OGTT Metrics Surpass Continuous Glucose Monitoring Data for T1D Prediction in Multiple-Autoantibody-Positive Individuals.

CONTEXT: The value of continuous glucose monitoring (CGM) for monitoring autoantibody (AAB)-positive individuals in clinical trials for progression of type 1 diabetes (T1D) is unknown. OBJECTIVE: Compare CGM with oral glucose tolerance test (OGTT)-based metrics in prediction of T1D. METHODS: At academic centers, OGTT and CGM data from multiple-AAB relatives were evaluated for associations with T1D diagnosis. Participants were multiple-AAB-positive individuals in a TrialNet Pathway to Prevention (TN01) CGM ancillary study (n = 93). The intervention was CGM for 1 week at baseline, 6 months, and 12 months. Receiver operating characteristic (ROC) curves of CGM and OGTT metrics for prediction of T1D were analyzed. RESULTS: Five of 7 OGTT metrics and 29/48 CGM metrics but not HbA1c differed between those who subsequently did or did not develop T1D. ROC area under the curve (AUC) of individual CGM values ranged from 50% to 69% and increased when adjusted for age and AABs. However, the highest-ranking metrics were derived from OGTT: 4/7 with AUC ∼80%. Compared with adjusted multivariable models using CGM data, OGTT-derived variables, Index60 and DPTRS (Diabetes Prevention Trial-Type 1 Risk Score), had higher discriminative ability (higher ROC AUC and positive predictive value with similar negative predictive value). CONCLUSION: Every 6-month CGM measures in multiple-AAB-positive individuals are predictive of subsequent T1D, but less so than OGTT-derived variables. CGM may have feasibility advantages and be useful in some settings. However, our data suggest there is insufficient evidence to replace OGTT measures with CGM in the context of clinical trials.

IL-6 receptor blockade does not slow ß cell loss in new-onset type 1 diabetes.

BackgroundIL-6 receptor (IL-6R) signaling drives development of T cell populations important to type 1 diabetes pathogenesis. We evaluated whether blockade of IL-6R with monoclonal antibody tocilizumab would slow loss of residual ß cell function in newly diagnosed type 1 diabetes patients.MethodsWe conducted a multicenter, randomized, placebo-controlled, double-blind trial with tocilizumab in new-onset type 1 diabetes. Participants were screened within 100 days of diagnosis. Eligible participants were randomized 2:1 to receive 7 monthly doses of tocilizumab or placebo. The primary outcome was the change from screening in the mean AUC of C-peptide collected during the first 2 hours of a mixed meal tolerance test at week 52 in pediatric participants (ages 6-17 years).ResultsThere was no statistical difference in the primary outcome between tocilizumab and placebo. Immunophenotyping showed reductions in downstream signaling of the IL-6R in T cells but no changes in CD4 memory subsets, Th17 cells, Tregs, or CD4+ T effector cell resistance to Treg suppression. A DC subset decreased during therapy but regressed to baseline once therapy stopped. Tocilizumab was well tolerated.ConclusionTocilizumab reduced T cell IL-6R signaling but did not modulate CD4+ T cell phenotypes or slow loss of residual ß cell function in newly diagnosed individuals with type 1 diabetes.Trial RegistrationClinicalTrials.gov NCT02293837.FundingNIH National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and National Institute of Allergy and Infectious Diseases (NIAID) UM1AI109565, UL1TR000004 from NIH/National Center for Research Resources (NCRR) Clinical and Translational Science Award (CTSA), NIH/NIDDK P30DK036836, NIH/NIDDK U01DK103266, NIH/NIDDK U01DK103266, 1UL1TR000064 from NIH/NCRR CTSA, NIH/National Center for Advancing Translational Sciences (NCATS) UL1TR001878, UL1TR002537 from NIH/CTSA; National Health and Medical Research Council Practitioner Fellowship (APP1136735), NIH/NIDDK U01-DK085476, NIH/CTSA UL1-TR002494, Indiana Clinical and Translational Science Institute Award UL1TR002529, Vanderbilt Institute for Clinical and Translational Research UL1TR000445. NIH/NCATS UL1TR003142, NIH/CTSA program UL1-TR002494, Veteran Affairs Administration, and 1R01AI132774.

