Unmet needs in the treatment of type 1 diabetes: why is it so difficult to achieve an improvement in metabolic control?

The development of advanced diabetes technology has permitted persons with type 1 diabetes mellitus to improve metabolic control significantly, particularly with the development of advanced hybrid closed-loop systems which have improved the quality of life by reducing hypoglycemia, decreasing macroangiopathy and microangiopathy-related complications, ameliorating HbA1c and improving glycemic variability. Despite the progression made over the past few decades, there is still significant margin for improvement to be made in terms of attaining appropriate metabolic control. Various factors are responsible for poor glycemic control including inappropriate carbohydrate counting, repeated bouts of hypoglycemia, hypoglycemia unawareness, cutaneous manifestations due to localized insulin use and prolonged use of diabetes technology, psychosocial comorbidities such as eating disorders or 'diabulimia', the coexistence of insulin resistance among people with type 1 diabetes and the inability to mirror physiological endogenous pancreatic insulin secretion appropriately. Hence, the aim of this review is to highlight and overcome the barriers in attaining appropriate metabolic control among people with type 1 diabetes by driving research into adjunctive treatment for coexistent insulin resistance and developing new advanced diabetic technologies to preserve ß cell function and mirror as much as possible endogenous pancreatic functions.

HLA alleles associated to susceptibility to gliptin-associated bullous pemphigoid in Italian patients.

Bullous pemphigoid (BP), although a rare disease, is the most frequent subepidermal autoimmune disorder. Treatment with gliptins, used for type 2 diabetes, was reported as associated with BP onset. To identify HLA alleles that may reflect a higher susceptibility to BP in the Italian population, we analysed 30 patients affected by idiopathic bullous pemphigoid (IBP) and 86 gliptin-associated BP (GABP) patients. A significant association between HLA-DQB1*03:01 allele and IBP and GABP patients was found. Of note, both IBP and GABP were significantly associated with one of the following haplotypes: DRB1*11:01, DRB3*02:02, DQA1*05:05, DQB1*03:01 or DRB1*11:04, DRB3*02:02, DQA1*05:05 and DQB1*03:01. These data identify, for the first time, potential markers of susceptibility to BP in the Italian population, especially when associated with gliptin intake.

Optical discrimination of pathological red blood cells.

Fast diagnostic methods are crucial to reduce the burden on healthcare systems. Currently, detection of diabetes complications such as neuropathy requires time-consuming approaches to observe the correlated red blood cells (RBCs) morphological changes. To tackle this issue, an optical analysis of RBCs in air was conducted in the 250-2500 nm range. The distinct oscillations present in the scattered and direct transmittance spectra have been analyzed with both Mie theory and anomalous diffraction approximation. The results provide information about the swelling at the ends of RBCs and directly relate the optical data to RBCs morphology and deformability. Both models agree on a reduction in the size and deformability of RBCs in diabetic patients, thus opening the way to diabetes diagnosis and disease progression assessment.

Secondary Hirata Syndrome in a Neonate: Practical Approach and Management.

Hirata disease, also known as insulin autoimmune syndrome (IAS), is a rare cause of hypoglycemia, due to the presence of insulin autoantibodies (IAA) in the circulating blood. These antibodies are immunoglobulin G (IgG), making placental transfer to the fetus possible. To our knowledge, no reports of IAS have been previously described in the neonatal population. We present a case report of hypoglycemia due to a secondary IAS in a neonate and discuss the management and treatment of the disease.

Evaluation of time in tight range and the glycaemia risk index in adults with type 1 diabetes using an advanced hybrid closed loop system: A 1-year real-world assessment.

