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Rosiglitazone improves insulin resistance but does not improve exercise capacity in individuals with impaired glucose tolerance: A randomized clinical study.
Abushamat, LA, Schauer, IE, Low Wang, CC, Mitchell, S, Herlache, L, Bridenstine, M, Durbin, R, Snell-Bergeon, JK, Regensteiner, JG, Reusch, JE
Journal of investigative medicine : the official publication of the American Federation for Clinical Research. 2024;(3):294-304
Abstract
Dysmetabolic states, such as type 2 diabetes (T2D), characterized by insulin resistance (IR), are associated with fatty liver, increased cardiovascular disease (CVD) risk, and decreased functional exercise capacity (FEC). Rosiglitazone (RO) improves exercise capacity and IR in T2D. However, the effects of RO on FEC and other markers of CVD risk in prediabetes are unknown. We hypothesized that insulin sensitization with RO would improve exercise capacity and markers of CVD risk in participants with impaired glucose tolerance (IGT). Exercise performance (peak oxygen consumption and oxygen uptake kinetics), IR (homeostasis model assessment of IR and quantitative insulin sensitivity check index), and surrogate cardiovascular endpoints (coronary artery calcium (CAC) volume and density and C-reactive protein (CRP)) were measured in participants with IGT after 12 and 18 months of RO or placebo (PL). RO did not significantly improve exercise capacity. Glycemic measures and IR were significantly lower in people on RO compared to PL at 18 months. CAC volume progression was not different between PL and RO groups. RO did not improve exercise capacity during an 18-month intervention despite improved IR and glycemia in people with IGT. Future studies should explore why effects on FEC with RO occur in T2D but not IGT. Understanding these questions may help in targeting therapeutic approaches in T2D and IGT.
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Hemoglobin A1c Variability Metrics Predict Coronary Artery Calcium and Cardiovascular Events in Type 1 Diabetes: The CACTI Study.
Horton, WB, Snell-Bergeon, JK
The Journal of clinical endocrinology and metabolism. 2023;(7):e444-e449
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CONTEXT Interventions that decrease mean glucose have reduced rates of micro- and macrovascular complications in type 1 diabetes (T1D). However, the difference in cardiovascular risk between people with T1D and the general population endures, suggesting that factors beyond hemoglobin A1C (HbA1c) normalization drive cardiovascular outcomes. OBJECTIVE To determine whether various HbA1c metrics predict anatomic cardiovascular disease (CVD) risk factors and/or CVD events in people with T1D. METHODS We used linear regression to analyze the relationship of several HbA1c metrics to anatomic CVD risk factors and then used Cox regression to model their relationship to incident CVD events in the CACTI Study (ClinicalTrials.gov Identifier: NCT00005754). RESULTS In linear regression models adjusted for age, sex, and T1D duration, baseline Hba1c (b = 0.3998, P = 0.0236), mean HbA1c (b = 0.5385, P = 0.0109), and HbA1c SD (b = 1.1521, P = 0.0068) were each positively associated with square root transformed coronary artery calcium volume. Conversely, only mean HbA1c (b = 1.659, P = 0.0048) positively associated with pericardial adipose tissue volume. In survival models adjusted for age, sex, and T1D duration, baseline HbA1c [hazard ratio (HR): 1.471, 95% CI: 1.257-1.721], mean HbA1c (HR: 1.850, 95% CI: 1.511-2.264), time-varying HbA1c (HR: 1.500, 95% CI: 1.236-1.821), and HbA1c SD (HR: 1.665, 95% CI: 1.022-2.711) each independently predicted CVD events over 14.3 ± 5.2 person-years of follow-up. CONCLUSIONS/INTERPRETATION We found that various HbA1c metrics positively correlated with CAC volume and independently predicted incident CVD events in the CACTI T1D cohort. These associations with CVD events persisted for baseline HbA1c, mean HbA1c, and time-varying HbA1c even after adjustment for numerous CVD risk factors.
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Copeptin and Estimated Insulin Sensitivity in Adults With and Without Type 1 Diabetes: The CACTI Study.