Imatinib therapy for patients with recent-onset type 1 diabetes: a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial.

BACKGROUND: Type 1 diabetes results from autoimmune-mediated destruction of ß cells. The tyrosine kinase inhibitor imatinib might affect relevant immunological and metabolic pathways, and preclinical studies show that it reverses and prevents diabetes. Our aim was to evaluate the safety and efficacy of imatinib in preserving ß-cell function in patients with recent-onset type 1 diabetes. METHODS: We did a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. Patients with recent-onset type 1 diabetes (<100 days from diagnosis), aged 18-45 years, positive for at least one type of diabetes-associated autoantibody, and with a peak stimulated C-peptide of greater than 0·2 nmol L-1 on a mixed meal tolerance test (MMTT) were enrolled from nine medical centres in the USA (n=8) and Australia (n=1). Participants were randomly assigned (2:1) to receive either 400 mg imatinib mesylate (4 × 100 mg film-coated tablets per day) or matching placebo for 26 weeks via a computer-generated blocked randomisation scheme stratified by centre. Treatment assignments were masked for all participants and study personnel except pharmacists at each clinical site. The primary endpoint was the difference in the area under the curve (AUC) mean for C-peptide response in the first 2 h of an MMTT at 12 months in the imatinib group versus the placebo group, with use of an ANCOVA model adjusting for sex, baseline age, and baseline C-peptide, with further observation up to 24 months. The primary analysis was by intention to treat (ITT). Safety was assessed in all randomly assigned participants. This study is registered with ClinicalTrials.gov, NCT01781975 (completed). FINDINGS: Patients were screened and enrolled between Feb 12, 2014, and May 19, 2016. 45 patients were assigned to receive imatinib and 22 to receive placebo. After withdrawals, 43 participants in the imatinib group and 21 in the placebo group were included in the primary ITT analysis at 12 months. The study met its primary endpoint: the adjusted mean difference in 2-h C-peptide AUC at 12 months for imatinib versus placebo treatment was 0·095 (90% CI -0·003 to 0·191; p=0·048, one-tailed test). This effect was not sustained out to 24 months. During the 24-month follow-up, 32 (71%) of 45 participants who received imatinib had a grade 2 severity or worse adverse event, compared with 13 (59%) of 22 participants who received placebo. The most common adverse events (grade 2 severity or worse) that differed between the groups were gastrointestinal issues (six [13%] participants in the imatinib group, primarily nausea, and none in the placebo group) and additional laboratory investigations (ten [22%] participants in the imatinib group and two [9%] in the placebo group). Per the trial protocol, 17 (38%) participants in the imatinib group required a temporary modification in drug dosing and six (13%) permanently discontinued imatinib due to adverse events; five (23%) participants in the placebo group had temporary modifications in dosing and none had a permanent discontinuation due to adverse events. INTERPRETATION: A 26-week course of imatinib preserved ß-cell function at 12 months in adults with recent-onset type 1 diabetes. Imatinib might offer a novel means to alter the course of type 1 diabetes. Future considerations are defining ideal dose and duration of therapy, safety and efficacy in children, combination use with a complimentary drug, and ability of imatinib to delay or prevent progression to diabetes in an at-risk population; however, careful monitoring for possible toxicities is required. FUNDING: Juvenile Research Diabetes Foundation.

Islets Transplantation at a Crossroads - Need for Urgent Regulatory Update in the United States: Perspective Presented During the Scientific Sessions 2021 at the American Diabetes Association Congress.