AIM: To assess the long-term glycaemic outcomes, with additional metrics, in adults with type 1 diabetes (T1D) using the Tandem t:slim X2 with Control-IQ technology advanced hybrid closed-loop (AHCL) system. METHODS: This was a single-centre, retrospective study involving 56 T1D patients who transitioned to the Tandem t:slim X2 with Control-IQ system. The primary and secondary endpoints consisted of variations in time in tight range (TiTR; 70-140 mg/dL) and the glycaemia risk index (GRI), respectively. Additional standardized continuous glucose monitoring (CGM) metrics, mean sensor glucose, coefficient of variation, the glucose management indicator (GMI), HbA1c and insulin daily dose, were also evaluated. Variables were measured at baseline and at 15 days, 3 months, 6 months and 1 year after Tandem t:slim X2 Control-IQ initiation. Glucose outcomes are expressed as mean (standard deviation). RESULTS: Use of Tandem t:slim X2 with Control-IQ over 1 year was associated with an increase in mean TiTR, from 38.11% (17.05%) to 43.10% (13.20%) (P = .059), and with a decline in the GRI, from 41.03 (25.48) to 28.55 (16.27) (P = .008). CGM metrics, including time in range and time above range, showed consistent improvements. Mean sensor glucose, the GMI and HbA1c decreased significantly over time. After an initial increase, insulin daily dose remained stable throughout the 12 months. CONCLUSIONS: The results highlight the sustained effectiveness of Tandem t:slim X2 with Control-IQ in improving glycaemic outcomes over 1 year and support the use of this technology for the management of T1D.

Reconsidering the role of depression and common psychiatric disorders as partners in the type 2 diabetes epidemic.

Common psychiatric disorders (CPDs) and depression contribute significantly to the global epidemic of type 2 diabetes (T2D). We postulated a possible pathophysiological mechanism that through Bridge-Symptoms present in depression and CPDs, promotes the establishment of emotional eating, activation of the reward system, onset of overweight and obesity and, ultimately the increased risk of developing T2D. The plausibility of the proposed pathophysiological mechanism is supported by the mechanism of action of drugs such as naltrexone-bupropion currently approved for the treatment of both obesity/overweight with T2D and as separate active pharmaceutical ingredients in drug addiction, but also from initial evidence that is emerging regarding glucagon-like peptide 1 receptor agonists that appear to be effective in the treatment of drug addiction. We hope that our hypothesis may be useful in interpreting the higher prevalence of CPDs and depression in patients with T2D compared with the general population and may help refine the integrated psychiatric-diabetic therapy approach to improve the treatment and or remission of T2D.

Potential pathogenetic role of a novel ABCC8 missense variant on both transient neonatal diabetes mellitus and fetal growth restriction: a case report.

BACKGROUND: The diagnosis of neonatal diabetes can be problematic in preterm infants with fetal growth restriction (FGR). Growth restricted fetuses may have impaired insulin production and secretion; low birthweight infants may have a reduced response to insulin. We report a novel missense ABCC8 variant associated with a clinical phenotype compatible with transient neonatal diabetes mellitus (TNDM) in a fetal growth restricted preterm infant. METHODS AND RESULTS: A preterm growth restricted infant experienced hyperglycemia from the first day of life, requiring insulin therapy on the 13th and 15th day of life and leading to the diagnosis of TNDM. Glycemic values normalized from the 35th day of life onwards. Genetic screening was performed by next generation sequencing, using a Clinical Exon panel of 4800 genes, filtered for those associated with the clinical presentation and by means of methylation-specific multiplex ligation-dependent probe amplification analysis to identify chromosomal aberrations at 6q24. Genetic tests excluded defects at 6q24 and were negative for KCNJ11, SLC2A2 (GLUT-2) and HNF1B, but revealed the presence of the heterozygous missense variant c.2959T > C (p.Ser987Pro) in ABCC8 gene. The presence of the variant was excluded in parents' DNA and the proband variant was then considered de novo. CONCLUSIONS: In our infant, the persistence of hyperglycemia beyond 3 weeks of life led us to the diagnosis of TNDM and to hypothesize a possible genetic cause. The genetic variant we found could be, most likely, the main cause of both FGR and TNDM.

Assessment of the influence of chewing pattern on glucose homeostasis through linear regression model.

