Slowed Metabolic Decline After 1 Year of Oral Insulin Treatment Among Individuals at High Risk for Type 1 Diabetes in the Diabetes Prevention Trial-Type 1 (DPT-1) and TrialNet Oral Insulin Prevention Trials.

We assessed whether oral insulin slowed metabolic decline after 1 year of treatment in individuals at high risk for type 1 diabetes. Two oral insulin trials that did not show efficacy overall and had type 1 diabetes as the primary end point were analyzed: the Diabetes Prevention Trial-Type 1 (DPT-1) and the TrialNet oral insulin trials. Oral glucose tolerance tests at baseline and after 1 year of treatment were analyzed. Among those at high risk (with a Diabetes Prevention Trial-Type 1 Risk Score [DPTRS] ≥6.75), the area under the curve (AUC) C-peptide increased significantly from baseline to 1 year in each oral insulin group, whereas the AUC glucose increased significantly in each placebo group. At 1 year, the AUC C-peptide/AUC glucose (AUC Ratio) was significantly higher in the oral insulin group than in the placebo group in each trial (P < 0.05; P = 0.057 when adjusted for age in the TrialNet trial) and in both trials combined (P < 0.01 with or without adjustment for age). For a DPTRS <6.75, oral insulin groups did not differ from placebo groups in the AUC Ratio. The findings suggest that 1 year of treatment with oral insulin slows metabolic deterioration in individuals at high risk for type 1 diabetes. Moreover, the findings further suggest that metabolic end points can be useful adjuncts to the diagnostic end point in assessments of preventive treatments for the disorder.

Provider-Guided Emergency Support for Persons Living With Type 1 Diabetes During Hurricanes Harvey, Irma, and Maria.

The 2017 Atlantic hurricane season was especially memorable for 3 major hurricanes-Harvey, Irma, and Maria-that devastated population centers across Texas, Florida, and Puerto Rico, respectively. Each storm had unique hazard properties that posed distinctive challenges for persons living with type 1 diabetes (T1D). Diabetes care specialists and educators took on leadership roles for coordinating care and establishing insulin supply lifelines for people with T1D living in the hardest-hit neighborhoods affected by these extreme storms. Strategies and resources were customized for each population. Diabetes specialists strategized to provide mutual support and shared insulins and supplies across sites.

Who Is Enrolling? The Path to Monitoring in Type 1 Diabetes TrialNet's Pathway to Prevention.

OBJECTIVE: To better understand potential facilitators of individual engagement in type 1 diabetes natural history and prevention studies through analysis of enrollment data in the TrialNet Pathway to Prevention (PTP) study. RESEARCH DESIGN AND METHODS: We used multivariable logistic regression models to examine continued engagement of eligible participants at two time points: 1) the return visit after screening to confirm an initial autoantibody-positive (Ab+) test result and 2) the initial oral glucose tolerance test (OGTT) for enrollment into the monitoring protocol. RESULTS: Of 5,387 subjects who screened positive for a single autoantibody (Ab), 4,204 (78%) returned for confirmatory Ab testing. Younger age was associated with increased odds of returning for Ab confirmation (age <12 years vs. >18 years: odds ratio [OR] 2.12, P < 0.0001). Racial and ethnic minorities were less likely to return for confirmation, particularly nonwhite non-Hispanic (OR 0.50, P < 0.0001) and Hispanic (OR 0.69, P = 0.0001) relative to non-Hispanic white subjects. Of 8,234 subjects, 5,442 (66%) were identified as eligible to be enrolled in PTP OGTT monitoring. Here, younger age and identification as multiple Ab+ were associated with increased odds of returning for OGTT monitoring (age <12 years vs. >18 years: OR 1.43, P < 0.0001; multiple Ab+: OR 1.36, P < 0.0001). Parents were less likely to enroll into monitoring than other relatives (OR 0.78, P = 0.004). Site-specific factors, including site volume and U.S. site versus international site, were also associated with differences in rates of return for Ab+ confirmation and enrollment into monitoring. CONCLUSIONS: These data confirm clear differences between successfully enrolled populations and those lost to follow-up, which can serve to identify strategies to increase ongoing participation.

Use of Dried Capillary Blood Sampling for Islet Autoantibody Screening in Relatives: A Feasibility Study.

