Development of a New Model of Insulin Sensitivity in Patients With Type 2 Diabetes and Association With Mortality.

CONTEXT: Despite being one of the major drivers of diabetes incidence, the degree of insulin resistance in patients with type 2 diabetes (T2D) is not usually evaluated in clinical practice or in large epidemiologic studies. OBJECTIVE: To identify a model of insulin sensitivity using widely available clinical and laboratory parameters in patients with T2D and evaluate its association with all-cause and cardiovascular mortality. METHODS: One hundred forty patients with T2D underwent a euglycemic hyperinsulinemic clamp to measure total body glucose disposal rate (mg kg-1 minute-1). We used demographic, clinical, and common laboratory parameters to estimate insulin sensitivity (IS) via stepwise linear regression on 85 patients (training cohort) and validated it in the remaining 55 (validation cohort). The identified equation was then applied to 3553 patients with T2D from the 1999-2010 cycles of the National Health and Nutrition Examination Survey (NHANES) to evaluate its association with all-cause and cardiovascular mortality up to December 2015. RESULTS: The best model included triglycerides, gamma glutamyl transpeptidase, albumin excretion rate, and body mass index. The identified IS score correlated well with the clamp-derived glucose disposal rate in both the training (r = 0.77, P < .001) and the validation (r = 0.74, P < .001) cohorts. In the NHANES cohort, after a median follow-up of 8.3 years, 1054 patients died, 265 of cardiovascular causes. In a multivariable Cox proportional hazard model adjusted for age, sex, race-ethnicity, education, cigarette smoke, total cholesterol, chronic kidney disease, blood pressure, prevalent cardiovascular disease, and alcohol consumption, a higher estimated IS was associated with a lower risk of both all-cause and cardiovascular mortality. CONCLUSION: We propose a new model of IS in patients with T2D based on readily available clinical and laboratory data. Its potential applications are in both diagnosis as well as prognostication.

Advanced Hybrid Closed-Loop System Achieves and Maintains Recommended Time in Range Levels for Up To 2 Years: Predictors of Best Efficacy.

Aim: To evaluate the long-term efficacy, up to 2 years, of an advanced hybrid closed-loop (AHCL) system and to assess predictors of best results of the therapy. Methods: We retrospectively evaluated 296 adults with type 1 diabetes mellitus [mean age 42.8 ± 16.5 years, men 42.9%, duration of diabetes 22.5 ± 12.8 years, body mass index 24.9 ± 4.7 kg/m2, baseline glycated hemoglobin (HbA1c) 63.4 ± 12.2 mmol/mol (8.0 ± 1.1%) ] who used the MiniMed™ 780G system. Demographic and clinical data were recorded. Continuous glucose monitoring (CGM)-derived metrics and insulin requirement were analyzed from the 4 weeks before and from every quarter after the switch to the AHCL system. Results: In the first quarter of AHCL treatment, all CGM metrics improved. Time in range (TIR) increased from 58.1 ± 17.5% to 70.3 ± 9.5% (P < 0.0001). The improvement lasted for up to 2 years of observation regardless of previous insulin therapies. Throughout the period of observation, 53.4% of participants achieved mean TIR >70%, 92.6% mean time below range <4%, and 46% mean glucose management indicator <53 mmol/mol (7.0%). At univariable logistic regression older age, lower baseline HbA1c and insulin requirement were associated with mean TIR >70%. At multivariable analysis, lower HbA1c remained independently associated with a better glycemic control. However, mean TIR increased more in participants with a higher baseline HbA1c. Conclusions: Switching to an AHCL leads to a rapid improvement in glycemic control lasting for up to 24 months along with a low risk for hypoglycemia, confirming the safety of the system. Lower baseline HbA1c was the main predictor of better efficacy of therapy, although higher baseline HbA1c was associated with the greatest improvement in mean TIR.

Rare forms of monogenic diabetes in non-European individuals. First reports of CEL and RFX6 mutations from the Indian subcontinent.

