HLA-A2-Matched Peripheral Blood Mononuclear Cells From Type 1 Diabetic Patients, but Not Nondiabetic Donors, Transfer Insulitis to NOD-scid/ cnull/HLA-A2 Transgenic Mice Concurrent With the Expansion of Islet-Specific CD8+ T cells

OBJECTIVEType 1 diabetes is an autoimmune disease characterized by the destruction of insulin-producing β-cells. NOD mice provide a useful tool for understanding disease pathogenesis and progression. Although much has been learned from studies with NOD mice, increased understanding of human type 1 diabetes can be gained by evaluating the pathogenic potential of human diabetogenic effector cells in vivo. Therefore, our objective in this study was to develop a small-animal model using human effector cells to study type 1 diabetes.RESEARCH DESIGN AND METHODSWe adoptively transferred HLA-A2–matched peripheral blood mononuclear cells (PBMCs) from type 1 diabetic patients and nondiabetic control subjects into transgenic NOD-scid/γcnull/HLA-A*0201 (NOD-scid/γcnull/A2) mice. At various times after adoptive transfer, we determined the ability of these mice to support the survival and proliferation of the human lymphoid cells. Human lymphocytes were isolated and assessed from the blood, spleen, pancreatic lymph node and islets of NOD-scid/γcnull/A2 mice after transfer.RESULTSHuman T and B cells proliferate and survive for at least 6 weeks and were recovered from the blood, spleen, draining pancreatic lymph node, and most importantly, islets of NOD-scid/γcnull/A2 mice. Lymphocytes from type 1 diabetic patients preferentially infiltrate the islets of NOD-scid/γcnull/A2 mice. In contrast, PBMCs from nondiabetic HLA-A2–matched donors showed significantly less islet infiltration. Moreover, in mice that received PBMCs from type 1 diabetic patients, we identified epitope-specific CD8+ T cells among the islet infiltrates.CONCLUSIONSWe show that insulitis is transferred to NOD-scid/γcnull/A2 mice that received HLA-A2–matched PBMCs from type 1 diabetic patients. In addition, many of the infiltrating CD8+ T cells are epitope-specific and produce interferon-γ after in vitro peptide stimulation. This indicates that NOD-scid/γcnull/A2 mice transferred with HLA-A2–matched PBMCs from type 1 diabetic patients may serve as a useful tool for studying epitope-specific T-cell–mediated responses in patients with type 1 diabetes

Differences in the Management of Type 1 Diabetes Among Adults Under Excellent Control Compared With Those Under Poor Control in the T1D Exchange Clinic Registry

OBJECTIVEOptimizing glycemic control in type 1 diabetes is important to minimize the risk of complications. We used the large T1D Exchange clinic registry database to identify characteristics and diabetes management techniques in adults with type 1 diabetes, differentiating those under excellent glycemic control from those with poorer control.RESEARCH DESIGN AND METHODSThe cross-sectional analysis included 627 participants with HbA1c <6.5% (excellent control) and 1,267 with HbA1c ≥8.5% (fair/poor control) at enrollment who were ≥26 years of age (mean ± SD 45.9 ± 13.2 years), were not using continuous glucose monitoring, and had type 1 diabetes for ≥2 years (22.8 ± 13.0 years).RESULTSCompared with the fair/poor control group, participants in the excellent control group had higher socioeconomic status, were more likely to be older and married, were less likely to be overweight, were more likely to exercise frequently, and had lower total daily insulin dose per kilogram (P < 0.0001 for each). Excellent control was associated with more frequent self-monitoring of blood glucose (SMBG), giving mealtime boluses before a meal rather than at the time of or after a meal, performing SMBG before giving a bolus, and missing an insulin dose less frequently (P < 0.0001 for each). Frequency of severe hypoglycemia was similar between groups, whereas diabetic ketoacidosis was more common in the fair/poor control group.CONCLUSIONSDiabetes self-management related to insulin delivery, glucose monitoring, and lifestyle tends to differ among adults with type 1 diabetes under excellent control compared with those under poorer control. Future studies should focus on modifying diabetes management skills in adult type 1 diabetes patients with suboptimal glycemic control

HLA-A2–Matched Peripheral Blood Mononuclear Cells From Type 1 Diabetic Patients, but Not Nondiabetic Donors, Transfer Insulitis to NOD-scid/γcnull/HLA-A2 Transgenic Mice Concurrent With the Expansion of Islet-Specific CD8+ T cells

