Prevaccination Glucose Time in Range Correlates With Antibody Response to SARS-CoV-2 Vaccine in Type 1 Diabetes.

CONTEXT: Poor glucose control has been associated with increased mortality in COVID-19 patients with type 1 diabetes (T1D). OBJECTIVE: This work aimed to assess the effect of prevaccination glucose control on antibody response to the SARS-CoV-2 vaccine BNT162b2 in T1D. METHODS: We studied 26 patients with T1D scheduled to receive 2 doses, 21 days apart, of BNT162b2, followed prospectively for 6 months with regular evaluation of SARS-CoV-2 antibodies and glucose control. Immunoglobulin G (IgG) to spike glycoprotein were assessed by enzyme-linked immunosorbent assay, and serum neutralization by a live SARS-CoV-2 assay (Vero E6 cells system). Glycated hemoglobin A1c (HbA1c) and continuous glucose monitoring (CGM), including time in range (TIR) and above range (TAR), were collected. The primary exposure and outcome measures were prevaccination glucose control, and antibody response after vaccination, respectively. RESULTS: Prevaccination HbA1c was unrelated to postvaccine spike IgG (r = -0.33; P = .14). Of note, the CGM profile collected during the 2 weeks preceding BNT162b2 administration correlated with postvaccine IgG response (TIR: r = 0.75; P = .02; TAR: r = -0.81; P = .008). Patients meeting the recommended prevaccination glucose targets of TIR (≥ 70%) and TAR (≤ 25%) developed stronger neutralizing antibody titers (P < .0001 and P = .008, respectively), regardless of HbA1c. Glucose control along the study time frame was also associated with IgG response during follow-up (TIR: r = 0.93; P < .0001; TAR: r = -0.84; P < .0001). CONCLUSION: In T1D, glucose profile during the 2 weeks preceding vaccination is associated with stronger spike antibody binding and neutralization, highlighting a role for well-controlled blood glucose in vaccination efficacy.

Autoantibody and T cell responses to oxidative post-translationally modified insulin neoantigenic peptides in type 1 diabetes.

AIMS/HYPOTHESIS: Antibodies specific to oxidative post-translational modifications (oxPTM) of insulin (oxPTM-INS) are present in most individuals with type 1 diabetes, even before the clinical onset. However, the antigenic determinants of such response are still unknown. In this study, we investigated the antibody response to oxPTM-INS neoepitope peptides (oxPTM-INSPs) and evaluated their ability to stimulate humoral and T cell responses in type 1 diabetes. We also assessed the concordance between antibody and T cell responses to the oxPTM-INS neoantigenic peptides. METHODS: oxPTM-INS was generated by exposing insulin to various reactive oxidants. The insulin fragments resulting from oxPTM were fractionated by size-exclusion chromatography further to ELISA and LC-MS/MS analysis to identify the oxidised peptide neoepitopes. Immunogenic peptide candidates were produced and then modified in house or designed to incorporate in silico-oxidised amino acids during synthesis. Autoantibodies to the oxPTM-INSPs were tested by ELISA using sera from 63 participants with new-onset type 1 diabetes and 30 control participants. An additional 18 fresh blood samples from participants with recently diagnosed type 1 diabetes, five with established disease, and from 11 control participants were used to evaluate, in parallel, CD4+ and CD8+ T cell activation by oxPTM-INSPs. RESULTS: We observed antibody and T cell responses to three out of six LC-MS/MS-identified insulin peptide candidates: A:12-21 (SLYQLENYCN, native insulin peptide 3 [Nt-INSP-3]), B:11-30 (LVEALYLVCGERGFFYTPKT, Nt-INSP-4) and B:21-30 (ERGFFYTPKT, Nt-INSP-6). For Nt-INSP-4 and Nt-INSP-6, serum antibody binding was stronger in type 1 diabetes compared with healthy control participants (p≤0.02), with oxidised forms of ERGFFYTPKT, oxPTM-INSP-6 conferring the highest antibody binding (83% binders to peptide modified in house by hydroxyl radical [●OH] and >88% to in silico-oxidised peptide; p≤0.001 vs control participants). Nt-INSP-4 induced the strongest T cell stimulation in type 1 diabetes compared with control participants for both CD4+ (p<0.001) and CD8+ (p=0.049). CD4+ response to oxPTM-INSP-6 was also commoner in type 1 diabetes than in control participants (66.7% vs 27.3%; p=0.039). Among individuals with type 1 diabetes, the CD4+ response to oxPTM-INSP-6 was more frequent than to Nt-INSP-6 (66.7% vs 27.8%; p=0.045). Overall, 44.4% of patients showed a concordant autoimmune response to oxPTM-INSP involving simultaneously CD4+ and CD8+ T cells and autoantibodies. CONCLUSIONS/INTERPRETATION: Our findings support the concept that oxidative stress, and neoantigenic epitopes of insulin, may be involved in the immunopathogenesis of type 1 diabetes.

