Purpose of Review
This review seeks to characterize emerging concepts related to disease-modifying therapy in type 1 diabetes.
Recent Findings
We begin by describing the new understanding that islet ...autoimmunity, as identified by the presence of islet autoantibodies, inevitably leads to clinical type 1 diabetes. This understanding informs the new staging paradigm for type 1 diabetes, which suggests that type 1 diabetes may be recognized and diagnosed long before symptoms develop. Although it is known that nearly all individuals with established islet autoimmunity will eventually develop symptomatic type 1 diabetes (T1D), individual characteristics such as age and biomarker profile may predict rate of disease progression and response to treatment and may therefore be used to individualize therapy.
Summary
Key research supports the use of immunotherapy in TID, although a paradigm shift is necessary before immunotherapy may transition from clinical trials to clinical practice. Recent and ongoing research as it relates to these concepts is described throughout.
Purpose of Review
To discuss the current understanding of “β cell identity” and factors underlying altered identity of pancreatic β cells in diabetes, especially in humans.
Recent Findings
Altered ...identity of β cells due to dedifferentiation and/or transdifferentiation has been proposed as a mechanism of loss of β cells in diabetes. In dedifferentiation, β cells do not undergo apoptosis; rather, they lose their identity and function. Dedifferentiation is well characterized by the decrease in expression of key β cell markers such as genes encoding major transcription factors, e.g., MafA, NeuroD1, Nkx6.1, and Foxo1, and an increase in atypical or “disallowed” genes for β cells such as lactate dehydrogenase, monocarboxylate transporter MCT1, or progenitor cell genes (Neurog3, Pax4, or Sox9). Moreover, altered identity of mature β cells in diabetes also involves transdifferentiation of β cells into other islet hormone producing cells. For example, overexpression of α cell specific transcription factor Arx or ablation of Pdx1 resulted in an increase of α cell numbers and a decrease in β cell numbers in rodents. The frequency of α-β double-positive cells was also prominent in human subjects with T2D. These altered identities of β cells likely serve as a compensatory response to enhance function/expand cell numbers and may also camouflage/protect cells from ongoing stress. However, it is equally likely that this may be a reflection of new cell formation as a frank regenerative response to ongoing tissue injury. Physiologically, all these responses are complementary.
Summary
In diabetes, (1) endocrine identity recapitulates the less mature/less-differentiated fetal/neonatal cell type, possibly representing an adaptive mechanism; (2) residual β cells may be altered in their subtype proportions or other molecular features; (3) in humans, “altered identity” is a preferable term to dedifferentiation as their cellular fate (differentiated cells losing identity or progenitors becoming more differentiated) is unclear as yet.
Purpose of the Review
The aim of this review is to discuss recent data pointing at an involvement of human endogenous retroviruses (HERVs) in type 1 diabetes (T1D) onset and progression.
Recent ...Findings
The envelope protein of HERV-W family, named HERV-W-Env, was detected in pancreata from T1D patients and was shown to display pro-inflammatory properties and direct toxicity toward pancreatic beta cells.
Summary
The etiopathogenesis of T1D remains elusive, even if conventional environmental viral infections have been recurrently involved. Nonetheless, a new category of pathogens may provide the missing link between genetic susceptibility and environmental factors long thought to contribute to T1D onset. A number of studies have now shown that HERV sequences, which are normally inactivated or repressed in the human genome, could be activated by environmental viruses. Thus, if similarly activated by viruses associated with T1D, disregarded HERV genes may underlie T1D genetic susceptibility. Moreover, once expressed, HERV elements may display broad pathogenic properties, which identify them as potential new therapeutic targets.