BACKGROUND: Islet autoantibody testing provides the basis for assessment of risk of progression to type 1 diabetes. We set out to determine the feasibility and acceptability of dried capillary blood spot-based screening to identify islet autoantibody-positive relatives potentially eligible for inclusion in prevention trials. MATERIALS AND METHODS: Dried blood spot (DBS) and venous samples were collected from 229 relatives participating in the TrialNet Pathway to Prevention Study. Both samples were tested for glutamic acid decarboxylase, islet antigen 2, and zinc transporter 8 autoantibodies, and venous samples were additionally tested for insulin autoantibodies and islet cell antibodies. We defined multiple autoantibody positive as two or more autoantibodies in venous serum and DBS screen positive if one or more autoantibodies were detected. Participant questionnaires compared the sample collection methods. RESULTS: Of 44 relatives who were multiple autoantibody positive in venous samples, 42 (95.5%) were DBS screen positive, and DBS accurately detected 145 of 147 autoantibody-negative relatives (98.6%). Capillary blood sampling was perceived as more painful than venous blood draw, but 60% of participants would prefer initial screening using home fingerstick with clinic visits only required if autoantibodies were found. CONCLUSIONS: Capillary blood sampling could facilitate screening for type 1 diabetes prevention studies.

The development and utility of a novel scale that quantifies the glycemic progression toward type 1 diabetes over 6 months.

OBJECTIVE: We developed a scale to serve as a potential end point for 6-month glycemic progression (PS6M) toward type 1 diabetes (T1D) in autoantibody-positive relatives of individuals with T1D. RESEARCH DESIGN AND METHODS: The PS6M was developed from Diabetes Prevention Trial-Type 1 (DPT-1) data and tested in the TrialNet Pathway to Prevention Study (PTP). It is the difference between 6-month glucose sum values (30-120 min oral glucose tolerance test values) and values predicted for nonprogressors. RESULTS: The PS6M predicted T1D in the PTP (P < 0.001). The area under the receiver operating chacteristic curve was greater (P < 0.001) for the PS6M than for the baseline-to-6-month difference. PS6M values were higher in those with two or more autoantibodies, 30-0 min C-peptide values <2.00 ng/mL, or DPT-1 Risk Scores >7.00 (P < 0.001 for all). CONCLUSIONS: The PS6M is an indicator of short-term glycemic progression to T1D that could be a useful tool for assessing preventive treatments and biomarkers.

A new approach for diagnosing type 1 diabetes in autoantibody-positive individuals based on prediction and natural history.

OBJECTIVE: We assessed whether type 1 diabetes (T1D) can be diagnosed earlier using a new approach based on prediction and natural history in autoantibody-positive individuals. RESEARCH DESIGN AND METHODS: Diabetes Prevention Trial-Type 1 (DPT-1) and TrialNet Natural History Study (TNNHS) participants were studied. A metabolic index, the T1D Diagnostic Index60 (Index60), was developed from 2-h oral glucose tolerance tests (OGTTs) using the log fasting C-peptide, 60-min C-peptide, and 60-min glucose. OGTTs with Index60 ≥2.00 and 2-h glucose <200 mg/dL (Ind60+Only) were compared with Index60 <2.00 and 2-h glucose ≥200 mg/dL (2hglu+Only) OGTTs as criteria for T1D. Individuals were assessed for C-peptide loss from the first Ind60+Only OGTT to diagnosis. RESULTS: Areas under receiver operating characteristic curves were significantly higher for Index60 than for the 2-h glucose (P < 0.001 for both DPT-1 and the TNNHS). As a diagnostic criterion, sensitivity was higher for Ind60+Only than for 2hglu+Only (0.44 vs. 0.15 in DPT-1; 0.26 vs. 0.17 in the TNNHS) OGTTs. Specificity was somewhat higher for 2hglu+Only OGTTs in DPT-1 (0.97 vs. 0.91) but equivalent in the TNNHS (0.98 for both). Positive and negative predictive values were higher for Ind60+Only OGTTs in both studies. Postchallenge C-peptide levels declined significantly at each OGTT time point from the first Ind60+Only OGTT to the time of standard diagnosis (range -22 to -34% in DPT-1 and -14 to -27% in the TNNHS). C-peptide and glucose patterns differed markedly between Ind60+Only and 2hglu+Only OGTTs. CONCLUSIONS: An approach based on prediction and natural history appears to have utility for diagnosing T1D.

Use of the Diabetes Prevention Trial-Type 1 Risk Score (DPTRS) for improving the accuracy of the risk classification of type 1 diabetes.

