Residual ß cell function and monogenic variants in long-duration type 1 diabetes patients.

BACKGROUNDIn the Joslin Medalist Study (Medalists), we determined whether significant associations exist between ß cell function and pathology and clinical characteristics.METHODSIndividuals with type 1 diabetes (T1D) for 50 or more years underwent evaluation including HLA analysis, basal and longitudinal autoantibody (AAb) status, and ß cell function by a mixed-meal tolerance test (MMTT) and a hyperglycemia/arginine clamp procedure. Postmortem analysis of pancreases from 68 Medalists was performed. Monogenic diabetes genes were screened for the entire cohort.RESULTSOf the 1019 Medalists, 32.4% retained detectable C-peptide levels (>0.05 ng/mL, median: 0.21 ng/mL). In those who underwent a MMTT (n = 516), 5.8% responded with a doubling of baseline C-peptide levels. Longitudinally (n = 181, median: 4 years), C-peptide levels increased in 12.2% (n = 22) and decreased in 37% (n = 67) of the Medalists. Among those with repeated MMTTs, 5.4% (3 of 56) and 16.1% (9 of 56) had waxing and waning responses, respectively. Thirty Medalists with baseline C-peptide levels of 0.1 ng/mL or higher underwent the clamp procedure, with HLA-/AAb- and HLA+/AAb- Medalists being most responsive. Postmortem examination of pancreases from 68 Medalists showed that all had scattered insulin-positive cells; 59 additionally had few insulin-positive cells within a few islets; and 14 additionally had lobes with multiple islets with numerous insulin-positive cells. Genetic analysis revealed that 280 Medalists (27.5%) had monogenic diabetes variants; in 80 (7.9%) of these Medalists, the variants were classified as "likely pathogenic" (rare exome variant ensemble learner [REVEL] >0.75).CONCLUSIONAll Medalists retained insulin-positive ß cells, with many responding to metabolic stimuli even after 50 years of T1D. The Medalists were heterogeneous with respect to ß cell function, and many with HLA+ diabetes risk alleles also had monogenic diabetes variants, indicating the importance of genetic testing for clinically diagnosed T1D.FUNDINGFunding for this work was provided by the Dianne Nunnally Hoppes Fund; the Beatson Pledge Fund; the NIH, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); and the American Diabetes Association (ADA).

Differential Association of Microvascular Attributions With Cardiovascular Disease in Patients With Long Duration of Type 1 Diabetes.

OBJECTIVE: Independent association of chronic kidney disease (CKD) and proliferative diabetic retinopathy (PDR) with cardiovascular disease (CVD) has not been established. In the Joslin 50-Year Medalist study, characterizing individuals with type 1 diabetes for 50 years or more, we examined the associations of CKD and PDR with CVD, which was validated by another cohort with type 1 diabetes from Finland. RESEARCH DESIGN AND METHODS: This cross-sectional study characterized U.S. residents (n = 762) with type 1 diabetes of 50 years or longer (Medalists) at a single site by questionnaire, clinical, ophthalmic, and laboratory studies. A replication cohort (n = 675) from the longitudinal Finnish Diabetic Nephropathy Study (FinnDiane) was used. CKD and PDR were defined as estimated glomerular filtration rate <45 mL/min/1.73 m2 (CKD stage 3b) and according to the Early Treatment Diabetic Retinopathy Study (ETDRS) protocol, respectively. CVD was based on questionnaires and/or hospital discharge registers. Associations of CVD status with CKD and PDR were analyzed by multivariable logistic regression. RESULTS: CVD prevalence in the Medalists with CKD and without PDR (+CKD/-PDR) (n = 30) and CVD prevalence in the -CKD/+PDR group (n = 339) were half the prevalence in the +CKD/+PDR group (n = 66) (34.5% and 42.8% vs. 68.2%, P = 0.002). PDR status was independently associated with CVD (odds ratio 0.21 [95% CI 0.08-0.58], P = 0.003) in patients with CKD. Among the Finnish cohort, a trend toward a lower prevalence of CVD in the +CKD/-PDR group (n = 21) compared with the +CKD/+PDR group (n = 170) (19.1% vs. 37.1%, P = 0.10) was also observed. CONCLUSIONS: Absence of PDR in people with type 1 diabetes and CKD was associated with a decreased prevalence of CVD, suggesting that common protective factors for PDR and CVD may exist.