Glycemic Status Assessment by the Latest Glucose Monitoring Technologies.

The advanced and performing technologies of glucose monitoring systems provide a large amount of glucose data that needs to be properly read and interpreted by the diabetology team in order to make therapeutic decisions as close as possible to the patient's metabolic needs. For this purpose, new parameters have been developed, to allow a more integrated reading and interpretation of data by clinical professionals. The new challenge for the diabetes community consists of promoting an integrated and homogeneous reading, as well as interpretation of glucose monitoring data also by the patient himself. The purpose of this review is to offer an overview of the glycemic status assessment, opened by the current data management provided by latest glucose monitoring technologies. Furthermore, the applicability and personalization of the different glycemic monitoring devices used in specific insulin-treated diabetes mellitus patient populations will be evaluated.

Flavonoids and Insulin-Resistance: From Molecular Evidences to Clinical Trials.

Insulin-resistance is one of the main factors responsible for the onset and progression of Metabolic Syndrome (MetS). Among all polyphenols, the effects of flavonoids and their main food sources on insulin sensitivity have been widely evaluated in molecular and clinical studies. The aim of this review is to analyse the data observed in vitro, in vivo and in clinical trials concerning the effects of flavonoids on insulin resistance and to determine the molecular mechanisms with which flavonoids interact with insulin signaling.

Retinal neurodegeneration in patients with type 1 diabetes mellitus: the role of glycemic variability.

AIMS: Recent studies have identified neuroretinal abnormalities in persons affected by diabetes mellitus, before the onset of microvascular alterations. However, the role of glycemic variability (GV) on early retinal neurodegeneration is still not clarified. METHODS: To explore the relationship between glycemic control and neuroretinal characteristics, 37 persons with Type 1 diabetes mellitus (Type 1 DM) divided into two groups with no signs (noRD) and with mild non-proliferative diabetic retinopathy (NPDR) compared to 13 healthy control participants (C) were recruited. All persons underwent an optical coherence tomography with automatic segmentation of all neuroretinal layers. Measurements of mean of nasal (N)/temporal (T)/superior (S)/inferior (I) macular quadrants for individual layer were also calculated. Metabolic control was evaluated by glycated hemoglobin (HbA1c), and indexes of GV were calculated from continuous glucose monitoring. RESULTS: The difference among the three groups in terms of RNFL thickness was significantly dependent on quadrant (F(6;132) = 2.315; p = 0.037). This interaction was due to a specific difference in RNFL-N thickness, where both Type 1 DM groups showed a similar reduction versus C (-3.9 for noDR and -4.9 for NPDR), without any relevant difference between them (-1.0). Inner nuclear layer (INL) was increased in all quadrants in the two Type 1 DM groups compared to C (mean difference = 7.73; 95% CI: 0.32-15.14, p = 0.043; mean difference = 7.74; 95% CI: 0.33-15.15, p = 0.043, respectively). A negative correlation between RNFL-N and low blood glucose index (r = -0.382, p = 0.034) and positive correlation between INL and continuous overall net glycemic action -1, -2, -4 h (r = 0.40, p = 0.025; r = 0.39, p = 0.031; r = 0.41, p = 0.021, respectively) were observed in Type 1 DM patients. The triglycerides were positively and significantly correlated to INL (r = 0.48, p = 0.011), in Type 1 DM subjects. GV and triglycerides resulted both independent predictors of increased INL thickness. No correlation was found with HbA1c. CONCLUSIONS: Early structural damage of neuroretina in persons with Type 1 DM patients is related to glucose fluctuations. GV should be addressed, even in the presence of a good metabolic control.

Acute hyperglycemia reduces cerebrovascular reactivity: the role of glycemic variability.

