Glycemic Control, Cardiac Autoimmunity, and Long-Term Risk of Cardiovascular Disease in Type 1 Diabetes Mellitus.

BACKGROUND: Poor glycemic control is associated with increased risk of cardiovascular disease (CVD) in type 1 diabetes mellitus (T1DM); however, little is known about mechanisms specific to T1DM. In T1DM, myocardial injury can induce persistent cardiac autoimmunity. Chronic hyperglycemia causes myocardial injury, raising the possibility that hyperglycemia-induced cardiac autoimmunity could contribute to long-term CVD complications in T1DM. METHODS: We measured the prevalence and profiles of cardiac autoantibodies (AAbs) in longitudinal samples from the DCCT (Diabetes Control and Complications Trial) in participants with mean hemoglobin A1c (HbA1c) ≥9.0% (n=83) and ≤7.0% (n=83) during DCCT. We assessed subsequent coronary artery calcification (measured once during years 7-9 in the post-DCCT EDIC [Epidemiology of Diabetes Interventions and Complications] observational study), high-sensitivity C-reactive protein (measured during EDIC years 4-6), and CVD events (defined as nonfatal myocardial infarction, stroke, death resulting from CVD, heart failure, or coronary artery bypass graft) over a 26-year median follow-up. Cardiac AAbs were also measured in matched patients with type 2 diabetes mellitus with HbA1c ≥9.0% (n=70) and ≤7.0% (n=140) and, as a control for cardiac autoimmunity, patients with Chagas cardiomyopathy (n=51). RESULTS: Apart from HbA1c levels, the DCCT groups shared similar CVD risk factors at the beginning and end of DCCT. The DCCT HbA1c ≥9.0% group showed markedly higher cardiac AAb levels than the HbA1c ≤7.0% group during DCCT, with a progressive increase and decrease in AAb levels over time in the 2 groups, respectively ( P<0.001). In the HbA1c ≥9.0% group, 46%, 22%, and 11% tested positive for ≥1, ≥2, and ≥3 different cardiac AAb types, respectively, similar to patients with Chagas cardiomyopathy, compared with 2%, 1%, and 0% in the HbA1c ≤7.0% group. Glycemic control was not associated with AAb prevalence in type 2 diabetes mellitus. Positivity for ≥2 AAbs during DCCT was associated with increased risk of CVD events (4 of 6; hazard ratio, 16.1; 95% CI, 3.0-88.2) and, in multivariable analyses, with detectable coronary artery calcification (13 of 31; odds ratio, 60.1; 95% CI, 8.4-410.0). Patients with ≥2 AAbs subsequently also showed elevated high-sensitivity C-reactive protein levels (6.0 mg/L versus 1.4 mg/L in patients with ≤1 AAbs; P=0.003). CONCLUSIONS: Poor glycemic control is associated with cardiac autoimmunity in T1DM. Furthermore, cardiac AAb positivity is associated with an increased risk of CVD decades later, suggesting a role for autoimmune mechanisms in the development of CVD in T1DM, possibly through inflammatory pathways.

Exogenous Insulin Infusion Can Decrease Atherosclerosis in Diabetic Rodents by Improving Lipids, Inflammation, and Endothelial Function.

OBJECTIVE: The objective of this study is to evaluate whether exogenously induced hyperinsulinemia may increase the development of atherosclerosis. APPROACH AND RESULTS: Hyperinsulinemia, induced by exogenous insulin implantation in high-fat fed (60% fat HFD) apolipoprotein E-deficient mice (ApoE-/-) mice, exhibited insulin resistance, hyperglycemia, and hyperinsulinemia. Atherosclerosis was measured by the accumulation of fat, macrophage, and extracellular matrix in the aorta. After 8 weeks on HFD, ApoE-/- mice were subcutaneously implanted with control (sham) or insulin pellet, and phlorizin, a sodium glucose cotransporters inhibitor (1/2)inhibitor, for additional 8 weeks. Intraperitoneal glucose tolerance test showed that plasma glucose levels were lower and insulin and IGF-1 (insulin-like growth factor-1) levels were 5.3- and 3.3-fold higher, respectively, in insulin-implanted compared with sham-treated ApoE-/- mice. Plasma triglyceride, cholesterol, and lipoprotein levels were decreased in mice with insulin implant, in parallel with increased lipoprotein lipase activities. Atherosclerotic plaque by en face and complexity staining showed significant reductions of fat deposits and expressions of vascular adhesion molecule-1, tumor necrosis factor-α, interleukin 6, and macrophages in arterial wall while exhibiting increased activation of pAKT and endothelial nitric oxide synthase (P<0.05) comparing insulin-implanted versus sham HFD ApoE-/- mice. No differences were observed in atherosclerotic plaques between phlorizin-treated and sham HFD ApoE-/- mice, except phlorizin significantly lowered plasma glucose and glycated hemoglobin levels while increased glucosuria. Endothelial function was improved only by insulin treatment through endothelial nitric oxide synthase/nitric oxide activations and reduced proinflammatory (M1) and increased anti-inflammatory (M2) macrophages, which were inhibited by endothelial nitric oxide synthase inhibitor. CONCLUSIONS: Exogenous insulin decreased atherosclerosis by lowering inflammatory cytokines, macrophages, and plasma lipids in HFD-induced hyperlipidemia, insulin resistant and mildly diabetic ApoE-/- mice.