Clinical islet allotransplantation has been successfully regulated as tissue/organ for transplantation in number of countries and is recognized as a safe and efficacious therapy for selected patients with type 1 diabetes mellitus. However, in the United States, the FDA considers pancreatic islets as a biologic drug, and islet transplantation has not yet shifted from the experimental to the clinical arena for last 20 years. In order to transplant islets, the FDA requires a valid Biological License Application (BLA) in place. The BLA process is costly and lengthy. However, despite the application of drug manufacturing technology and regulations, the final islet product sterility and potency cannot be confirmed, even when islets meet all the predetermined release criteria. Therefore, further regulation of islets as drugs is obsolete and will continue to hinder clinical application of islet transplantation in the US. The Organ Procurement and Transplantation Network together with the United Network for Organ Sharing have developed separately from the FDA and BLA regulatory framework for human organs under the Human Resources & Services Administration to assure safety and efficacy of transplantation. Based on similar biologic characteristics of islets and human organs, we propose inclusion of islets into the existing regulatory framework for organs for transplantation, along with continued FDA oversight for islet processing, as it is for other cell/tissue products exempt from BLA. This approach would reassure islet quality, efficacy and access for Americans with diabetes to this effective procedure.

The demise of islet allotransplantation in the United States: A call for an urgent regulatory update.

Islet allotransplantation in the United States (US) is facing an imminent demise. Despite nearly three decades of progress in the field, an archaic regulatory framework has stymied US clinical practice. Current regulations do not reflect the state-of-the-art in clinical or technical practices. In the US, islets are considered biologic drugs and "more than minimally manipulated" human cell and tissue products (HCT/Ps). In contrast, across the world, human islets are appropriately defined as "minimally manipulated tissue" and not regulated as a drug, which has led to islet allotransplantation (allo-ITx) becoming a standard-of-care procedure for selected patients with type 1 diabetes mellitus. This regulatory distinction impedes patient access to islets for transplantation in the US. As a result only 11 patients underwent allo-ITx in the US between 2016 and 2019, and all as investigational procedures in the settings of a clinical trials. Herein, we describe the current regulations pertaining to islet transplantation in the United States. We explore the progress which has been made in the field and demonstrate why the regulatory framework must be updated to both better reflect our current clinical practice and to deal with upcoming challenges. We propose specific updates to current regulations which are required for the renaissance of ethical, safe, effective, and affordable allo-ITx in the United States.

Noninvasive mapping of pancreatic inflammation in recent-onset type-1 diabetes patients.

The inability to visualize the initiation and progression of type-1 diabetes (T1D) noninvasively in humans is a major research and clinical stumbling block. We describe an advanced, exportable method for imaging the pancreatic inflammation underlying T1D, based on MRI of the clinically approved magnetic nanoparticle (MNP) ferumoxytol. The MNP-MRI approach, which reflects nanoparticle uptake by macrophages in the inflamed pancreatic lesion, has been validated extensively in mouse models of T1D and in a pilot human study. The methodological advances reported here were enabled by extensive optimization of image acquisition at 3T, as well as by the development of improved MRI registration and visualization technologies. A proof-of-principle study on patients recently diagnosed with T1D versus healthy controls yielded two major findings: First, there was a clear difference in whole-pancreas nanoparticle accumulation in patients and controls; second, the patients with T1D exhibited pronounced inter- and intrapancreatic heterogeneity in signal intensity. The ability to generate noninvasive, 3D, high-resolution maps of pancreatic inflammation in autoimmune diabetes should prove invaluable in assessing disease initiation and progression and as an indicator of response to emerging therapies.

Evaluation of renal quantitative T2* changes on MRI following administration of ferumoxytol as a T2* contrast agent.