OBJECTIVE We studied the utility of the Diabetes Prevention Trial-Type 1 Risk Score (DPTRS) for improving the accuracy of type 1 diabetes (T1D) risk classification in TrialNet Natural History Study (TNNHS) participants. RESEARCH DESIGN AND METHODS The cumulative incidence of T1D was compared between normoglycemic individuals with DPTRS values >7.00 and dysglycemic individuals in the TNNHS (n = 991). It was also compared between individuals with DPTRS values <7.00 or >7.00 among those with dysglycemia and those with multiple autoantibodies in the TNNHS. DPTRS values >7.00 were compared with dysglycemia for characterizing risk in Diabetes Prevention Trial-Type 1 (DPT-1) (n = 670) and TNNHS participants. The reliability of DPTRS values >7.00 was compared with dysglycemia in the TNNHS. RESULTS The cumulative incidence of T1D for normoglycemic TNNHS participants with DPTRS values >7.00 was comparable to those with dysglycemia. Among those with dysglycemia, the cumulative incidence was much higher (P < 0.001) for those with DPTRS values >7.00 than for those with values <7.00 (3-year risks: 0.16 for <7.00 and 0.46 for >7.00). Dysglycemic individuals in DPT-1 were at much higher risk for T1D than those with dysglycemia in the TNNHS (P < 0.001); there was no significant difference in risk between the studies among those with DPTRS values >7.00. The proportion in the TNNHS reverting from dysglycemia to normoglycemia at the next visit was higher than the proportion reverting from DPTRS values >7.00 to values <7.00 (36 vs. 23%). CONCLUSIONS DPTRS thresholds can improve T1D risk classification accuracy by identifying high-risk normoglycemic and low-risk dysglycemic individuals. The 7.00 DPTRS threshold characterizes risk more consistently between populations and has greater reliability than dysglycemia.

Acceleration of the loss of the first-phase insulin response during the progression to type 1 diabetes in diabetes prevention trial-type 1 participants.

We studied the change in the first-phase insulin response (FPIR) during the progression to type 1 diabetes (T1D). Seventy-four oral insulin trial progressors to T1D from the Diabetes Prevention Trial-Type 1 with at least one FPIR measurement after baseline and before diagnosis were studied. The FPIR was examined longitudinally in 26 progressors who had FPIR measurements during each of the 3 years before diagnosis. The association between the change from the baseline FPIR to the last FPIR and time to diagnosis was studied in the remainder (n = 48). The 74 progressors had lower baseline FPIR values than nonprogressors (n = 270), with adjustments made for age and BMI. In the longitudinal analysis of the 26 progressors, there was a greater decline in the FPIR from 1.5 to 0.5 years before diagnosis than from 2.5 to 1.5 years before diagnosis. This accelerated decline was also evident in a regression analysis of the 48 remaining progressors in whom the rate of decline became more marked with the approaching diagnosis. The patterns of decline were similar between the longitudinal and regression analyses. There is an acceleration of decline in the FPIR during the progression to T1D, which becomes especially marked between 1.5 and 0.5 years before diagnosis.

Decision-making in diabetes mellitus type 1.

Decreased treatment adherence in patients with diabetes mellitus type 1 (type 1 DM) may reflect impairments in decision-making and underlying associated deficits in working memory and executive functioning. Other factors, including comorbid major depression, may also interfere with decision-making. The authors sought to review the clinically relevant characteristics of decision-making in type 1 DM by surveying the literature on decision-making by patients with type 1 DM. Deficiencies in decision-making in patients with type 1 DM or their caregivers contribute to treatment nonadherence and poorer metabolic control. Animal models of type 1 DM reveal deficits in hippocampal-dependent memory tasks, which are reversible with insulin. Neurocognitive studies of patients with type 1 DM reveal lowered performance on ability to apply knowledge to solve problems in a new situation and acquired scholarly knowledge, psychomotor efficiency, cognitive flexibility, visual perception, speed of information-processing, and sustained attention. Other factors that might contribute to poor decision-making in patients with type 1 DM, include "hypoglycemia unawareness" and comorbid major depression (given its increased prevalence in type 1 DM). Future studies utilizing novel treatment strategies to help patients with type 1 DM make better decisions about their disease may improve their glycemic control and quality of life, while minimizing the impact of end-organ disease.