AIMS: Monogenic diabetes is one of the few examples in metabolic diseases in which a real precision medicine approach can be implemented in daily clinical work. Unfortunately, most of what is known today comes from studies in Whites, thus leaving much uncertainty about the genetics and the clinical presentation of monogenic diabetes in non-Europeans. To fill this gap, we report here two pedigrees from Bangladesh with CEL- and RFX6- diabetes, two rare types of monogenic diabetes which have never been described so far in individuals of the Indian subcontinent. METHODS: Next generation, Sanger sequencing and Multiplex Ligation-dependent Probe Amplification (MLPA) were performed. Variants' interpretation was according to the American College of Medical Genetics and Genomics guidelines. RESULTS: In the pedigree with CEL-diabetes, a large and never described deletion of exon 2-11 of CEL (confirmed by MLPA) affecting the entire catalytic domain and being likely pathogenic (LP) was observed in both the proband (who had diabetes at 16) and his mother (diabetes at 31), but not in relatives with normoglycemia. In the pedigree with RFX6-diabetes, a LP protein truncation variant (PTV, p.Tyr192*) in RFX6 was found in both the proband (diabetes at 9) and his mother (diabetes at 30), thus suggesting high heterogeneity in disease onset. Normoglycemic relatives were not available for genetic testing. CONCLUSIONS: We report genetic features and clinical presentation of the first two cases of CEL- and RFX6-diabetes from the Indian subcontinent, thus contributing to fill the gap of knowledge on monogenic diabetes in non-Europeans.

Measurable urinary albumin predicts cardiovascular risk among normoalbuminuric patients with type 2 diabetes.

Micro- or macroalbuminuria is associated with increased cardiovascular risk factors among patients with type 2 diabetes, but whether albuminuria within the normal range predicts long-term cardiovascular risk is unknown. We evaluated the relationships between albuminuria and cardiovascular events in 1208 hypertensive, normoalbuminuric patients with type 2 diabetes from the BErgamo NEphrologic Diabetes Complication Trial (BENEDICT), all of whom received angiotensin-converting enzyme inhibitor (ACEI) therapy at the end of the trial and were followed for a median of 9.2 years. The main outcome was time to the first of fatal or nonfatal myocardial infarction; stroke; coronary, carotid, or peripheral artery revascularization; or hospitalization for heart failure. Overall, 189 (15.6%) of the patients experienced a main outcome event (2.14 events/100 patient-years); 24 events were fatal. Albuminuria independently predicted events (hazard ratio [HR], 1.05; 95% confidence interval [CI], 1.02-1.08). Second-degree polynomial multivariable analysis showed a continuous nonlinear relationship between albuminuria and events without thresholds. Considering the entire study population, even albuminuria at 1-2 µg/min was significantly associated with increased risk compared with albuminuria <1 µg/min (HR, 1.04; 95% CI, 1.02-1.07). This relationship was similar in the subgroup originally randomly assigned to non-ACEI therapy. Among those originally receiving ACEI therapy, however, the event rate was uniformly low and was not significantly associated with albuminuria. Taken together, among normoalbuminuric patients with type 2 diabetes, any degree of measurable albuminuria bears significant cardiovascular risk. The association with risk is continuous but is lost with early ACEI therapy.

Switching to the Minimed™ 780G system achieves clinical targets for CGM in adults with type 1 diabetes regardless of previous insulin strategy and baseline glucose control.

AIMS: Advanced hybrid closed-loop (AHCL) systems represent the latest introduction in the treatment of type 1 diabetes (T1DM). Randomized controlled trials and real-world evidence studies showed that AHCL systems are a safe and effective insulin management strategy. Aim of this retrospective, single-center, real-life study was to evaluate the effect on metabolic control, evaluated by continuous glucose monitoring (CGM) metrics, of the switch from four available insulin strategies to an AHCL system in adult patients with type 1 diabetes. METHODS: A total of 102 patients with T1DM (mean age 42.1 ± 16.3 years, males/females 47/55, duration of diabetes 21.4 ± 13.3 years, BMI 24.4 ± 4.5 kg/m2, HbA1c 59.9 ± 9.6 mmol/mol or 7.6 ± 0.9%), treated with four different insulin therapies [multiple daily insulin (MDI) therapy, continuous subcutaneous insulin infusion (CSII), sensor-augmented pump (SAP) with predictive low-glucose suspend (PLGS), and hybrid closed loop (HCL) system] were evaluated before hand, two months and six months after switching to an AHCL (Minimed™ 780G system, Medtronic, Northridge, CA) system. RESULTS: Two months after the switch, mean GCM metrics improved in all four treatment groups. Six months after the switch, the participants of all four groups achieved a mean GMI < 53 mmol/mol, TIR > 70%, TBR < 4%, and CV < 36%, which is recommended by the ADA Standard of Medical Care in Diabetes 2022, including the MDI group with worse baseline glycemic control. CONCLUSIONS: Switching to an AHCL leads to a rapid improvement in glycemic control lasting for up to six months independently of previous insulin treatment and baseline conditions.

