately 1 out of 10 newly diagnosed subjects. This rapid decline can be predicted by widely accessible clinical features, such as albuminuria. Identification of rapid decliners may help to reduce progression toward advanced stages of nephropathy.

Depressive symptoms and glycaemic control in adults with type 1 diabetes: an exploratory study on the role of family functioning.

AIMS: Psychological distress and family functioning have a considerable impact on diabetes self-management and glycaemic control in individuals with type 1 diabetes (T1D). However, the influence of both individual and family factors on glycaemic control has not been adequately investigated yet. This study aimed at examining the relationship between perceived family functioning and depressive symptoms with the frequency of capillary self-monitoring of blood glucose (SMBG) and glycaemic control (HbA1c) in a large sample of adults with T1D. METHODS: In a cross-sectional study design, we consecutively enrolled 90 adults with T1D diagnosis from at least 1 year and currently living in their family of origin or conjugal family from at least 1 year before the enrolment. Questionnaires were administered to assess family functioning and depressive symptoms. The SMBG frequency over the past 3 months and the most recent HbA1c measurement were also collected in each individual. Correlation and mediation analyses were carried out. RESULTS: Glycaemic control showed a positive relationship with depressive symptoms and family balanced cohesion, while SMBG frequency was correlated with family balanced flexibility and rigidity, but not with depressive symptoms. Mediation analyses showed that family rigidity mediates the effect of depressive symptoms on glycaemic control. CONCLUSIONS: This exploratory study highlighted the significance of a cohesive family context to facilitate the achievement of individual glycaemic goals in individuals with T1D. These observations, if confirmed in larger data sets, would timely call for a comprehensive family care assessment as part of the evaluations routinely carried out in the ambulatory care of these individuals.

Echocardiographic parameters according to insulin dose in young patients affected by type 1 diabetes.

Insulin dose has been found to associate to several cardiometabolic risk factors in type 1 diabetes. Changes over time in body weight and composition may partly explain this association. However, no data are available on the relationship between insulin dose and echocardiographic parameters of both systolic and diastolic function in type 1 diabetes. Therefore, the aim of the present study was to examine systolic and diastolic echocardiographic parameters in relation to insulin dose in young patients with type 1 diabetes. The study was carried out on 93 consecutive outpatients with type 1 diabetes with a mean age of 32.8 ± 9.8 years. All patients were examined with a transthoracic echocardiography. Clinical and laboratory data were collected. The median value of daily insulin dose was used to categorized patients in two groups: high and low insulin dose group. Patients belonging to the high insulin dose group showed higher levels of cardiometabolic risk factors such as BMI, triglycerides and TG/HDL cholesterol ratio. Indexes of both systolic and diastolic function were similar in both groups except isovolumetric relaxation time (IVRT), that was significantly prolonged in patients of the high insulin group (94.4 ± 15.0 vs 86.7 ± 13.1 ms, p = 0.008). In the multivariate regression analysis, insulin dose was positively and significantly associated with IVRT. In this study we report an association between insulin dose and impaired active diastolic myocardial relaxation. Future studies are needed to further explore this observation.

Chronic complications in patients with newly diagnosed type 2 diabetes: prevalence and related metabolic and clinical features: the Verona Newly Diagnosed Type 2 Diabetes Study (VNDS) 9.

INTRODUCTION: We explored the presence of chronic complications in subjects with newly diagnosed type 2 diabetes referred to the Verona Diabetes Clinic. Metabolic (insulin secretion and sensitivity) and clinical features associated with complications were also investigated. RESEARCH DESIGN AND METHODS: The comprehensive assessment of microvascular and macrovascular complications included detailed medical history, resting ECG, ultrasonography of carotid and lower limb arteries, quantitative neurological evaluation, cardiovascular autonomic tests, ophthalmoscopy, kidney function tests. Insulin sensitivity and beta-cell function were assessed by state-of-the-art techniques (insulin clamp and mathematical modeling of glucose/C-peptide curves during oral glucose tolerance test). RESULTS: We examined 806 patients (median age years, two-thirds males), of whom prior clinical cardiovascular disease (CVD) was revealed in 11.2% and preclinical CVD in 7.7%. Somatic neuropathy was found in 21.2% and cardiovascular autonomic neuropathy in 18.6%. Retinopathy was observed in 4.9% (background 4.2%, proliferative 0.7%). Chronic kidney disease (estimated glomerular filtration rate <60 mL/min/1.73 m2) was found in 8.8% and excessive albuminuria in 13.2% (microalbuminuria 11.9%, macroalbuminuria 1.3%).Isolated microvascular disease occurred in 30.8%, isolated macrovascular disease in 9.3%, a combination of both in 9.1%, any complication in 49.2% and no complications in 50.8%.Gender, age, body mass index, smoking, hemoglobin A1c and/or hypertension were independently associated with one or more complications. Insulin resistance and beta-cell dysfunction were associated with macrovascular but not microvascular disease. CONCLUSIONS: Despite a generally earlier diagnosis for an increased awareness of the disease, as many as ~50% of patients with newly diagnosed type 2 diabetes had clinical or preclinical manifestations of microvascular and/or macrovascular disease. Insulin resistance might play an independent role in macrovascular disease. TRIAL REGISTRATION NUMBER: NCT01526720.