Jensen, T, Bjornstad, P, Johnson, RJ, Sippl, R, Rewers, M, Snell-Bergeon, JK
Canadian journal of diabetes. 2019;(1):34-39
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OBJECTIVES Copeptin, a surrogate marker for vasopressin, is elevated in participants with insulin resistance (IR) and type 2 diabetes. Whereas adults with type 1 diabetes also demonstrate elevated copeptin concentrations and IR compared to controls without diabetes, the relationship between copeptin and IR in type 1 diabetes is unclear. METHODS Participants with (n=209) and without (n=244) type 1 diabetes in the Coronary Artery Calcification in Type 1 Diabetes (CACTI) study were assessed for serum copeptin, vitals, estimated glomerular filtration rate, urinary albumin-to-creatinine ratio, glycated hemoglobin and lipid panels. Estimated insulin sensitivity (eIS) was calculated by validated equations in participants with and without type 1 diabetes. The relationships among copeptin, IR, waist circumference (WC) and body mass index (BMI) were examined with unadjusted and adjusted linear regression models. RESULTS Copeptin was correlated with eIS (R=-0.17, R2=0.029), WC (R=0.16, R2=0.026) and BMI (R=0.22, R2=0.048) for type 1 diabetes and with eIS (R=-0.37, R2=0.14), WC (R=0.40, R2=0.16) and BMI (R=0.25, R2=0.063) in non-type 1 diabetes. In multivariable analysis, copeptin correlated with total cholesterol (beta±SE: -0.12±0.04, p=0.008) and low-density lipoprotein (beta±SE: -0.11±0.04, p=0.01) in type 1 diabetes. In non-type 1 diabetes, copeptin was associated with WC (beta±SE: 0.14±0.04, p=0.0024), BMI (beta±SE: 0.13±0.04, p=0.007) and eIS (beta±SE: -0.14±0.04, p=0.0013). CONCLUSIONS Copeptin does not correlate with markers of IR in type 1 diabetes but strongly correlates in non-type 1 diabetes. Thus, elevated vasopressin activity and IR appear to be independent risk factors for vascular complications in type 1 diabetes.
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Dietary fiber intake and glycemic control: coronary artery calcification in type 1 diabetes (CACTI) study.
Basu, A, Alman, AC, Snell-Bergeon, JK
Nutrition journal. 2019;18(1):23
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The incidence of type 1 diabetes and cardiovascular disease, the major vascular complication of diabetes, have been increasing wordwide. The aim of the study is to identify the associations of dietary fibre with glycaemic control. The study is a cross-sectional longitudinal study which enrolled 1257 individuals in the cross-sectional analysis and a total of 990 participants were included in the longitudinal analysis. The participants had no known history of coronary heart disease. Results indicate an inverse association between total fibre intake and the average blood glucose levels for the last two to three months in both diabetic and nondiabetic participants. Authors conclude that their study provides some evidence on the role dietary fibre intake plays on glycaemic control, which is important in the management of type 1 diabetes in patients at high risk of cardiovascular disease.
Abstract
BACKGROUND Dietary fiber has been recommended for glucose control, and typically low intakes are observed in the general population. The role of fiber in glycemic control in reported literature is inconsistent and few reports are available in populations with type 1 diabetes (T1D). METHODS Using data from the Coronary Artery Calcification in Type 1 Diabetes (CACTI) study [n = 1257; T1D: n = 568; non-diabetic controls: n = 689] collected between March 2000 and April 2002, we examined cross-sectional (baseline) and longitudinal (six-year follow-up in 2006-2008) associations of dietary fiber and HbA1c. Participants completed a validated food frequency questionnaire, and a physical examination and fasting biochemical analyses (12 h fast) at baseline visit and at the year 6 visit. We used a linear regression model stratified by diabetes status, and adjusted for age, sex and total calories, and diabetes duration in the T1D group. We also examined correlations of dietary fiber with HbA1c. RESULTS Baseline dietary fiber intake and serum HbA1c in the T1D group were 16 g [median (IQ): 11-22 g) and 7.9 ± 1.3% mean (SD), respectively, and in the non-diabetic controls were 15 g [median (IQ): 11-21 g) and 5.4 ± 0.4%, respectively. Pearson partial correlation coefficients revealed a significant but weak inverse association of total dietary fiber with HbA1c when adjusted for age, sex, diabetes status and total calories (r = - 0.07, p = 0.01). In the adjusted linear regression model at baseline, total dietary fiber revealed a significant inverse association with HbA1c in the T1D group [β ± SE = - 0.32 ± 0.15, p = 0.034], as well as in the non-diabetic controls [- 0.10 ± 0.04, p = 0.009]. However, these results were attenuated after adjustment for dietary carbohydrates, fats and proteins, or for cholesterol and triglycerides. No such significance was observed at the year 6 follow-up, and with the HbA1c changes over 6 years. CONCLUSION Thus, at observed levels of intake, total dietary fiber reveals modest inverse associations with poor glycemic control. Future studies must further investigate the role of overall dietary quality adjusting for fiber-rich foods in T1D management.