CONTEXT: Cerebral vasomotor reactivity (CVR) is reduced in patients with diabetes mellitus (DM), and glucose variability (GV) might be responsible for cerebrovascular damage. OBJECTIVE: Studying patients with insulin resistance without DM, we explored the role of GV in impairing CVR. PATIENTS: We studied 18 metabolic syndrome (MS) patients without DM, 9 controls (C), and 26 patients with DM. MAIN OUTCOME MEASURES: Groups were compared in terms of CVR, GV, and 24-hour blood pressure. To evaluate the impact of acute hyperglycemia on CVR, a hyperglycemic clamp was performed in MS patients and controls. RESULTS: Baseline CVR was reduced in DM vs C and MS (C vs DM = 20.2, 95% CI = 3.5-36.9, P = .014; and MS vs DM = 22.2, 95% CI = 8.6-35.8, P = .001), but similar between MS and C (MS vs C = 2.0, 95% CI = -14.7 to 18.7, P = .643). During acute hyperglycemia, CVR fell in MS and C to values comparable to DM. GV progressively increased from C to MS to DM. In MS, CVR at 120 minutes and GV displayed a negative correlation (r = -0.48, P = .043), which did not change after controlling for mean 24-hour systolic and diastolic blood pressure. In MS, the CVR reduction was significantly correlated to GV (r = 0.55, P = .02). CONCLUSIONS: GV is increased in patients with MS but without DM and is the major predictor of CVR reduction induced by acute hyperglycemia, possibly representing the earliest cause of cerebrovascular damage in DM.

Preliminary evidence that obese patients with obstructive sleep apnea/hypopnea syndrome are refractory to the acute beneficial metabolic effects of a very low calorie diet.

Since obesity seems to play a causal role in both obstructive sleep apnea/hypopnea syndrome (OSAHS) and type 2 diabetes, the question arises whether diet-induced weight loss is equally efficacious in type 2 diabetic patients with and without OSAHS. The present study was aimed to investigate the effect of 1 week very low calorie diet (VLCD) on oxygen desaturation index (ODI) and on glucose regulation in OSAHS versus non-OSAHS patients. Fourteen patients with type 2 diabetes mellitus and morbid obesity were enrolled. According to ODI, patients were divided into 2 groups (with and without OSAHS) and evaluated by a hyperglycemic clamp study, before and after a 7 day-VLCD. After a VLCD, a significant reduction of anthropometric parameters, in the overall group and in subgroups, was observed. M-value and acute insulin response increased significantly only in patients without obstructive sleep apnea (990.10 ± 170.19 vs. 1,205.22 ± 145.73 µmol min(-1) m(-2), p = 0.046; -1.05 ± 8.40 vs. 48.26 ± 11. 90 pmol/L, p = 0.028, respectively). The average 24-h heart rate (24-h HR) fell significantly (p = 0.05), primarily because of a decrease during daytime (p = 0.041), in the whole group. In conclusion, we observed that morbidly obese patients with type 2 diabetes and OSAHS are specifically resistant to the acute beneficial effects of VLCD on metabolic parameters. Our preliminary observation deserves further investigation to clarify the pathogenetic mechanisms involved.

Cerebral hemodynamics and systemic endothelial function are already impaired in well-controlled type 2 diabetic patients, with short-term disease.

OBJECTIVE: Impaired cerebral vasomotor reactivity (VMR) and flow-mediated dilation (FMD) were found in selected subgroups of type 2 diabetes mellitus (T2DM) patients with long-term disease. Our study aimed to evaluate cerebral hemodynamics, systemic endothelial function and sympatho-vagal balance in a selected population of well-controlled T2DM patients with short-term disease and without cardiac autonomic neuropathy (CAN). RESEARCH DESIGN AND METHODS: Twenty-six T2DM patients with short-term (4.40±4.80 years) and well-controlled (HbA1C = 6.71±1.29%) disease, without any complications, treated with diet and/or metformin, were consecutively recruited. Eighteen controls, comparable by sex and age, were enrolled also. RESULTS: FMD and shear rate FMD were found to be reduced in T2DM subjects with short-term disease (8.5% SD 3.5 and 2.5 SD 1.3, respectively) compared to controls (15.4% SD 4.1 and 3.5 SD 1.4; p<.001 and p<.05). T2DM patients also displayed reduced VMR values than controls (39.4% SD 12.4 vs 51.7%, SD 15.5; p<.05). Sympatho-vagal balance was not different in T2DM patients compared to healthy subjects. FMD and shear rate FMD did not correlate with VMR in T2DM patients or in controls (p>.05). CONCLUSIONS: In well-controlled T2DM patients with short-term disease cerebral hemodynamics and systemic endothelial function are altered while autonomic balance appeared to be preserved.