Loss of ZnT8 function protects against diabetes by enhanced insulin secretion.

A rare loss-of-function allele p.Arg138* in SLC30A8 encoding the zinc transporter 8 (ZnT8), which is enriched in Western Finland, protects against type 2 diabetes (T2D). We recruited relatives of the identified carriers and showed that protection was associated with better insulin secretion due to enhanced glucose responsiveness and proinsulin conversion, particularly when compared with individuals matched for the genotype of a common T2D-risk allele in SLC30A8, p.Arg325. In genome-edited human induced pluripotent stem cell (iPSC)-derived ß-like cells, we establish that the p.Arg138* allele results in reduced SLC30A8 expression due to haploinsufficiency. In human ß cells, loss of SLC30A8 leads to increased glucose responsiveness and reduced KATP channel function similar to isolated islets from carriers of the T2D-protective allele p.Trp325. These data position ZnT8 as an appealing target for treatment aimed at maintaining insulin secretion capacity in T2D.

Metabolic abnormalities underlying the different prediabetic phenotypes in obese adolescents.

OBJECTIVE: The aim of this study was to define the metabolic abnormalities underlying the prediabetic status of isolated impaired fasting glucose (IFG), isolated impaired glucose tolerance (IGT), and combined IFG/IGT in obese youth. RESEARCH DESIGN AND METHODS: We used state-of-the-art techniques (hyperinsulinemic-euglycemic and hyperglycemic clamps), applying a model of glucose-stimulated insulin secretion to the glucose and C-peptide concentration, in 40 normal glucose tolerance (NGT), 17 IFG, 23 IGT, and 11 IFG/IGT obese adolescents. Percent fat (by dual-energy x-ray absorptiometry), age, gender and ethnicity were comparable among groups. RESULTS: Peripheral insulin sensitivity was similar between the IFG and NGT groups. In contrast, the IGT and IFG/IGT groups showed marked reductions in peripheral insulin sensitivity (P < 0.002). Basal hepatic insulin resistance index (basal hepatic glucose production x fasting plasma insulin) was significantly increased in IFG, IGT, and IFG/IGT (P < 0.009) compared with NGT. Glucose sensitivity of first-phase insulin secretion was progressively lower in IFG, IGT, and IFG/IGT compared with NGT. Glucose sensitivity of second-phase secretion showed a statistically significant defect only in the IFG/IGT group. In a multivariate regression analysis, glucose sensitivity of first-phase secretion and basal insulin secretion rate were significant independent predictors of FPG (total r(2) = 25.9%). CONCLUSIONS: IFG, in obese adolescents, is linked primarily to alterations in glucose sensitivity of first-phase insulin secretion and liver insulin sensitivity. The IGT group is affected by a more severe degree of peripheral insulin resistance and reduction in first-phase secretion. IFG/IGT is hallmarked by a profound insulin resistance and by a new additional defect in second-phase insulin secretion.

Insulin sensitivity is correlated with subcutaneous but not visceral body fat in overweight and obese prepubertal children.

AIM: Our aim was to explore the relationship between insulin sensitivity, body fat distribution, ectopic (liver and skeletal muscle) fat deposition, adipokines (leptin and adiponectin), and inflammation markers (highly sensitive C-reactive protein, IL-6, IL-10, and TNF-alpha) in prepubertal children. SUBJECTS AND METHODS: Thirty overweight and obese children (16 males and 14 females with body mass index z-score range of 1.1-3.2) were recruited. Body fat distribution and fat accumulation in liver and skeletal muscle were measured using magnetic resonance imaging. Insulin sensitivity was assessed by iv glucose tolerance test. RESULTS: Insulin sensitivity was associated with sc abdominal adipose tissue (SAT) (r = -0.52; P < 0.01) and liver fat content (r = -0.44; P < 0.02) but not with visceral abdominal adipose tissue (VAT) (r = -0.193; P value not significant) and fat accumulation in skeletal muscle (r = -0.210; P value not significant). Adipokines, but not inflammation markers, were significantly correlated to insulin sensitivity. VAT correlated with C-reactive protein (r = 0.55; P < 0.01) as well as adiponectin (r = -0.53; P <0.01). Multiple regression analysis showed that only SAT and liver fat content were independently correlated to insulin sensitivity (P < 0.01; 20 and 16% of explained variance, respectively). CONCLUSIONS: In overweight and moderately obese prepubertal children, insulin sensitivity was negatively correlated with SAT and liver fat content. Furthermore, contrary to adults, VAT and inflammation markers were not correlated with insulin sensitivity in children.