Diabetes Care Disparities in Long-standing Type 1 Diabetes in Canada and the U.S.: A Cross-sectional Comparison.

OBJECTIVE: To assess national differences in diabetes care and quality of life (QOL) between individuals with long-standing type 1 diabetes (≥50 years) in Canada and the U.S. RESEARCH DESIGN AND METHODS: Cross-sectional data from identical surveys administered in the Canadian Study of Longevity in Diabetes and the Joslin Medalist Study, collected in 2013-2016 and 2005-2011, respectively, were compared. Laboratory values and ophthalmic examination were completed by clinical care physicians for Canadians and the Joslin Clinic for Americans. Univariate comparisons and multivariable regression for HbA1c, QOL, insulin pump use, and coronary artery disease (CAD) were performed. Nephropathy, CAD, and peripheral arterial disease (PAD) were self-reported; neuropathy was defined by a Michigan Neuropathy Screening Instrument (Questionnaire component) score ≥3, and proliferative retinopathy was documented from ophthalmic examination. QOL was self-reported on an ordinal scale. RESULTS: Three hundred sixty-one Canadians and 668 Americans had similar ages (mean 65.78 years [SD 8.67] vs. 66.38 years [7.66], P = 0.27) and durations of diabetes (median 53.00 years [interquartile range 51.00, 58.00] vs. 53.00 years [51.00, 57.00], P = 0.51). Canadians had higher HbA1c (mean 7.53% [SD 1.03] [59 mmol/mol] vs. 7.22% [0.98] [55 mmol/mol], P < 0.0001), lower QOL (36.9% vs. 48.7% with "excellent" QOL, P = 0.0002), and less CAD (29.7% vs. 41.2%, P = 0.0003) and insulin pump use (43.3% vs. 55.6%, P = 0.0002). Other complication rates were similar. Residual differences for Canadians compared with Americans remained after adjustment for age, sex, CAD, PAD, education, and relevant a priori selected variables: 0.28% higher HbA1c (P = 0.0004); and odds ratios of 0.68 (95% CI 0.51, 0.90), 0.46 (0.31, 0.68), and 0.71 (0.52, 0.96) for higher QOL, CAD, and insulin pump use, respectively. CONCLUSIONS: Although Canadians and Americans have similar rates of complications other than CAD, further research is required to understand why Canadians have higher HbA1c levels, lower QOL, and less insulin pump use.

Association of Glycemic Control With Reduced Risk for Large-Vessel Disease After More Than 50 Years of Type 1 Diabetes.

Context: Previously we demonstrated, in individuals who have had type 1 diabetes (T1D) for 50 or more years (Medalists), that glycemic control was unrelated to diabetic complications, with the exception of cardiovascular disease (CVD), contrary to what has been documented in registry-based studies. Objective: The purpose of this study is to validate these initial findings and identify contributors to mortality on an individual basis in a large cohort. Design: Cross-sectional and longitudinal study. Setting: Joslin Diabetes Center (JDC), Boston, Massachusetts. Patients: 50-year Medalists presenting to JDC for study participation. Interventions: None. Main Outcomes Measures: Microvascular and macrovascular complications of diabetes and mortality. Results: Glycemic control was not significantly associated with small-vessel complications in Medalists but was associated with CVD in the overall cohort, yet with varying effect by tertile of cohort duration. CVD was the largest contributor to mortality, whereas hemoglobin A1c was not an independent predictor of mortality either overall or substantially by diagnosis interval. Additionally, exercise mitigated mortality risk imparted by CVD. Conclusions: Few large populations with long duration of (T1D) have been available to examine the effects of long-term exposure to hyperglycemia. These data indicate that an association of glycemic control, complications, and mortality may change in an older population with T1D. These results suggest that careful control is still warranted in older populations with T1D.