OBJECTIVE: Maintaining plasma glucose homeostasis is vital for mammalian survival, but the masticatory function, which influences glucose regulation, has, to our knowledge, been overlooked. RESEARCH METHODS AND PROCEDURES: In this study, we investigated the relationship between the glycemic response curve and chewing performance in a group of 8 individuals who consumed 80 g of apple. A device called "Chewing" utilizing electromyographic (EMG) technology quantitatively assesses chewing pattern, while glycemic response is analyzed using continuous glucose monitoring. We assessed chewing pattern characterizing chewing time (tchew), number of bites (nchew), work (w), power (wr), and chewing cycles (tcyc). Moreover, we measured the principal features of the glycemic response curve, including the area under the curve (α) and the mean time to reach the glycemic peak (tmean). We used linear regression models to examine the correlations between these variables. RESULTS: tchew, nchew, and wr were correlated with α (R2 =  0.44,   P  <  0.05 for tchew and nchew, P  <  0.001 for wr), and tmean was correlated with tchew (R2  =  0.25,  P  <  0.05). These findings suggest that increasing chewing time and power, while reducing the number of chews, resulted in a wider glycemic curve and an earlier attainment of the glycemic peak. CONCLUSIONS: These results emphasize the influence of proper chewing techniques on blood sugar levels. Implementing correct chewing habits could serve as an additional approach to managing the glycemic curve, particularly for individuals with diabetes.

Autoimmunity in Type 2 Diabetes: When the Only Effective Therapy Becomes Immunosuppressive.

BACKGROUND: Type B insulin resistance syndrome is a rare form of diabetes due to the presence of anti-insulin receptor antibodies [1, 2], which causes glycemic decompensation and antidiabetic therapy failure and instead responds to immunosuppressive therapy. CASE REPORT: A 67-year-old patient was admitted to the hospital due to autoimmune hemolytic anemia and glycemic decompensation. We first prescribed subcutaneous basal-bolus insulin and then intravenous insulin without improvement in blood sugar levels (between 300 and 500 mg/dL). Considering the non-response to therapy and the autoimmune diathesis of the patient (hemolytic anemia and mixed connective tissue disease), we suspected an autoimmune etiopathogenesis of glycemic decompensation; we excluded type 1 diabetes mellitus (specific antibodies were negative), and we considered the anti-insulin-antibodies-(-assayed and negative) and anti-insulin receptor antibodies (not assayed due to the lack of a center specialized in this assay in the area). Therefore, we decided to start Rituximab. After 2 weeks from the infusion, the patient improved glycemic compensation, reducing insulin requirement. Further, 2 months after the first infusion, the patient stopped insulin, returning to oral therapy with Metformin. To date, the patient has completed 3 cycles of Rituximab with the benefit of glycemic control (HbA1c 6.7%). CONCLUSION: The brilliant response to Rituximab supports the hypothesis of an autoimmune pathogenesis. The anti-insulin receptor antibodies (in the type B insulin resistance syndrome) affect mostly middle-aged adults, especially women, in the context of other autoimmune diseases. Hence, it is necessary to consider the diagnosis of this rare disease in order to perform timely and effective treatment.

Associations between continuous glucose monitoring (CGM) metrics and psycholinguistic measures: a correlational study.

AIM: Recently, the relationship between diabetes and mental health has been widely studied. With the advent of continuous glucose monitoring (CGM), some researchers have been interested in exploring the association between glucose-related metrics and psychological aspects. These studies have primarily relied on self-report questionnaires which present some limitations. Therefore, the present multicenter study aims at testing potential associations between CGM metrics and affective processes derived from narratives about using a CGM sensor. METHODS: An exploratory correlational design was used. Fifty-eight adults with type 1 diabetes using CGM were enrolled and invited to complete an online survey, where they replied to an open-ended question regarding their personal experience with the CGM sensor. Texts derived from the answers were analyzed through Linguistic Inquiry and Word Count, a widely used text analysis tool that can automatically identify and quantify linguistic patterns related to various psychological dimensions. Psycholinguistic measures were correlated with CGM metrics. RESULTS: Higher levels of sadness/depression correlated with lower %TIR (r = - 339; p < .01) and higher %TAR (r = .342; p < .01). CONCLUSIONS: The study highlights the relationship between CGM metrics and psychological variables derived from patients' narratives. In particular, it is possible to hypothesize a positive role of %TIR in reducing depressive feelings in individuals with diabetes, as well as a negative role of depressive feelings in achieving desirable CGM outcomes. Additionally, there is a potential role of glycemic variability, particularly hyperglycemia, in the expression of depressive and sad feelings, which has been less studied compared to the effects of hypoglycemia.

Effect of very long-term storage and multiple freeze and thaw cycles on 11-dehydro-thromboxane-B2 and 8-iso-prostaglandin F2α, levels in human urine samples by validated enzyme immunoassays.