The field of bioprinting has recently gained heightened attention as providing a promising technology that gives rise to achieving successful therapeutic outcomes where other methods have been met ...with limitations. However, bioprinting 3-Dimensional (3D), layered tissue constructs requires optimization of the appropriate size/shape of the desired construct, pressures to avoid shear stress, and the amount of bioink needed to sustain the printing process. To measure the behavior of the bioprinted products in response to terminal mechanical assays independent of the aforementioned factors, other models may be suitable. Therefore, I propose that an alginate cast may be used as a suitable alternative to bioprinting to extrapolate the results of assays aimed at modeling the physical properties of 3D bioprinted tissue constructs in vitro.
The alginate casts have demonstrated their capacity to withstand the effects of both physiological and mechanical pressures, suspend 3D cell cultures, and respond to assays designed to measure physical characterization and cytocompatibility. The casts are cylindrical and composed of primarily 1.5% UltraPure Low Viscosity Monolaurate (UP LVM) and crosslinked with 100 mM calcium or 25 mM strontium. The cylinders occupy a volume of ∼40 µL with a diameter of 5 mm and height of 2 mm.
The results of the permeability test revealed that the highest degree of permeation was achieved by MAL-1, followed by RCA I. However, SNA was nearly entirely excluded from the cast due to the pore size exclusion of the cast. A pre-incubation overnight at 37°C increased the vulnerability of the alginate to permeation. The compression tests yielded Young's Modulus’ that revealed each cast was only displaced marginally by a degree of a few millimeters at the average compressive strength of a human pancreas, indicating the mechanical stress of vascularization the constructs may withstand in vivo. Lastly, there was no statistically significant difference (p <0.05) between the resulting viabilities of free HepG2 spheroids compared to HepG2 spheroids in cast obtained from the MultiTox.
Thus, the advantages and the applications of using alginate-derived structures to model the characteristics of bioprinted scaffolds are elucidated. Ultimately, this provides insight into to the opportunities of using alginate casts to model therapeutic approaches.
There are still many insulin-containing β-cells in the pancreatic islets at diagnosis of clinical type 1 diabetes (T1D), with a morphological and functional reserve capacity for insulin ...production.The initiating event in the demise of the insulin-producing β-cells may be a low-grade persistent enterovirus infection.This sets in motion a cascade of both innate and adaptive immune responses (inflammation) and induces autoimmunity.Persistent infection may lead to endoplasmic reticulum stress, formation of neoantigens and autoantibodies, apoptosis, and loss of β-cells.Antiviral treatment preserves residual insulin production in newly diagnosed T1D.
Type 1 diabetes (T1D), a severe disease requiring intensive insulin treatment, carries an increased risk for complications and reduced lifespan. Certain viruses have been implicated in T1D’s etiology, with ‘live‘, replicating enteroviruses (EVs) recently found in the pancreas at diagnosis. This discovery prompted a trial to slow down disease progression using antiviral drugs. A 6-month treatment combining pleconaril and ribavirin in new-onset T1D patients preserved residual insulin production after 1 year, unlike placebo. The results support the theory that viruses may cause T1D in genetically susceptible individuals. A low-grade, persistent viral infection may initiate a cascade of pathogenic mechanisms initially involving the innate immune system, inducing β-cell stress and neoantigen release, leading to autoimmunity, and eventually the destruction of insulin-producing β-cells.
Type 1 diabetes (T1D), a severe disease requiring intensive insulin treatment, carries an increased risk for complications and reduced lifespan. Certain viruses have been implicated in T1D’s etiology, with ‘live‘, replicating enteroviruses (EVs) recently found in the pancreas at diagnosis. This discovery prompted a trial to slow down disease progression using antiviral drugs. A 6-month treatment combining pleconaril and ribavirin in new-onset T1D patients preserved residual insulin production after 1 year, unlike placebo. The results support the theory that viruses may cause T1D in genetically susceptible individuals. A low-grade, persistent viral infection may initiate a cascade of pathogenic mechanisms initially involving the innate immune system, inducing β-cell stress and neoantigen release, leading to autoimmunity, and eventually the destruction of insulin-producing β-cells.