Very-low-calorie diet: a quick therapeutic tool to improve ß cell function in morbidly obese patients with type 2 diabetes.

BACKGROUND: Caloric restriction in obese diabetic patients quickly improves glucose control, independently from weight loss. However, the early effects of a very-low-calorie diet (VLCD) on insulin sensitivity and insulin secretion in morbidly obese patients with type 2 diabetes are still unclear. OBJECTIVE: The objective was to study the relative contributions of insulin sensitivity, insulin secretion, or both to improvement in glucose metabolism, after 1 wk of caloric restriction, in severely obese diabetic patients. DESIGN: Hyperglycemic clamps were performed in 14 severely obese (BMI, in kg/m(2): >40) patients with type 2 diabetes in good glucose control (glycated hemoglobin < 7.5%) before and after 7 d of a VLCD (400 kcal/d). RESULTS: The VLCD caused a 3.22 ± 0.56% weight loss (P < 0.001), 42.0% of which was fat loss, accompanied by decreases in fasting plasma glucose (P < 0.05) and triglycerides (P < 0.01). In parallel, the Disposition Index, which measures the body's capability to dispose of a glucose load, increased from 59.0 ± 6.3 to 75.5 ± 6.3 mL· min(-1) · m(-2) body surface area (P < 0.01), because of improvements in indexes of both first- and second-phase insulin secretion (P < 0.02), but with no changes in insulin sensitivity (P = 0.33). CONCLUSION: The marked improvement in metabolic profile, observed in severely obese patients with type 2 diabetes after a 7-d VLCD, was primarily due to the amelioration of ß cell function, whereas no contribution of insulin sensitivity was shown. This trial was registered at www.clinicaltrials.gov as NCT01447524.

Impact of glycemic and blood pressure variability on surrogate measures of cardiovascular outcomes in type 2 diabetic patients.

OBJECTIVE: The effect of glycemic variability (GV) on cardiovascular risk has not been fully clarified in type 2 diabetes. We evaluated the effect of GV, blood pressure (BP), and oxidative stress on intima-media thickness (IMT), left ventricular mass index (LVMI), flow-mediated dilation (FMD), and sympathovagal balance (low frequency [LF]/high frequency [HF] ratio) in 26 type 2 diabetic patients (diabetes duration 4.41±4.81 years; HbA1c 6.70±1.25%) receiving diet and/or metformin treatment, with no hypotensive treatment or complications. RESEARCH DESIGN AND METHODS: Continuous glucose monitoring (CGM) data were used to calculate mean amplitude of glycemic excursion (MAGE), continuous overall net glycemic action (CONGA)-2, mean blood glucose (MBG), mean postprandial glucose excursion (MPPGE), and incremental area under the curve (IAUC). Blood pressure (BP), circadian rhythm, and urinary 15-F2t-isoprostane (8-iso-prostaglandin F2α [PGF2α]) were also evaluated. Subjects were divided into dipper (D) and nondipper (ND) groups according to ΔBP. RESULTS: IMT and LVMI were increased in ND versus D (0.77±0.08 vs. 0.68±0.13 [P=0.04] and 67±14 vs. 55±11 [P=0.03], respectively). MBG, MAGE, and IAUC were significantly associated with LF/HF ratio at night (r=0.50, P=0.01; r=0.40, P=0.04; r=0.41, P=0.04, respectively), MPPGE was negatively associated with FMD (r=-0.45, P=0.02), and CONGA-2 was positively associated with LVMI (r=0.55, P=0.006). The Δsystolic BP was negatively associated with IMT (r=-0.43, P=0.03) and with LVMI (r=-0.52, P=0.01). Urinary 8-iso-PGF2α was positively associated with LVMI (r=0.68 P<0.001). CONCLUSIONS: An impaired GV and BP variability is associated with endothelial and cardiovascular damage in short-term diabetic patients with optimal metabolic control. Oxidative stress is the only independent predictor of increased LV mass and correlates with glucose and BP variability.