PURPOSE: To evaluate the time-dependent changes in regional quantitative T2* maps of the kidney following intravenous administration of ferumoxytol. MATERIALS AND METHODS: Twenty-four individuals with normal kidney function underwent T2*-weighted MRI of the kidney before, immediately after, and 48 hours after intravenous administration of ferumoxytol at a dose of 4 mg/kg (group A, n=12) or 6 mg/kg (group B, n=12). T2* values were statistically analyzed using two-tailed paired t-tests. RESULTS: In group A, the percentage changes from baseline to immediate post and baseline to 48 hours were 85.3% and 64.2% for the cortex and 90.8% and 64.6% for the medulla, respectively. In group B, the percentage changes from baseline to immediate post and baseline to 48 hours were 85.2% and 73.4% for the cortex and 94.5% and 74% for the medulla, respectively. This difference was significant for both groups (P<0.0001). CONCLUSION: There is significant and differential uptake of ferumoxytol in the cortex and medulla of physiologically normal kidneys. This differential uptake may offer the ability to interrogate renal cortex and medulla with possible clinical applications in medical renal disease and transplant organ assessment. We propose an organ of interest based dose titration of ferumoxytol to better differentiate circulating from intracellular ferumoxytol particles.

A Computer-Interpretable Version of the AACE, AME, ETA Medical Guidelines for Clinical Practice for the Diagnosis and Management of Thyroid Nodules.

OBJECTIVE: Clinical practice guidelines (CPGs) could have a more consistent and meaningful impact on clinician behavior if they were delivered as electronic algorithms that provide patient-specific advice during patient-physician encounters. We developed a computer-interpretable algorithm for U.S. and European users for the purpose of diagnosis and management of thyroid nodules that is based on the "AACE, AME, ETA Medical Guidelines for Clinical Practice for the Diagnosis and Management of Thyroid Nodules," a narrative, evidence-based CPG. METHODS: We initially employed the guideline-modeling language GuideLine Interchange Format, version 3, known as GLIF3, which emphasizes the organization of a care algorithm into a flowchart. The flowchart specified the sequence of tasks required to evaluate a patient with a thyroid nodule. PROforma, a second guideline-modeling language, was then employed to work with data that are not necessarily obtained in a rigid flowchart sequence. Tallis-a user-friendly web-based "enactment tool"- was then used as the "execution engine" (computer program). This tool records and displays tasks that are done and prompts users to perform the next indicated steps. The development process was iteratively performed by clinical experts and knowledge engineers. RESULTS: We developed an interactive web-based electronic algorithm that is based on a narrative CPG. This algorithm can be used in a variety of regions, countries, and resource-specific settings. CONCLUSION: Electronic guidelines provide patient-specific decision support that could standardize care and potentially improve the quality of care. The "demonstrator" electronic thyroid nodule guideline that we describe in this report is available at http://demos.deontics.com/trace-review-app (username: reviewer; password: tnodule1). The demonstrator must be more extensively "trialed" before it is recommended for routine use.

Soluble factors secreted by T cells promote ß-cell proliferation.

Type 1 diabetes is characterized by infiltration of pancreatic islets with immune cells, leading to insulin deficiency. Although infiltrating immune cells are traditionally considered to negatively impact ß-cells by promoting their death, their contribution to proliferation is not fully understood. Here we report that islets exhibiting insulitis also manifested proliferation of ß-cells that positively correlated with the extent of lymphocyte infiltration. Adoptive transfer of diabetogenic CD4(+) and CD8(+) T cells, but not B cells, selectively promoted ß-cell proliferation in vivo independent from the effects of blood glucose or circulating insulin or by modulating apoptosis. Complementary to our in vivo approach, coculture of diabetogenic CD4(+) and CD8(+) T cells with NOD.RAG1(-/-) islets in an in vitro transwell system led to a dose-dependent secretion of candidate cytokines/chemokines (interleukin-2 [IL-2], IL-6, IL-10, MIP-1α, and RANTES) that together enhanced ß-cell proliferation. These data suggest that soluble factors secreted from T cells are potential therapeutic candidates to enhance ß-cell proliferation in efforts to prevent and/or delay the onset of type 1 diabetes.