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Dynamic changes in retinal vessel diameter during acute hyperglycemia in type 1 diabetes.
Bucca, BC, Maahs, DM, Snell-Bergeon, JK, Hokanson, J, Rinella, S, Bishop, F, Boufard, A, Homann, J, Cheung, CY, Wong, TY
Journal of diabetes and its complications. 2018;(2):234-239
Abstract
AIMS: To investigate changes in retinal vessel diameter during acute hyperglycemia in patients with type 1 diabetes. METHODS We conducted a study on 11 subjects with type 1 diabetes. Euglycemia was maintained for 3h followed by induction of hyperglycemia and simultaneous bolus of rapid acting insulin. Two fundus photos were captured during euglycemia and five fundus photos, blood glucose and blood pressure were taken every 30min for 2.5h post-prandial. Central retinal artery equivalent (CRAE) and central retinal vein equivalent (CRVE) were measured over the study visit and examined using generalized linear mixed models. RESULTS In a multivariate mixed model, mean CRAE and CRVE were reduced at 90min post-prandial in both zones B and C. In repeated measures analysis, arterioles exhibited a significant association with change in vessel caliber per change in blood glucose. Inconsistent effects of blood pressure on vessel diameter were also measured. CONCLUSIONS We document a change in retinal vessel diameter during acute hyperglycemia in persons with type 1 diabetes. Larger controlled studies are required to further investigate this phenomenon and to more accurately assess if hyperglycemia has direct effects on retinal vessel diameter.
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Intracellular localization of diacylglycerols and sphingolipids influences insulin sensitivity and mitochondrial function in human skeletal muscle.
Perreault, L, Newsom, SA, Strauss, A, Kerege, A, Kahn, DE, Harrison, KA, Snell-Bergeon, JK, Nemkov, T, D'Alessandro, A, Jackman, MR, et al
JCI insight. 2018;(3)
Abstract
BACKGROUND Accumulation of diacylglycerol (DAG) and sphingolipids is thought to promote skeletal muscle insulin resistance by altering cellular signaling specific to their location. However,the subcellular localization of bioactive lipids in human skeletal muscle is largely unknown. METHODS We evaluated subcellular localization of skeletal muscle DAGs and sphingolipids in lean individuals (n = 15), endurance-trained athletes (n = 16), and obese men and women with (n = 12) and without type 2 diabetes (n = 15). Muscle biopsies were fractionated into sarcolemmal, cytosolic, mitochondrial/ER, and nuclear compartments. Lipids were measured using liquid chromatography tandem mass spectrometry, and insulin sensitivity was measured using hyperinsulinemic-euglycemic clamp. RESULTS Sarcolemmal 1,2-DAGs were not significantly related to insulin sensitivity. Sarcolemmal ceramides were inversely related to insulin sensitivity, with a significant relationship found for the C18:0 species. Sarcolemmal sphingomyelins were also inversely related to insulin sensitivity, with the strongest relationships found for the C18:1, C18:0, and C18:2 species. In the mitochondrial/ER and nuclear fractions, 1,2-DAGs were positively related to, while ceramides were inversely related to, insulin sensitivity. Cytosolic lipids as well as 1,3-DAG, dihydroceramides, and glucosylceramides in any compartment were not related to insulin sensitivity. All sphingolipids but only specific DAGs administered to isolated mitochondria decreased mitochondrial state 3 respiration. CONCLUSION These data reveal previously unknown differences in subcellular localization of skeletal muscle DAGs and sphingolipids that relate to whole-body insulin sensitivity and mitochondrial function in humans. These data suggest that whole-cell concentrations of lipids obscure meaningful differences in compartmentalization and suggest that subcellular localization of lipids should be considered when developing therapeutic interventions to treat insulin resistance. FUNDING National Institutes of Health General Clinical Research Center (RR-00036), National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (R01DK089170), NIDDK (T32 DK07658), and Colorado Nutrition Obesity Research Center (P30DK048520).