OBJECTIVE: Type 1 diabetes is an autoimmune disease characterized by the destruction of insulin-producing beta-cells. NOD mice provide a useful tool for understanding disease pathogenesis and progression. Although much has been learned from studies with NOD mice, increased understanding of human type 1 diabetes can be gained by evaluating the pathogenic potential of human diabetogenic effector cells in vivo. Therefore, our objective in this study was to develop a small-animal model using human effector cells to study type 1 diabetes. RESEARCH DESIGN AND METHODS: We adoptively transferred HLA-A2-matched peripheral blood mononuclear cells (PBMCs) from type 1 diabetic patients and nondiabetic control subjects into transgenic NOD-scid/gammac(null)/HLA-A*0201 (NOD-scid/gammac(null)/A2) mice. At various times after adoptive transfer, we determined the ability of these mice to support the survival and proliferation of the human lymphoid cells. Human lymphocytes were isolated and assessed from the blood, spleen, pancreatic lymph node and islets of NOD-scid/gammac(null)/A2 mice after transfer. RESULTS: Human T and B cells proliferate and survive for at least 6 weeks and were recovered from the blood, spleen, draining pancreatic lymph node, and most importantly, islets of NOD-scid/gammac(null)/A2 mice. Lymphocytes from type 1 diabetic patients preferentially infiltrate the islets of NOD-scid/gammac(null)/A2 mice. In contrast, PBMCs from nondiabetic HLA-A2-matched donors showed significantly less islet infiltration. Moreover, in mice that received PBMCs from type 1 diabetic patients, we identified epitope-specific CD8(+) T cells among the islet infiltrates. CONCLUSIONS: We show that insulitis is transferred to NOD-scid/gammac(null)/A2 mice that received HLA-A2-matched PBMCs from type 1 diabetic patients. In addition, many of the infiltrating CD8(+) T cells are epitope-specific and produce interferon-gamma after in vitro peptide stimulation. This indicates that NOD-scid/gammac(null)/A2 mice transferred with HLA-A2-matched PBMCs from type 1 diabetic patients may serve as a useful tool for studying epitope-specific T-cell-mediated responses in patients with type 1 diabetes

The effects of baseline characteristics, glycaemia treatment approach, and glycated haemoglobin concentration on the risk of severe hypoglycaemia: post hoc epidemiological analysis of the ACCORD study

Objectives To investigate potential determinants of severe hypoglycaemia, including baseline characteristics, in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial and the association of severe hypoglycaemia with levels of glycated haemoglobin (haemoglobin A1C) achieved during therapy

Durable change in glycaemic control following intensive management of type 2 diabetes in the ACCORD clinical trial

We aimed to determine the persistence of glycaemic control 1 year after a limited period of intensive glycaemic management of type 2 diabetes

Association of fenofibrate therapy with long-term cardiovascular risk in statin-treated patients with type 2 diabetes

IMPORTANCE: Patients with type 2 diabetes are at high risk of cardiovascular disease (CVD) in part owing to hypertriglyceridemia and low high-density lipoprotein cholesterol. It is unknown whether adding triglyceride-lowering treatment to statin reduces this risk. OBJECTIVE: To determine whether fenofibrate reduces CVD risk in statin-treated patients with type 2 diabetes. DESIGN, SETTING, AND PARTICIPANTS: Posttrial follow-up of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Lipid Study between July 2009 and October 2014; 5 years of follow-up were completed for a total of 9.7 years at general community and academic outpatient research clinics in the United States and Canada. Of the original 5518 ACCORD Lipid Trial participants, 4644 surviving participants were selected based on the presence of type 2 diabetes and either prevalent CVD or CVD risk factors and high-density lipoprotein levels less than 50 mg/dL (<55 mg/dL for women and African American individuals). INTERVENTIONS: Passive follow-up of study participants previously treated with fenofibrate or masked placebo. MAIN OUTCOMES AND MEASURES: Occurrence of cardiovascular outcomes including primary composite outcome of fatal and nonfatal myocardial infarction and stroke in all participants and in prespecified subgroups. RESULTS: The 4644 follow-on study participants were broadly representative of the original ACCORD study population and included significant numbers of women (n = 1445; 31%), nonwhite individuals (n = 1094; 21%), and those with preexisting cardiovascular events (n = 1620; 35%). Only 4.3% of study participants continued treatment with fenofibrate following completion of ACCORD. High-density lipoprotein and triglyceride values rapidly equalized among participants originally randomized to fenofibrate or placebo. Over a median total postrandomization follow-up of 9.7 years, the hazard ratio (HR) for the primary study outcome among participants originally randomized to fenofibrate vs placebo (HR, 0.93; 95% CI, 0.83-1.05; P = .25) was comparable with that originally observed in ACCORD (HR, 0.92; 95% CI, 0.79-1,08; P = .32). Despite these overall neutral results, we continued to find evidence that fenofibrate therapy effectively reduced CVD in study participants with dyslipidemia, defined as triglyceride levels greater than 204 mg/dL and high-density lipoprotein cholesterol levels less than 34 mg/dL (HR, 0.73; 95% CI, 0.56-0.95). CONCLUSIONS AND RELEVANCE: Extended follow-up of ACCORD-lipid trial participants confirms the original neutral effect of fenofibrate in the overall study cohort. The continued observation of heterogeneity of treatment response by baseline lipids suggests that fenofibrate therapy may reduce CVD in patients with diabetes with hypertriglyceridemia and low high-density lipoprotein cholesterol. A definitive trial of fibrate therapy in this patient population is needed to confirm these findings. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00000620