Primary hyperparathyroidism and familial hypocalciuric hypercalcemia: relationships and clinical implications.

OBJECTIVE: To discuss the unusual occurrence of both familial hypocalciuric hypercalcemia (FHH) and primary hyperparathyroidism in the same patient and to explore potential mechanisms of association and issues related to clinical management. METHODS: We discuss the diagnosis, compare the clinical presentations of FHH and primary hyperparathyroidism, review the literature regarding patients who have presented with both disorders, and discuss management considerations. We also describe 2 patients who have both FHH (confirmed by genetic testing for a mutation in the gene encoding the calcium-sensing receptor [CASR]) and primary hyperparathyroidism. RESULTS: The occurrence of both FHH and primary hyperparathyroidism in the same patient has been reported in a few cases, including 2 patients described here, one of whom was documented to have a novel CASR mutation. In those with clinical sequelae of hyperparathyroidism, parathyroidectomy has led to reduction, but not normalization, of serum calcium levels. CONCLUSIONS: The coexistence of FHH and primary hyperparathyroidism should be considered in patients with hypercalcemia, hypophosphatemia, frankly elevated parathyroid hormone levels, and low urinary calcium excretion. Genetic testing for inactivating CASR gene mutations can confirm the diagnosis of FHH. Although surgical intervention does not resolve hypercalcemia, it may be beneficial by reducing the degree of hypercalcemia, alleviating the symptoms, and preventing potential complications of hyperparathyroidism.

Noninvasive imaging of pancreatic islet inflammation in type 1A diabetes patients.

Type 1A diabetes (T1D) is an autoimmune disease characterized by leukocyte infiltration of the pancreatic islets of Langerhans. A major impediment to advances in understanding, preventing, and curing T1D has been the inability to "see" the disease initiate, progress, or regress, especially during the occult phase. Here, we report the development of a noninvasive method to visualize T1D at the target organ level in patients with active insulitis. Specifically, we visualized islet inflammation, manifest by microvascular changes and monocyte/macrophage recruitment and activation, using magnetic resonance imaging of magnetic nanoparticles (MNPs). As a proof of principle for this approach, imaging of infused ferumoxtran-10 nanoparticles permitted effective visualization of the pancreas and distinction of recent-onset diabetes patients from nondiabetic controls. The observation that MNPs accumulate in the pancreas of T1D patients opens the door to exploiting this noninvasive imaging method to follow T1D progression and monitoring the ability of immunomodulatory agents to clear insulitis.

Noninvasive imaging of islet transplantation and rejection.

Immunologic and nonimmunologic events lead to significant graft loss after islet transplantation. Unfortunately, current metabolic testing methods are inadequate to detect many of these changes, leading to a critical need for noninvasive monitoring of islet rejection. However, their small size and distribution after transplantation pose specific problems for direct islet imaging. This article reviews the relative merits of several imaging modalities for the noninvasive monitoring of islet transplantation and rejection.

Islet recovery and reversal of murine type 1 diabetes in the absence of any infused spleen cell contribution.

A cure for type 1 diabetes will probably require the provision or elicitation of new pancreatic islet beta cells as well as the reestablishment of immunological tolerance. A 2003 study reported achievement of both advances in the NOD mouse model by coupling injection of Freund's complete adjuvant with infusion of allogeneic spleen cells. It was concluded that the adjuvant eliminated anti-islet autoimmunity and the donor splenocytes differentiated into insulin-producing (presumably beta) cells, culminating in islet regeneration. Here, we provide data indicating that the recovered islets were all of host origin, reflecting that the diabetic NOD mice actually retain substantial beta cell mass, which can be rejuvenated/regenerated to reverse disease upon adjuvant-dependent dampening of autoimmunity.

Islet transplantation: progress and challenge.

For over 30 years, investigators have explored islet transplantation as a logical approach to restoring glucose homeostasis in persons with diabetes. Islet transplantation can currently provide improved glycemic control, relief from recurrent severe hypoglycemia, and potentially insulin independence. In this review, we describe details of the evolution of modern islet transplantation and provide insight into ongoing clinical and basic research efforts to overcome current obstacles for this promising therapy.