High density lipoprotein modulates osteocalcin expression in circulating monocytes: a potential protective mechanism for cardiovascular disease in type 1 diabetes.

BACKGROUND: Cardiovascular disease (CVD) is a major cause of mortality in type 1 diabetes (T1D). A pro-calcific drift of circulating monocytes has been linked to vascular calcification and is marked by the surface expression of osteocalcin (OCN). We studied OCN+ monocytes in a unique population with ≥50 years of T1D, the 50-Year Joslin Medalists (J50M). METHODS: CD45 bright/CD14+/OCN+ cells in the circulating mononuclear blood cell fraction were quantified by flow cytometry and reported as percentage of CD45 bright cells. Mechanisms were studied by inducing OCN expression in human monocytes in vitro. RESULTS: Subjects without history of CVD (n = 16) showed lower levels of OCN+ monocytes than subjects with CVD (n = 14) (13.1 ± 8.4% vs 19.9 ± 6.4%, p = 0.02). OCN+ monocytes level was inversely related to total high density lipoprotein (HDL) cholesterol levels (r = -0.424, p = 0.02), large (r = -0.413, p = 0.02) and intermediate (r = -0.445, p = 0.01) HDL sub-fractions, but not to small HDL. In vitro, incubation with OxLDL significantly increased the number of OCN+ monocytes (p < 0.01). This action of OxLDL was significantly reduced by the addition of HDL in a concentration dependent manner (p < 0.001). Inhibition of the scavenger receptor B1 reduced the effects of both OxLDL and HDL (p < 0.05). CONCLUSIONS: Low OCN+ monocytes levels are associated with lack of CVD in people with long duration T1D. A possible mechanism for the increased OCN+ monocytes could be the elevated levels of oxidized lipids due to diabetes which may be inhibited by HDL. These findings suggest that circulating OCN+ monocytes could be a marker for vascular disease in diabetic patients and possibly modified by HDL elevation.

Bone health in subjects with type 1 diabetes for more than 50 years.

AIMS: Few data regarding prevalence of and risk factors for poor bone health in aging individuals with long-standing T1D are available. In this study, we aim to describe the prevalence of bone fragility and to identify factors associated with low bone density in individuals with long-term T1D. METHODS: We examined the prevalence of non-vertebral fractures in 985 subjects enrolled in the Joslin 50-Year Medalist Study and measured bone mineral density (BMD) by dual-energy X-ray absorptiometry at the femoral neck, lumbar spine and radius in a subset (65 subjects, mean age 62.6 years, duration 52.5 years, HbA1c 7.1%) with no significant clinical or demographic differences from the rest of the cohort. RESULTS: Medalists have low prevalence of fractures (0.20% hip and 0.91% wrist) and normal Z-score values (spine +1.15, total hip +0.23, femoral neck -0.01, radius +0.26; p > 0.05 for differences vs. 0 at all sites). A significant relationship was found between lower BMD and higher total cholesterol, triglycerides and LDL levels, but not HbA1c. Low BMD at the femoral neck was associated with cardiovascular disease after adjustment for confounding factors: prevalence risk ratio of CVD [95% CI] 4.6 [1.2-18.1], p = 0.03. No other diabetic vascular complication was found to be associated with low BMD. CONCLUSIONS: These are the first data regarding bone health in aging individuals who have had diabetes for 50 or more years. The low rates of non-vertebral fractures and the normal Z-score suggest the long T1D diabetes duration did not increase the risk of bone fractures in Medalists compared to non-diabetic peers. Additionally, the association with cardiovascular disease demonstrates the BMD differences in groups are likely not due to glycemic control alone.