Switching from Suspend-Before-Low Insulin Pump Technology to a Hybrid Closed-Loop System Improves Glucose Control and Reduces Glucose Variability: A Retrospective Observational Case-Control Study.

There are no data whether hybrid closed-loop (HCL) systems are superior to sensor-augmented pump (SAP) therapy with predictive low glucose suspend (PLGS) feature in improving glucose control. Aim of our study was to evaluate the effect on metabolic control and glucose variability of the switch from SAP therapy with PLGS to a HCL system in type 1 diabetic individuals. Forty adults with type 1 diabetes, who had been using SAP therapy with PLGS feature (Minimed 640G; Medtronic, Northridge, CA) for at least 12 months were evaluated in a 6-month case-control observational retrospective study. Twenty subjects who consecutively switched from Minimed 640G to a HCL system (Minimed 670G; Medtronic) (670G group) were compared with a control group consisting of 20 subjects who continued with the MiniMed 640G pump (640G group) matched for age, gender, and HbA1c. At the end of the study there was a significant reduction in average HbA1c levels (-4.9 ± 6.4 mmol/mol [-0.4% ± 0.6%], P < 0.01), sensor glucose concentrations (-15.4 ± 17.7 mg/dL, P < 0.005), coefficient of variation of sensor glucose concentrations (-3.8% ± 3.6%, P < 0.01), percentage time spent in both hyperglycemic range 181-250 mg/dL (-5.1% ± 4.5%, P < 0.05), and >250 mg/dL (-6.1% ± 6.9%, P < 0.05) in the 670G group, whereas they remained unchanged in the 640G group. Percentage of time spent in euglycemic range significantly increased (11.6% ± 8.3%, P < 0.005) only in the 670G group. There was no change in time spent in hypoglycemic range in both groups. In adults with type 1 diabetes, switching from a 640G to a 670G system significantly improved glucose control and reduced glucose variability, thus reaching in most cases the recommended targets for time spent in euglycemic and hyperglycemic ranges without increasing the risk of hypoglycemia.

Sitagliptin Treatment at the Time of Hospitalization Was Associated With Reduced Mortality in Patients With Type 2 Diabetes and COVID-19: A Multicenter, Case-Control, Retrospective, Observational Study.

OBJECTIVE: Poor outcomes have been reported in patients with type 2 diabetes and coronavirus disease 2019 (COVID-19); thus, it is mandatory to explore novel therapeutic approaches for this population. RESEARCH DESIGN AND METHODS: In a multicenter, case-control, retrospective, observational study, sitagliptin, an oral and highly selective dipeptidyl peptidase 4 inhibitor, was added to standard of care (e.g., insulin administration) at the time of hospitalization in patients with type 2 diabetes who were hospitalized with COVID-19. Every center also recruited at a 1:1 ratio untreated control subjects matched for age and sex. All patients had pneumonia and exhibited oxygen saturation <95% when breathing ambient air or when receiving oxygen support. The primary end points were discharge from the hospital/death and improvement of clinical outcomes, defined as an increase in at least two points on a seven-category modified ordinal scale. Data were collected retrospectively from patients receiving sitagliptin from 1 March through 30 April 2020. RESULTS: Of the 338 consecutive patients with type 2 diabetes and COVID-19 admitted in Northern Italy hospitals included in this study, 169 were on sitagliptin, while 169 were on standard of care. Treatment with sitagliptin at the time of hospitalization was associated with reduced mortality (18% vs. 37% of deceased patients; hazard ratio 0.44 [95% CI 0.29-0.66]; P = 0.0001), with an improvement in clinical outcomes (60% vs. 38% of improved patients; P = 0.0001) and with a greater number of hospital discharges (120 vs. 89 of discharged patients; P = 0.0008) compared with patients receiving standard of care, respectively. CONCLUSIONS: In this multicenter, case-control, retrospective, observational study of patients with type 2 diabetes admitted to the hospital for COVID-19, sitagliptin treatment at the time of hospitalization was associated with reduced mortality and improved clinical outcomes as compared with standard-of-care treatment. The effects of sitagliptin in patients with type 2 diabetes and COVID-19 should be confirmed in an ongoing randomized, placebo-controlled trial.