Biological samples are often frozen and stored for years and/or thawed multiple times, thus assessing their stability on long-term storage and repeated freeze-thaw cycles is crucial. The study aims were to assess:-the long-term stability of two major enzymatic and non-enzymatic metabolites of arachidonic acid, i.e. urinary 11-dehydro-thromboxane-(Tx) B2, 8-iso-prostaglandin (PG)F2α, and creatinine in frozen urine samples;-the effect of multiple freeze-thaw cycles. Seven-hundred and three urine samples measured in previously-published studies, stored at -40 °C, and measured for a second time for 11-dehydro-TxB2 (n = 677) and/or 8-iso-PGF2α (n = 114) and/or creatinine (n = 610) were stable over 10 years and the 2 measurements were highly correlated (all rho = 0.99, P < 0.0001). Urine samples underwent 10 sequential freeze-thaw cycles, with and without the antioxidant 4-hydroxy-2,2,6,6-tetramethylpiperidin-1-oxyl (10 mM); urinary 11-dehydro-TxB2 and creatinine were stable across all cycles (11-dehydro-TxB2: 100.4 ± 21%; creatinine: 101 ± 7% of baseline at cycle ten; n = 17), while 8-iso-PGF2α significantly increased by cycle 6 (151 ± 22% of baseline at cycle ten, n = 17, P < 0.05) together with hydrogen peroxide only in the absence of antioxidant. Arachidonic acid metabolites and creatinine appear stable in human urines stored at -40 °C over 10 years. Multiple freeze-thaw cycles increase urinary 8-iso-PGF2α in urine samples without antioxidants. These data are relevant for studies using urine samples stored over long-term and/or undergoing multiple freezing-thawing.

Translating trial results into interpretable risk estimates: Systematic analysis of cardiorenal outcome trials of glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter-2 inhibitors.

BACKGROUND AND AIMS: In a randomised controlled trial (RCT), the between-arm difference in the average probability of an event per unit of time (i.e., yearly incidence risk difference, YIRD) is an easy-to-interpret treatment effect metric. We aimed to quantify the YIRD in cardiorenal RCTs of GLP-1RAs or SGLT-2is. METHODS AND RESULTS: We digitally searched for RCTs published up to March 1st, 2023, including subjects with type 2 diabetes randomised to GLP-1RAs or SGLT-2is and investigating cardiorenal outcomes or death. We extracted information from Kaplan-Meier (KM) plots to obtain time-to-event individual data and estimate within-arm yearly incidence risk and YIRD. Data from 19 RCTs (28 kM plots) were analysed: comparing treatment to placebo, in GLP-1RA RCTs the YIRD ranged from 0.2 % (95 % CI: -0.7 %, 1.1 %) to -1.9 % (-3.1, -0.7), for primary outcome; and from -0.2 % (-0.5, 0.2) to -0.4 % (-0.7 %, -0.0 %), for mortality. With the exception of SOLOIST-WHF (YIRD 11.9 % for primary outcome), corresponding estimates in SGLT-2is RCTs were: from -0.1 % (-0.4, 0.1) to -5.0 % (-7.7, -2.6), for primary outcome; and from -0.1 % (-0.2, 0.1) to -1.9 % (-4.4 %, 0.6 %), for mortality. CONCLUSION: The YIRD metric complements other relative treatment effect estimates and helps quantify the absolute benefit of GLP-1RAs and SGLT-2is.

IDegLira for the real-world treatment of type 2 diabetes in Italy. Final results from the REX observational study.

AIM: The study was designed to generate real-world evidence on IDegLira in the Italian clinical practice in two groups of patients with type 2 diabetes (T2D), switching to IDegLira either from a basal only (basal group) or basal-bolus insulin regimen (BB group). MATERIALS AND METHODS: This was a non-interventional, multicentre, single-cohort, prospective study assessing the long-term glycaemic control in patients with T2D, who switched to IDegLira from a basal insulin ± glucose-lowering medication regimen with or without a bolus insulin component for approximately 18 months, conducted in 28 Italian diabetes centres. The primary endpoint was the change in glycated haemoglobin (HbA1c) levels from baseline to 6 months after IDegLira initiation. RESULTS: The study included 358 patients with a mean age 67.2 years and diabetes duration of 15.7 years. HbA1c significantly decreased from IDegLira start to all study time points in the overall population (basal group -1.19%; BB group -0.60% at the end of observation). Patients achieving HbA1c <7% levels increased from 12.9% (n = 43) to 40.3% (n = 110) at 18 months. Fasting blood glucose and body weight also significantly decreased in both groups, although more in the BB group. Overall, 14.3% of completed patients had an intensification of treatment (mainly in the basal group) and 48.6% had a simplification of treatment (mainly in the BB group). CONCLUSIONS: Switching to IDegLira in a real-world clinical setting is a valid therapeutic option for patients with T2D with inadequate glycaemic control on basal or BB insulin regimen and/or need to simplify their insulin therapy, with specific reasons and therapeutic goals according to different T2D management trajectories.