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Insulin sensitivity and complications in type 1 diabetes: New insights.
Bjornstad, P, Snell-Bergeon, JK, Nadeau, KJ, Maahs, DM
World journal of diabetes. 2015;(1):8-16
Abstract
Despite improvements in glucose, lipids and blood pressure control, vascular complications remain the most important cause of morbidity and mortality in patients with type 1 diabetes. For that reason, there is a need to identify additional risk factors to utilize in clinical practice or translate to novel therapies to prevent vascular complications. Reduced insulin sensitivity is an increasingly recognized component of type 1 diabetes that has been linked with the development and progression of both micro- and macrovascular complications. Adolescents and adults with type 1 diabetes have reduced insulin sensitivity, even when compared to their non-diabetic counterparts of similar adiposity, serum triglycerides, high-density lipoprotein cholesterol, level of habitual physical activity, and in adolescents, pubertal stage. Reduced insulin sensitivity is thought to contribute both to the initiation and progression of macro- and microvascular complications in type 1 diabetes. There are currently clinical trials underway examining the benefits of improving insulin sensitivity with regards to vascular complications in type 1 diabetes. Reduced insulin sensitivity is an increasingly recognized component of type 1 diabetes, is implicated in the pathogenesis of vascular complications and is potentially an important therapeutic target to prevent vascular complications. In this review, we will focus on the pathophysiologic contribution of insulin sensitivity to vascular complications and summarize related ongoing clinical trials.
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Estimated insulin sensitivity predicts regression of albuminuria in Type 1 diabetes.
Bjornstad, P, Maahs, DM, Johnson, RJ, Rewers, M, Snell-Bergeon, JK
Diabetic medicine : a journal of the British Diabetic Association. 2015;(2):257-61
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AIM: To test the hypothesis that greater baseline insulin sensitivity would predict regression of albuminuria over 6 years in adults with Type 1 diabetes. METHOD We enrolled 81 people aged 30-48 years with albuminuria at baseline in the present study and re-examined them 6 years later. Urinary albumin excretion rate was measured and albuminuria was defined as urinary albumin excretion rate ≥ 20 μg/min. Regression of albuminuria was defined as normoalbuminuria (urinary albumin excretion rate < 20 μg/min) at follow-up. Predictors of regression of albuminuria were examined in stepwise logistic regression. The variables age, diabetes duration, sex, serum uric acid, HbA1c , systolic blood pressure, LDL cholesterol, HDL cholesterol, BMI, baseline albumin excretion rate, estimated insulin sensitivity at baseline, change in estimated insulin sensitivity from baseline to follow-up and angiotensin-converting enzyme inhibitor/angiotensin receptor blocker use were considered for inclusion in the model. RESULTS Estimated insulin sensitivity was significantly higher at both baseline (4.6 ± 1.2 vs 3.4 ± 1.7; P = 0.002) and follow-up (5.2 ± 1.9 vs. 3.5 ± 1.7; P < 0.0001) in people who had regression of albuminuria vs those who did not. HbA1c (odds ratio 0.4, 95% CI 0.2-0.8; P = 0.006), estimated insulin sensitivity (odds ratio 2.5, 95% CI 1.3-4.9; P = 0.006) at baseline and change in estimated insulin sensitivity from baseline to follow-up (odds ratio 2.7, 95% CI 1.4-5.3; P = 0.003) were independently associated with regression of albuminuria in a multivariable stepwise model. CONCLUSIONS In conclusion, over 6 years, higher baseline estimated insulin sensitivity and change in estimated insulin sensitivity independently predicted regression of albuminuria. Improving insulin sensitivity in people with Type 1 diabetes is a potential therapeutic target to increase rates of regression of albuminuria.