"MySweetGestation": A novel smartphone application for women with or at risk of diabetes during pregnancy.

Mobile health (mHealth) applications (apps) have been recently introduced as an easily accessible tool for providing information to pregnant women with diabetes. Despite the growing number of apps on the topic "diabetes & pregnancy", a smartphone app offering comprehensive and individualized information to both women (before and during gestation) and their healthcare professionals was still missing. To overcome this lack, the Italian Diabetes and Pregnancy Study Group conceived and realized in 2016 a novel mobile app called "MySweetGestation". It is designed to be an interactive educational tool for both patients and physicians not expert in the field. Through an interactive way of learning, it provides validated information to the user, focusing on different area of interest: from prevention and risk factors for developing diabetes during pregnancy to treatment and follow-up strategies after gestation. Three years since its publication, MySweetGestation has been downloaded in different western and eastern countries worldwide, suggesting a widespread social impact. Easily accessible personalized information made available via mHealth technology may be of great importance to spread controlled information among the pregnant population. MySweetGestation, being an interactive educational device for both patients and healthcare professionals, may contribute to improve the management of pregnant women with diabetes.

Impact of a Complement Factor H Gene Variant on Renal Dysfunction, Cardiovascular Events, and Response to ACE Inhibitor Therapy in Type 2 Diabetes.

Complement activation has been increasingly implicated in the pathogenesis of type 2 diabetes and its chronic complications. It is unknown whether complement factor H (CFH) genetic variants, which have been previously associated with complement-mediated organ damage likely due to inefficient complement modulation, influence the risk of renal and cardiovascular events and response to therapy with angiotensin-converting enzyme inhibitors (ACEi) in type 2 diabetic patients. Here, we have analyzed the c.2808G>T, (p.Glu936Asp) CFH polymorphism, which tags the H3 CFH haplotype associated to low plasma factor H levels and predisposing to atypical hemolytic uremic syndrome, in 1,158 type 2 diabetics prospectively followed in the Bergamo nephrologic complications of type 2 diabetes randomized, controlled clinical trial (BENEDICT) that evaluated the effect of the ACEi trandolapril on new onset microalbuminuria. At multivariable Cox analysis, the p.Glu936Asp polymorphism (Asp/Asp homozygotes, recessive model) was associated with increased risk of microalbuminuria [adjusted hazard ratio (HR) 3.25 (95% CI 1.46-7.24), P = 0.0038] and cardiovascular events [adjusted HR 2.68 (95% CI 1.23-5.87), P = 0.013]. The p.Glu936Asp genotype significantly interacted with ACEi therapy in predicting microalbuminuria. ACEi therapy was not nephroprotective in Asp/Asp homozygotes [adjusted HR 1.54 (0.18-13.07), P = 0.691 vs. non-ACEi-treated Asp/Asp patients], whereas it significantly reduced microalbuminuria events in Glu/Asp or Glu/Glu patients [adjusted HR 0.38 (0.24-0.60), P < 0.0001 vs. non-ACEi-treated Glu/Asp or Glu/Glu patients]. Among ACEi-treated patients, the risk of developing cardiovascular events was higher in Asp/Asp homozygotes than in Glu/Asp or Glu/Glu patients [adjusted HR 3.26 (1.29-8.28), P = 0.013]. Our results indicate that type 2 diabetic patients Asp/Asp homozygotes in the p.Glu936Asp CFH polymorphism are at increased risk of microalbuminuria and cardiovascular complications and may be less likely to benefit from ACEi therapy. Further studies are required to confirm our findings.

The risk stratification of adverse neonatal outcomes in women with gestational diabetes (STRONG) study.