Acute hyperglycemic crisis in the elderly.

The geriatric population is at particular risk for developing hyperglycemic crises with the development of diabetes. With increasing age, insulin secretory reserve, insulin sensitivity, and thirst mechanisms decrease. The elderly are particularly vulnerable to hyperglycemia and dehydration, the key components of hyperglycemic emergencies. If recognized early, hyperglycemia can frequently be treated in the outpatient setting even with moderate or large ketonuria, provided patients can take fluids, monitor blood glucose frequently, and follow standard "sick day rules." With increased diabetes surveillance and aggressive early treatment of hyperglycemia and its complications, morbidity and mortality from acute diabetic crises in the geriatric population can be greatly reduced.

Benefits and risks of solitary islet transplantation for type 1 diabetes using steroid-sparing immunosuppression: the National Institutes of Health experience.

OBJECTIVE: The aim of this study was to describe the National Institutes of Health's experience initiating an islet isolation and transplantation center, including descriptions of our first six recipients, and lessons learned. RESEARCH DESIGN AND METHODS: Six females with chronic type 1 diabetes, hypoglycemia unawareness, and no endogenous insulin secretion (undetectable serum C-peptide) were transplanted with allogenic islets procured from brain dead donors. To prevent islet rejection, patients received daclizumab, sirolimus, and tacrolimus. RESULTS: All patients noted less frequent and less severe hypoglycemia, and one-half were insulin independent at 1 year. Serum C-peptide persists in all but one patient (follow-up 17-22 months), indicating continued islet function. Two major procedure-related complications occurred: partial portal vein thrombosis and intra-abdominal hemorrhage. While we observed no cytomegalovirus infection or malignancy, recipients frequently developed transient mouth ulcers, diarrhea, edema, hypercholesterolemia, weight loss, myelosuppression, and other symptoms. Three patients discontinued immunosuppressive therapy: two because of intolerable toxicity (deteriorating kidney function and sirolimus-induced pneumonitis) while having evidence for continued islet function (one was insulin independent) and one because of gradually disappearing islet function. CONCLUSIONS: We established an islet isolation and transplantation program and achieved a 50% insulin-independence rate after at most two islet infusions. Our experience demonstrates that centers not previously engaged in islet transplantation can initiate a program, and our data and literature analysis support not only the promise of islet transplantation but also its remaining hurdles, which include the limited islet supply, procedure-associated complications, imperfect immunosuppressive regimens, suboptimal glycemia control, and loss of function over time.

Th1-specific cell surface protein Tim-3 regulates macrophage activation and severity of an autoimmune disease.

Activation of naive CD4(+) T-helper cells results in the development of at least two distinct effector populations, Th1 and Th2 cells. Th1 cells produce cytokines (interferon (IFN)-gamma, interleukin (IL)-2, tumour-necrosis factor (TNF)-alpha and lymphotoxin) that are commonly associated with cell-mediated immune responses against intracellular pathogens, delayed-type hypersensitivity reactions, and induction of organ-specific autoimmune diseases. Th2 cells produce cytokines (IL-4, IL-10 and IL-13) that are crucial for control of extracellular helminthic infections and promote atopic and allergic diseases. Although much is known about the functions of these two subsets of T-helper cells, there are few known surface molecules that distinguish between them. We report here the identification and characterization of a transmembrane protein, Tim-3, which contains an immunoglobulin and a mucin-like domain and is expressed on differentiated Th1 cells. In vivo administration of antibody to Tim-3 enhances the clinical and pathological severity of experimental autoimmune encephalomyelitis (EAE), a Th1-dependent autoimmune disease, and increases the number and activation level of macrophages. Tim-3 may have an important role in the induction of autoimmune diseases by regulating macrophage activation and/or function.