Purpose of Review
Regulatory T cells (Tregs) are critical contributors to immune homeostasis and their dysregulation can lead to the loss of immune tolerance and autoimmune diseases like type 1 ...diabetes (T1D). Recent studies have highlighted microRNAs (miRNAs) as important regulators of the immune system, by fine-tuning relevant genes in various immune cell types. In this review article, we discuss recent insights into miRNA regulation of immune tolerance and activation. Specifically, we discuss how the dysregulation of miRNAs in T cells contributes to their aberrant function and the onset of islet autoimmunity, as well as their potential as targets of novel intervention strategies to interfere with autoimmune activation.
Recent Findings
Several studies have shown that the dysregulation of individual miRNAs in T cells can contribute to impaired immune tolerance, contributing to onset and progression of islet autoimmunity. Importantly, the targeting of these miRNAs, including miR-92a, miR-142-3p and miR-181a, resulted in relevant effects on downstream pathways, improved Treg function and reduced islet autoimmunity in murine models.
Summary
miRNAs are critical regulators of immune homeostasis and the dysregulation of individual miRNAs in T cells contributes to aberrant T cell function and autoimmunity. The specific targeting of individual miRNAs could improve Treg homeostasis and therefore limit overshooting T cell activation and islet autoimmunity.
Aim
To investigate the long‐term efficacy and safety of dapagliflozin as an adjunct to adjustable insulin in adults with type 1 diabetes (T1D) and inadequate glycaemic control.
Materials and Methods
...Dapagliflozin Evaluation in Patients with Inadequately Controlled Type 1 Diabetes (DEPICT‐2) was a placebo‐controlled, double‐blind, multicentre, phase III study of adults with T1D (HbA1c 7.5%‐10.5%) randomized (1:1:1) to receive dapagliflozin 5, 10 mg, or placebo. The efficacy and safety of dapagliflozin over 52 weeks were exploratory endpoints in this extension to DEPICT‐2.
Results
Of 813 participants randomized, 88.2% completed the study. From baseline to 52 weeks, dapagliflozin 5 and 10 mg were associated with reduction in HbA1c (difference 95% CI vs. placebo: −0.20% −0.34, −0.06 and −0.25% −0.38, −0.11, respectively) and adjusted mean percentage change in body weight (difference 95% CI vs. placebo: −4.42% −5.19, −3.64 and −4.86% −5.63, −4.08, respectively). Serious adverse events were reported in the dapagliflozin 5, 10 mg, and placebo groups (32 11.8%, 19 7.0% and 16 5.9%, respectively). The proportion of hypoglycaemic events was similar across groups; severe hypoglycaemia was uncommon. More participants with events adjudicated as definite diabetic ketoacidosis (DKA) were in the dapagliflozin 5 and 10 mg groups versus placebo (11 4.1%, 10 3.7% and 1 0.4%, respectively); the majority of events were mild or moderate in severity and all were resolved with treatment.
Conclusions
Dapagliflozin led to long‐term reductions in HbA1c and body weight in adults with T1D, but increased DKA risk compared with placebo.
Aims/hypothesis: Against a background of a near-universally increasing incidence of childhood type 1 diabetes, recent reports from some countries suggest a slowing in this increase. Occasional ...reports also describe cyclical variations in incidence, with periodicities of between 4 and 6years.
Methods: Age/sex-standardised incidence rates for the 0- to 14-year-old age group are reported for 26 European centres (representing 22 countries) that have registered newly diagnosed individuals in geographically defined regions for up to 25years during the period 1989-2013. Poisson regression was used to estimate rates of increase and test for cyclical patterns. Joinpoint regression software was used to fit segmented log-linear relationships to incidence trends.