AIMS: To assess the risk of adverse neonatal outcomes in women with gestational diabetes (GDM) by identifying subgroups of women at higher risk to recognize the characteristics most associated with an excess of risk. METHODS: Observational, retrospective, multicenter study involving consecutive women with GDM. To identify distinct and homogeneous subgroups of women at a higher risk, the RECursive Partitioning and AMalgamation (RECPAM) method was used. Overall, 2736 pregnancies complicated by GDM were analyzed. The main outcome measure was the occurrence of adverse neonatal outcomes in pregnancies complicated by GDM. RESULTS: Among study participants (median age 36.8 years, pre-gestational BMI 24.8 kg/m2), six miscarriages, one neonatal death, but no maternal death was recorded. The occurrence of the cumulative adverse outcome (OR 2.48, 95% CI 1.59-3.87), large for gestational age (OR 3.99, 95% CI 2.40-6.63), fetal malformation (OR 2.66, 95% CI 1.00-7.18), and respiratory distress (OR 4.33, 95% CI 1.33-14.12) was associated with previous macrosomia. Large for gestational age was also associated with obesity (OR 1.46, 95% CI 1.00-2.15). Small for gestational age was associated with first trimester glucose levels (OR 1.96, 95% CI 1.04-3.69). Neonatal hypoglycemia was associated with overweight (OR 1.52, 95% CI 1.02-2.27) and obesity (OR 1.62, 95% CI 1.04-2.51). The RECPAM analysis identified high-risk subgroups mainly characterized by high pre-pregnancy BMI (OR 1.68, 95% CI 1.21-2.33 for obese; OR 1.38 95% CI 1.03-1.87 for overweight). CONCLUSIONS: A deep investigation on the factors associated with adverse neonatal outcomes requires a risk stratification. In particular, great attention must be paid to the prevention and treatment of obesity.

The Hyperfiltering Kidney in Diabetes.

Hyperfiltering kidney is a typical feature of diabetes. Improvement observed with regard to glucose control and blood pressure control reduces the high glomerular filtration rate and may contribute to retard the appearance and the progression of diabetic renal disease. Although the mechanism of hyperfiltration is still unclear, there is mounting evidence that the increased reabsorption of glucose and sodium by sodium glucose transporter-2 (SGLT-2) is involved in this altered renal function. There is a possibility that SGLT-2 inhibition may correct hyperfiltration in diabetes, adding a new therapeutic approach to halt renal disease in patients with diabetes.

Level of implementation of guidelines on screening and diagnosis of gestational diabetes: A national survey.

AIMS: To describe the degree of diffusion and acceptance of national guideline on screening and diagnosis of gestational diabetes (GDM) among Italian diabetes centers and to detect possible areas for benchmarking. METHODS: In 2013 the Italian Diabetes in Pregnancy Study Group structured a national survey, focused on GDM screening and diagnostic procedures, that was administered to diabetologists. RESULTS: Overall, 122 diabetologists of 122 different diabetes centers (21.7% territorial, 78.3% hospital/University) completed the questionnaire. All respondents declared to execute a 75 g-oral glucose tolerance test (OGTT) as diagnostic test. Almost one in five centers preferred a universal screening procedure, the others executing a selective risk factors-based screening. In patients at high risk for GDM the OGTT was performed at 16-18 weeks' gestation in 84.0% of the cases; only 6.5% of respondents preferred to execute it as soon as possible; and 9.5% used to wait until 24-28 weeks' gestation. In the case of fasting plasma glucose (FPG) ≥ 5.1 mmol/l (92 mg/dl), two third of respondents used to proceed with the execution of the complete diagnostic OGTT, the others considering sufficient the FPG value for the diagnosis. CONCLUSIONS: Good level of reception of national recommendations was documented. The diagnostic procedure was generally accepted and applied. Some criticisms were specifically linked to the choice of universal or risk factor-based screening procedure, and to the right time for executing the OGTT in women at high risk.

Glomerular hyperfiltration and renal disease progression in type 2 diabetes.