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The effects of lowering nighttime and breakfast glucose levels with sensor-augmented pump therapy on hemoglobin A1c levels in type 1 diabetes.
Maahs, DM, Chase, HP, Westfall, E, Slover, R, Huang, S, Shin, JJ, Kaufman, FR, Pyle, L, Snell-Bergeon, JK
Diabetes technology & therapeutics. 2014;(5):284-91
Abstract
OBJECTIVE This study determined the association of continuous glucose monitoring glucose (CGM-glucose) levels at different times of the day with improvement in glycated hemoglobin (HbA1c) levels. The potential application of these data is to focus effort to improve glucose control in patients with type 1 diabetes. RESEARCH DESIGN AND METHODS Data were analyzed from 196 patients with type 1 diabetes who were randomized to receive sensor-augmented pump therapy in the 1-year STAR 3 trial. CGM-glucose values and HbA1c levels from baseline and after 1 year were evaluated to determine associations of improvement in CGM-glucose at different times of the day with longitudinal improvement in HbA1c. RESULTS Improvement in HbA1c levels after 1 year was related to improvement in mean CGM-glucose levels in daytime (6 a.m.-midnight), overnight (midnight-6 a.m.), and each mealtime period (P<0.0001 for each). In multivariable analysis, only improvement in breakfast meal period was associated with improvement in HbA1c after 1 year, explaining 59% of the HbA1c improvement using the partial R(2) test. Moreover, among those patients who only improved CGM-glucose in the overnight period there was an associated improvement in breakfast meal period CGM-glucose of 26 ± 22 mg/dL (P<0.01). CONCLUSIONS Breakfast period glucose improvement had the greatest effect on lowering HbA1c levels in patients with type 1 diabetes. Improving glucose control overnight resulted in subsequent improvement in the breakfast period. Although glucose control should be improved at all times, methods to improve overnight and post-breakfast glucose levels may be of primary importance in improving glucose control in patients with type 1 diabetes.
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Serum uric acid predicts vascular complications in adults with type 1 diabetes: the coronary artery calcification in type 1 diabetes study.
Bjornstad, P, Maahs, DM, Rivard, CJ, Pyle, L, Rewers, M, Johnson, RJ, Snell-Bergeon, JK
Acta diabetologica. 2014;(5):783-91
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Epidemiologic evidence supports a link between serum uric acid (SUA) and vascular complications in diabetes, but it remains unclear whether SUA improves the ability of conventional risk factor to predict complications. We hypothesized that SUA at baseline would independently predict the development of vascular complications over 6 years and that the addition of SUA to American Diabetes Association's ABC risk factors (HbA1c, BP, LDL-C) would improve vascular complication prediction over 6 years in adults with type 1 diabetes. Study participants (N = 652) were 19-56 year old at baseline and re-examined 6 years later. Diabetic nephropathy was defined as incident albuminuria or rapid GFR decline (>3.3 %/year) estimated by the CKD-EPI cystatin C. Diabetic retinopathy (DR) was based on self-reported history, and proliferative diabetic retinopathy (PDR) was defined as laser eye therapy; coronary artery calcium (CAC) was measured using electron-beam computed tomography. Progression of CAC (CACp) was defined as a change in the square-root-transformed CAC volume ≥2.5. Predictors of each complication were examined in stepwise logistic regression with subjects with complications at baseline excluded from analyses. C-statistics, integrated discrimination indices and net-reclassification improvement were utilized for prediction performance analyses. SUA independently predicted development of incident albuminuria (OR 1.8, 95 % CI 1.2-2.7), rapid GFR decline (1.9, 1.1-3.3), DR (1.4, 1.1-1.9), PDR (2.1, 1.4-3.0) and CACp (1.5, 1.1-1.9). SUA improved the discrimination and net-classification risk of vascular complications over 6 years. SUA independently predicted the development of vascular complications in type 1 diabetes and also improved the reclassification of vascular complications.