Effect of glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter-2 inhibitors on time to outcome in type 2 diabetes cardiorenal outcome trials.

INTRODUCTION: In randomized controlled trials (RCTs), treatment effects are commonly reported as hazard ratio, a measure often misinterpreted as a relative risk reduction. The acceleration factor (AF) indicates the extent to which a treatment increases/decreases the time before the occurrence of an outcome and gives useful insights in the interpretation of trials' results. METHODS: Using individual time-to-event data reconstructed from Kaplan-Meier plots, we estimated AFs for the primary outcomes (POs) and all-cause mortality in glucagon-like peptide-1 receptor agonists (GLP1-RAs) or sodium-glucose cotransporter-2 inhibitors (SGLT2-is) cardiorenal outcome trials in subjects with type 2 diabetes. RESULTS: AFs were estimated from 28 Kaplan-Meier plots of 19 RCTs. Compared to placebo, most GLP1-RAs increased the time before the onset of POs (from 9 % to 59 %) and all-cause mortality (from 8 to 13 %). Similarly, SGLT2-is increased time before the onset of POs (from 19 % to 87 %) and all-cause mortality (from 13 % to 42 %). CONCLUSIONS: The AFs provide a complementary and easier-to-interpret measure of treatment effect that could be useful to improve the shared decision-making.

Insulin pump treatment vs. multiple daily insulin injections in patients with poorly controlled Type 2 diabetes mellitus: a comparison of cardiovascular effects.

AIMS: Both hyperglycaemia and large glycaemic variability are associated with worse outcomes in patients with Type 2 diabetes mellitus (T2DM), possibly causing sympatho-vagal imbalance and endothelial dysfunction. Continuous subcutaneous insulin injection (CSII) improves glycemic control compared to multiple daily insulin injections (MDI). We aimed to assess whether CSII may improve cardiac autonomic and vascular dilation function compared to MDI. METHODS: We enrolled T2DM patients without cardiovascular disease with poor glycaemic control, despite optimized MDI therapy. Patients were randomized to continue MDI (with multiple daily peripheral glucose measurements) or CSII; insulin dose was adjusted to achieve optimal target ranges of blood glucose levels. Patients were studied at baseline and after 6 months by: 1) flow-mediated dilation (FMD) and nitrate-mediated dilation (NMD) of the brachial artery; 2) heart rate variability (HRV) by 24-hour ECG Holter monitoring (HM). 7-day continuous glucose monitoring (CGM) was performed in 9 and 8 patients of Group 1 and 2, respectively. RESULTS: Overall, 21 patients were enrolled, 12 randomized to CSII (Group 1) and 9 to MDI (Group 2). The daily dose of insulin and Hb1AC did not differ significantly between the 2 groups, both at baseline and at follow-up. Glucose variability showed some significant improvement at follow-up in the whole population, but no differences were observed between the 2 groups. Both FMD and NMD, as well as HRV parameters, showed no significant differences between the 2 groups at 6-month follow-up. CONCLUSIONS: In this randomized small study we show that, in T2DM patients, CSII achieves a similar medium-term glycemic control compared to MDI, without any adverse effect on the cardiovascular system.

Von Willebrand factor hyperactivity affects the outcome of lower limb revascularization in subjects with type 2 diabetes mellitus complicated by diabetic foot vasculopathy: An observational pilot study.