Improving the quality of foods available in a rural kibbutz cafeteria in Israel to align with a freshly prepared Mediterranean-style diet through a community culinary coaching programme.

OBJECTIVE: To examine the impact of a community culinary coaching programme (CCCP) on cafeteria food alignment with a freshly prepared Mediterranean-style diet, and diners' consumption habits and satisfaction. DESIGN: A non-randomized, controlled, community-based participatory research programme. CCCP included eight 90 min coaching sessions with a community steering committee, 22 h of kitchen staff training, 12 h of pre-school staff training and 30 h of education for diners; control communities received no intervention. Outcomes, measured before and 12 months after programme initiation, included cafeteria food alignment with a freshly prepared Mediterranean-style diet through a food items list derived from the cafeteria food purchasing software, and adult diners' consumption habits and satisfaction through questionnaires. SETTING: Communal cafeterias of rural kibbutzim. PARTICIPANTS: Intervention: kibbutz with 493 adults and 214 children. Control: Two kibbutzim with a total of 487 adults and 206 children. RESULTS: Intervention cafeteria food improved significantly in all Mediterranean index categories except nuts (legumes, wholegrain products, fish, MUFA/SFA P < 0·0001; fruits, vegetables P < 0·001; processed meats P = 0·004), and in the proportion of ultra-processed and unprocessed or minimally processed foods categories of the NOVA classification (-22 %, P < 0·001 and +7 %, P < 0·001, respectively), compared with the control community. The intervention group's satisfaction was significantly improved in twenty-five (83 %) out of the thirty satisfaction items, compared with twelve (40 %) in the control group. No changes were identified in diners' consumption habits in either intervention or control communities. CONCLUSIONS: CCCP might be useful in improving alignment of cafeteria food with a freshly prepared Mediterranean-style diet.

Preventing Type 2 Diabetes with Home Cooking: Current Evidence and Future Potential.

PURPOSE OF REVIEW: Various dietary regimes have proven effective in preventing diabetes, yet its prevalence is growing. This review's goals are to examine the relationship between home cooking and diabetes and to present the literature on home cooking education programs as a novel strategy to improve adherence to healthy nutrition, thus decreasing the risk of diabetes. RECENT FINDINGS: Consumption of home-cooked food is linked to healthier nutrition and decreased risk of diabetes. Further, home cooking interventions have a short-term positive impact on nutritional intake of both children and adults, and on diabetes prevention. Well-designed randomized controlled studies are needed to rigorously evaluate the long-term impact of home cooking interventions on cooking behavior, dietary intake, diabetes, and healthcare costs. Culinary education is an emerging field that aims to change nutrition education paradigms. Clinicians can empower patients to adopt home cooking by role modeling home cooking themselves, including home cooking content in their medical encounters, and through comprehensive lifestyle medicine interventions.

Effects of nutrition therapy on HbA1c and cardiovascular disease risk factors in overweight and obese patients with type 2 diabetes.