HLA-A2-matched peripheral blood mononuclear cells from type 1 diabetic patients, but not nondiabetic donors, transfer insulitis to NOD-scid/gammac(null)/HLA-A2 transgenic mice concurrent with the expansion of islet-specific CD8+ T cells.

OBJECTIVE: Type 1 diabetes is an autoimmune disease characterized by the destruction of insulin-producing beta-cells. NOD mice provide a useful tool for understanding disease pathogenesis and progression. Although much has been learned from studies with NOD mice, increased understanding of human type 1 diabetes can be gained by evaluating the pathogenic potential of human diabetogenic effector cells in vivo. Therefore, our objective in this study was to develop a small-animal model using human effector cells to study type 1 diabetes. RESEARCH DESIGN AND METHODS: We adoptively transferred HLA-A2-matched peripheral blood mononuclear cells (PBMCs) from type 1 diabetic patients and nondiabetic control subjects into transgenic NOD-scid/gammac(null)/HLA-A*0201 (NOD-scid/gammac(null)/A2) mice. At various times after adoptive transfer, we determined the ability of these mice to support the survival and proliferation of the human lymphoid cells. Human lymphocytes were isolated and assessed from the blood, spleen, pancreatic lymph node and islets of NOD-scid/gammac(null)/A2 mice after transfer. RESULTS: Human T and B cells proliferate and survive for at least 6 weeks and were recovered from the blood, spleen, draining pancreatic lymph node, and most importantly, islets of NOD-scid/gammac(null)/A2 mice. Lymphocytes from type 1 diabetic patients preferentially infiltrate the islets of NOD-scid/gammac(null)/A2 mice. In contrast, PBMCs from nondiabetic HLA-A2-matched donors showed significantly less islet infiltration. Moreover, in mice that received PBMCs from type 1 diabetic patients, we identified epitope-specific CD8(+) T cells among the islet infiltrates. CONCLUSIONS: We show that insulitis is transferred to NOD-scid/gammac(null)/A2 mice that received HLA-A2-matched PBMCs from type 1 diabetic patients. In addition, many of the infiltrating CD8(+) T cells are epitope-specific and produce interferon-gamma after in vitro peptide stimulation. This indicates that NOD-scid/gammac(null)/A2 mice transferred with HLA-A2-matched PBMCs from type 1 diabetic patients may serve as a useful tool for studying epitope-specific T-cell-mediated responses in patients with type 1 diabetes

Differences in the Management of Type 1 Diabetes Among Adults Under Excellent Control Compared With Those Under Poor Control in the T1D Exchange Clinic Registry

OBJECTIVE: Optimizing glycemic control in type 1 diabetes is important to minimize the risk of complications. We used the large T1D Exchange clinic registry database to identify characteristics and diabetes management techniques in adults with type 1 diabetes, differentiating those under excellent glycemic control from those with poorer control. RESEARCH DESIGN AND METHODS: The cross-sectional analysis included 627 participants with HbA(1c) <6.5% (excellent control) and 1,267 with HbA(1c) ≥8.5% (fair/poor control) at enrollment who were ≥26 years of age (mean ± SD 45.9 ± 13.2 years), were not using continuous glucose monitoring, and had type 1 diabetes for ≥2 years (22.8 ± 13.0 years). RESULTS: Compared with the fair/poor control group, participants in the excellent control group had higher socioeconomic status, were more likely to be older and married, were less likely to be overweight, were more likely to exercise frequently, and had lower total daily insulin dose per kilogram (P < 0.0001 for each). Excellent control was associated with more frequent self-monitoring of blood glucose (SMBG), giving mealtime boluses before a meal rather than at the time of or after a meal, performing SMBG before giving a bolus, and missing an insulin dose less frequently (P < 0.0001 for each). Frequency of severe hypoglycemia was similar between groups, whereas diabetic ketoacidosis was more common in the fair/poor control group. CONCLUSIONS: Diabetes self-management related to insulin delivery, glucose monitoring, and lifestyle tends to differ among adults with type 1 diabetes under excellent control compared with those under poorer control. Future studies should focus on modifying diabetes management skills in adult type 1 diabetes patients with suboptimal glycemic control