Aim of this study is to evaluate any differences in VWF antigen, VWF activity and ADAMTS-13 activity before and after successful and non-successful Percutaneous Transluminal Angioplasty (PTA) in subjects with type 2 diabetes (T2DM) complicated by Chronic limb-threatening ischemia (CLTI) in diabetic foot vasculopathy. METHODS: In this prospective observational pilot study, we enrolled 35 T2DM subjects who underwent lower limb PTA. Transcutaneous oximetry was performed in all patients before and 6 weeks after PTA. The change in oxygen partial pressure (TcpO2) before and after PTA was expressed as TcpO2-delta (ΔTcpO2). VWF antigen, VWF activity and ADAMTS-13 activity were measured before and 6 weeks after PTA; changes were expressed as delta and ratio from baseline. RESULTS: Subjects with ∆TcpO2 < 15 mmHg presented higher ΔVWF activity (p = 0.050) and lower ADAMTS-13 activity ratio (p = 0.080). Subjects with ∆TcpO2 < 30 mmHg showed lower ADAMTS-13 activity Δ and ratio (p = 0.028). CONCLUSIONS: VWF antigen levels and VWF activity may potentially affect PTA outcome. Higher levels of VWF could derive from VWF release as consequence of PTA-induced mechanical endothelial damage and/or oxidative stress-induced modifications of VWF structure with impairment of VWF-ADAMTS13 interactions.

An updated algorithm for an effective choice of continuous glucose monitoring for people with insulin-treated diabetes.

PURPOSE: Continuous Glucose Monitoring (CGM) is a key tool for insulin-treated people with diabetes (PwD). CGM devices include both real-time CGM (rtCGM) and intermittently scanned CGM (isCGM), which are associated with an improvement of glucose control and less hypoglycemia in clinical trials of people with type 1 and type 2 diabetes. METHODS: This is an expert position to update a previous algorithm on the most suitable choice of CGM for insulin-treated PwD in light of the recent evidence and clinical practice. RESULTS: We identified six different clinical scenarios, including type 1 diabetes, type 2 diabetes, pregnancy on intensive insulin therapy, regular physical exercise, new onset of diabetes, and frailty. The use of rtCGM or isCGM is suggested, on the basis of the predominant clinical issue, as suboptimal glucose control or disabling hypoglycemia, regardless of baseline HbA1c or individualized HbA1c target. CONCLUSION: The present algorithm may help to select the best CGM device based on patients' clinical characteristics, needs and clinical context, offering a further opportunity of a "tailored" therapy for people with insulin-treated diabetes.

Predisposition to eating disorders in adults with type 1 diabetes: Comparison between multiple daily injections and continuous subcutaneous insulin infusion.

AIM: To evaluate predisposition to eating disorders (ED) or body dissatisfaction in adults with type 1 diabetes mellitus (T1DM); to further investigate any differences in ED predisposition between subjects with T1DM on multiple daily injections (MDI) or insulin pumps (CSII) and in respect to control healthy subjects. METHODS: We conducted a monocentric, cross-sectional, observational study. We enrolled subjects with T1DM, aged ≥ 18 years, and healthy subjects (HS) as control group. All participants completed two questionnaires to detect possible predisposition to ED: 34-items Body Shape Questionnaire (BSQ) and Eating Disorder Inventory-3 (EDI-3). HS only filled BSQ. For subjects with T1DM data about glycated hemoglobin and duration of disease were also collected. RESULTS: 162 subjects with T1DM (age 41 ± 12 years, 77 [47%] males) and 50 HS (age 38 ± 13 years, 18 (36%) males) were enrolled. 87 subjects with T1DM (54%) were on MDI and 75 (46%) were on CSII. No significant difference in the distribution of BSQ scores between subjects with T1DM and HS was observed (p = 0.551), although 16% of subjects with T1DM scored BSQ class 1 points while 8% of HS scored a BSQ class 1 points. No significant difference in BSQ scores was observed between subjects with T1DM on MDI or CSII. Between these two groups, no differences in EDI-3 scores were observed except for perfectionism score: subjects on MDI present more frequently a predisposition for perfectionism (p < 0.05) and, at a trend level, for bulimia. CONCLUSION: A non -significant higher percentage of BSQ class 1 was detected in subjects T1DM compared to healthy controls. Among subjects with T1DM, no differences between MDI and CSII were observed in ED predisposition. A more perfectionist personality has been detected among subjects on MDI.