OBJECTIVE: To describe the prevalence and determinants of hyperfiltration (glomerular filtration rate [GFR] ≥120 mL/min/1.73 m(2)), GFR decline, and nephropathy onset or progression in type 2 diabetic patients with normo- or microalbuminuria. RESEARCH DESIGN AND METHODS: We longitudinally studied 600 hypertensive type 2 diabetic patients with albuminuria <200 µg/min and who were retrieved from two randomized trials testing the renal effect of trandolapril and delapril. Target blood pressure (BP) was <120/80 mmHg, and HbA(1c) was <7%. GFR, albuminuria, and glucose disposal rate (GDR) were centrally measured by iohexol plasma clearance, nephelometry in three consecutive overnight urine collections, and hyperinsulinemic euglycemic clamp, respectively. RESULTS: Over a median (range) follow-up of 4.0 (1.7-8.1) years, GFR declined by 3.37 (5.71-1.31) mL/min/1.73 m(2) per year. GFR change was bimodal over time: a larger reduction at 6 months significantly predicted slower subsequent decline (coefficient: -0.0054; SE: 0.0009), particularly among hyperfiltering patients. A total of 90 subjects (15%) were hyperfiltering at inclusion, and 11 of 47 (23.4%) patients with persistent hyperfiltration progressed to micro- or macroalbuminuria versus 53 (10.6%) of the 502 who had their hyperfiltration ameliorated at 6 months or were nonhyperfiltering since inclusion (hazard ratio 2.16 [95% CI 1.13-4.14]). Amelioration of hyperfiltration was independent of baseline characteristics or ACE inhibition. It was significantly associated with improved BP and metabolic control, amelioration of GDR, and slower long-term GFR decline on follow-up. CONCLUSIONS: Despite intensified treatment, patients with type 2 diabetes have a fast GFR decline. Hyperfiltration affects a subgroup of patients and may contribute to renal function loss and nephropathy onset or progression. Whether amelioration of hyperfiltration is renoprotective is worth investigating.

Effects of manidipine and delapril in hypertensive patients with type 2 diabetes mellitus: the delapril and manidipine for nephroprotection in diabetes (DEMAND) randomized clinical trial.

To assess whether angiotensin-converting enzyme inhibitors and third-generation dihydropyridine calcium channel blockers ameliorate diabetic complications, we compared glomerular filtration rate (GFR; primary outcome), cardiovascular events, retinopathy, and neuropathy in 380 hypertensive type 2 diabetics with albuminuria <200 mg/min included in a multicenter, double-blind, placebo-controlled trial (DEMAND [Delapril and Manidipine for Nephroprotection in Diabetes]) and randomized to 3-year treatment with manidipine/delapril combination (10/30 mg/d; n=126), delapril (30 mg/d; n=127), or placebo (n=127). GFR was centrally measured by iohexol plasma clearance. Median monthly GFR decline (interquartile range [IQR]) was 0.32 mL/min per 1.73 m(2) (IQR: 0.16-0.50 mL/min per 1.73 m(2)) on combined therapy, 0.36 mL/min per 1.73 m(2) (IQR: 0.18-0.53 mL/min per 1.73 m(2)) on delapril, and 0.30 mL/min per 1.73 m(2) (IQR: 0.12-0.50 mL/min per 1.73 m(2)) on placebo (P=0.87 and P=0.53 versus combined therapy or delapril, respectively). Similar findings were observed when baseline GFR values were not considered for slope analyses. Albuminuria was stable in the 3 treatment groups. The hazard ratio (95% CI) for major cardiovascular events between combined therapy and placebo was 0.17 (0.04-0.78; P=0.023). Among 192 subjects without retinopathy at inclusion, the hazard ratio for developing retinopathy between combined therapy and placebo was 0.27 (0.07-0.99; P=0.048). Among 200 subjects with centralized neurological evaluation, the odds ratios for peripheral neuropathy at 3 years between combined therapy or delapril and placebo were 0.45 (0.24-0.87; P=0.017) and 0.52 (0.27-0.99; P=0.048), respectively. Glucose disposal rate decreased from 5.8±2.4 to 5.3±1.9 mg/kg per min on placebo (P=0.03) but did not change on combined or delapril therapy. Treatment was well tolerated. In hypertensive type 2 diabetic patients, combined manidipine and delapril therapy failed to slow GFR decline but safely ameliorated cardiovascular disease, retinopathy, and neuropathy and stabilized insulin sensitivity.