Results: Significant increases in incidence were noted in all but two small centres, with a maximum rate of increase of 6.6% per annum in a Polish centre. Several centres in high-incidence countries showed reducing rates of increase in more recent years. Despite this, a pooled analysis across all centres revealed a 3.4% (95% CI 2.8%, 3.9%) per annum increase in incidence rate, although there was some suggestion of a reduced rate of increase in the 2004-2008 period. Rates of increase were similar in boys and girls in the 0- to 4-year-old age group (3.7% and 3.7% per annum, respectively) and in the 5- to 9-year-old age group (3.4% and 3.7% per annum, respectively), but were higher in boys than girls in the 10- to 14-year-old age group (3.3% and 2.6% per annum, respectively). Significant 4year periodicity was detected in four centres, with three centres showing that the most recent peak in fitted rates occurred in 2012.
Conclusions/interpretation: Despite reductions in the rate of increase in some high-risk countries, the pooled estimate across centres continues to show a 3.4% increase per annum in incidence rate, suggesting a doubling in incidence rate within approximately 20years in Europe. Although four centres showed support for a cyclical pattern of incidence with a 4year periodicity, no plausible explanation for this can be given.
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•In Sardinia, the incidence rate (IR) of type 1 diabetes is higher than in other regions of Italy.•We investigated the IR of type 1 diabetes in Sardinian children in 2019–2022 and the ...temporal trend since 1989.•Our study has shown that the incidence rate of T1D in In Sardinia, the IR of T1D has almost doubled in the last 20 years and currently appears to be the highest in the world.
The primary objectives were to investigate the incidence rate (IR) of type 1 diabetes (T1D) in Sardinian children aged 0–14 years in 2019–2022 and to examine the temporal trend from 1989-1999.
Data from new-onset T1D patients aged 0–14 years who were residents of Sardinia were collected from all pediatric diabetology clinics. The overall, sex- and age specific (groups 0–4, 5–9, and 10–14 years), and calendar year IRs were calculated. The standardized IR (SIR) was also calculated using the direct method. Poisson regression was used to estimate the temporal trend in the SIRs from 1989-1999 to 2019–2022.
In 2019–2022, 512 patients aged 0–14 years were diagnosed with T1D in Sardinia. The overall IR was 73.9 per 100,000 person-years (95 % CI 67.6–80.0). Since 1989, the SIR has increased by 2.3 % per year (CI 1.7–2.8, p < 0.0001). The frequency of ketoacidosis at onset was 26.4 %, with no significant differences among the four years.
The incidence of T1D in Sardinia, unlike in other countries such as Finland, has almost doubled in the last 20 years, and currently, it appears to be the highest in the world.
Background:
As the use of continuous glucose monitoring (CGM) increases, there is a need to better understand key metrics of time in range 70-180 mg/dL (TIR70-180) and hyperglycemia and how they ...relate to hemoglobin A1c (A1C).
Methods:
Analyses were conducted utilizing datasets from four randomized trials encompassing 545 adults with type 1 diabetes (T1D) who had central-laboratory measurements of A1C. CGM metrics were calculated and compared with each other and A1C cross-sectionally and longitudinally.
Results:
Correlations among CGM metrics (TIR70-180, time >180 mg/dL, time >250 mg/dL, mean glucose, area under the curve above 180 mg/dL, high blood glucose index, and time in range 70-140 mg/dL) were typically 0.90 or greater. Correlations of each metric with A1C were lower (absolute values 0.66-0.71 at baseline and 0.73-0.78 at month 6). For a given TIR70-180 percentage, there was a wide range of possible A1C levels that could be associated with that TIR70-180 level. On average, a TIR70-180 of 70% and 50% corresponded with an A1C of approximately 7% and 8%, respectively. There also was considerable spread of change in A1C for a given change in TIR70-180, and vice versa. An increase in TIR70-180 of 10% (2.4 hours per day) corresponded to a decrease in A1C of 0.6%, on average.
Conclusions:
In T1D, CGM measures reflecting hyperglycemia (including TIR and mean glucose) are highly correlated with each other but only moderately correlated with A1C. For a given TIR or change in TIR there is a wide range of possible corresponding A1C values.
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