Immune profiling by multiple gene expression analysis in patients at-risk and with type 1 diabetes.

There is a need for biomarkers to monitor the development and progression of type 1 DM. We analyzed mRNA expression levels for granzyme B, perforin, fas ligand, TNF-α, IFN-γ, Foxp3, IL-10, TGF-ß, IL-4, IL-6, IL-17, Activation-induced cytidine deaminase (AID) and Immunoglobulin G gamma chain (IgG) genes in peripheral blood of at-risk, new-onset and long-term type 1 DM , and healthy controls. The majority of the genes were suppressed in long-term type 1 DM compared to controls and new-onset patients. IFN-γ, IL-4 and IL-10 mRNA levels were significantly higher in new-onset compared to at-risk and long-term groups. There was decreased mRNA expression for AID and IgG and up-regulation of IFN-γ with age in controls. Data suggest an overall depressed immunity in long-term type 1 DM. Increased gene expression levels for IFN-γ, IL-4 and IL-10 in new-onset patients from at-risk patients might be used as potential markers for progression of the disease.

Glucose and C-peptide changes in the perionset period of type 1 diabetes in the Diabetes Prevention Trial-Type 1.

OBJECTIVE: We examined metabolic changes in the period immediately after the diagnosis of type 1 diabetes and in the period leading up to its diagnosis in Diabetes Prevention Trial-Type 1 (DPT-1) participants. RESEARCH DESIGN AND METHODS: The study included oral insulin trial participants and parenteral insulin trial control subjects (n = 63) in whom diabetes was diagnosed by a 2-h diabetic oral glucose tolerance test (OGTT) that was confirmed by another diabetic OGTT within 3 months. Differences in glucose and C-peptide levels between the OGTTs were assessed. RESULTS: Glucose levels increased at 90 (P = 0.006) and 120 min (P < 0.001) from the initial diabetic OGTT to the confirmatory diabetic OGTT (mean +/- SD interval 5.5 +/- 2.8 weeks). Peak C-peptide levels fell substantially between the OGTTs (median change -14.3%, P < 0.001). Among the 55 individuals whose last nondiabetic OGTT was approximately 6 months before the initial diabetic OGTT, peak C-peptide levels decreased between these two OGTTs (median change -14.0%, P = 0.052). Among those same individuals the median change in peak C-peptide levels from the last normal OGTT to the confirmatory OGTT (interval 7.5 +/- 1.3 months) was -23.8% (P < 0.001). Median rates of change in peak C-peptide levels were 0.00 ng x ml(-1) x month(-1) (P = 0.468, n = 36) from approximately 12 to 6 months before diagnosis, -0.10 ng x ml(-1) x month(-1) (P = 0.059, n = 55) from 6 months before diagnosis to diagnosis, and -0.43 ng x ml(-1) x month(-1) (P = 0.002, n = 63) from the initial diabetic OGTT to the confirmatory diabetic OGTT. CONCLUSIONS: It seems that postchallenge C-peptide levels begin to decrease appreciably in the 6 months before diagnosis and decrease even more rapidly within 3 months after diagnosis.

Unexplained hyperglycemia in continuous subcutaneous insulin infusion: evaluation and treatment.

PURPOSE: The purpose of this review study was to determine and categorize common causes of intermittent hyperglycemia and suggest potential measures to prevent and treat the identified causes. METHODS: A literature review was conducted to obtain relevant information on hyperglycemia and continuous subcutaneous insulin infusion (CSII). Medical departments from Novo/Nordisk, Eli Lilly and Company, and Sanofi/Aventis were contacted requesting information on their insulin temperature stability, the compatibility of insulin with insulin/pump reservoirs, and tubing sets/catheters. Endocrinologists, Certified Diabetes Educators, and pump manufacturing company trainers were interviewed for their clinical observations and to determine the incidence of reported hyperglycemia and relationships to pump failures. RESULTS: Causes of intermittent hyperglycemia in CSII patients included problems with mechanical evaluation of the pump, basal/bolus review, reservoir/tubing, catheter site selection/placement, and insulin compatibility/stability. CONCLUSIONS: As more patients and health care providers strive to improve control of diabetes, use of insulin pump therapy will continue to increase. Unexplained hyperglycemia will continue to occur, which can lead to increased health care costs due to complications such as diabetic ketoacidosis. Evaluation of patient techniques and pump programming can uncover many potential causes, and the health care provider can assist in patient education to prevent further episodes.