BACKGROUND: Nutrition Therapy (NT) is essential in type 2 diabetes (T2D) management. Standards of care recommend that each patient engages with a nutritionist (RDN) to develop an individualized eating plan. However, it is unclear if it is the most efficient method of NT. This study evaluates the effects of three different methods of NT on HbA1c and cardiovascular disease risk factors in overweight and obese patients with T2D. METHODS: We randomized 108 overweight and obese patients with T2D (46 M/62F; age 60 ± 10 years; HbA1c 8.07 ± 1.05%; weight 101.4 ± 21.1 kg and BMI 35.2 ± 7.7 kg/m2) into three groups. Group A met with RDN to develop an individualized eating plan. Group B met with RDN and followed a structured meal plan. Group C did similar to group B and received weekly phone support by RDN. RESULTS: After 16 weeks, all three groups had a significant reduction of their energy intake compared to baseline. HbA1c did not change from baseline in group A, but decreased significantly in groups B (- 0.66%, 95% CI -1.03 to - 0.30) and C (- 0.61%, 95% CI -1.0 to - 0.23) (p value for difference among groups over time < 0.001). Groups B and C also had significant reductions in body weight, body fat percentage and waist circumference. CONCLUSION: Structured NT alone improves glycemia in comparison to individualized eating plans in overweight and obese patients with T2D. It also reduces other important cardiovascular disease risk factors like body fat percentage and waist circumference. TRIAL REGISTRATION: The trial was retrospectively registered at clinicaltrials.gov( NCT02520050 ).

Rheumatoid arthritis T cell and muscle oxidative metabolism associate with exercise-induced changes in cardiorespiratory fitness.

Rheumatoid arthritis (RA) T cells drive autoimmune features via metabolic reprogramming that reduces oxidative metabolism. Exercise training improves cardiorespiratory fitness (i.e., systemic oxidative metabolism) and thus may impact RA T cell oxidative metabolic function. In this pilot study of RA participants, we took advantage of heterogeneous responses to a high-intensity interval training (HIIT) exercise program to identify relationships between improvements in cardiorespiratory fitness with changes in peripheral T cell and skeletal muscle oxidative metabolism. In 12 previously sedentary persons with seropositive RA, maximal cardiopulmonary exercise tests, fasting blood, and vastus lateralis biopsies were obtained before and after 10 weeks of HIIT. Following HIIT, improvements in RA cardiorespiratory fitness were associated with changes in RA CD4 + T cell basal and maximal respiration and skeletal muscle carnitine acetyltransferase (CrAT) enzyme activity. Further, changes in CD4 + T cell respiration were associated with changes in naïve CD4 + CCR7 + CD45RA + T cells, muscle CrAT, and muscle medium-chain acylcarnitines and fat oxidation gene expression profiles. In summary, modulation of cardiorespiratory fitness and molecular markers of skeletal muscle oxidative metabolism during exercise training paralleled changes in T cell metabolism. Exercise training that improves RA cardiorespiratory fitness may therefore be valuable in managing pathologically related immune and muscle dysfunction.Trial registration: ClinicalTrials.gov, NCT02528344. Registered on 19 August 2015.

Altered skeletal muscle metabolic pathways, age, systemic inflammation, and low cardiorespiratory fitness associate with improvements in disease activity following high-intensity interval training in persons with rheumatoid arthritis.

BACKGROUND: Exercise training, including high-intensity interval training (HIIT), improves rheumatoid arthritis (RA) inflammatory disease activity via unclear mechanisms. Because exercise requires skeletal muscle, skeletal muscle molecular pathways may contribute. The purpose of this study was to identify connections between skeletal muscle molecular pathways, RA disease activity, and RA disease activity improvements following HIIT. METHODS: RA disease activity assessments and vastus lateralis skeletal muscle biopsies were performed in two separate cohorts of persons with established, seropositive, and/or erosive RA. Body composition and objective physical activity assessments were also performed in both the cross-sectional cohort and the longitudinal group before and after 10 weeks of HIIT. Baseline clinical assessments and muscle RNA gene expression were correlated with RA disease activity score in 28 joints (DAS-28) and DAS-28 improvements following HIIT. Skeletal muscle gene expression changes with HIIT were evaluated using analysis of covariance and biological pathway analysis. RESULTS: RA inflammatory disease activity was associated with greater amounts of intramuscular adiposity and less vigorous aerobic exercise (both p < 0.05). HIIT-induced disease activity improvements were greatest in those with an older age, elevated erythrocyte sedimentation rate, low cardiorespiratory fitness, and a skeletal muscle molecular profile indicative of altered metabolic pathways (p < 0.05 for all). Specifically, disease activity improvements were linked to baseline expression of RA skeletal muscle genes with cellular functions to (1) increase amino acid catabolism and interconversion (GLDC, BCKDHB, AASS, PYCR, RPL15), (2) increase glycolytic lactate production (AGL, PDK2, LDHB, HIF1A), and (3) reduce oxidative metabolism via altered beta-oxidation (PXMP2, ACSS2), TCA cycle flux (OGDH, SUCLA2, MDH1B), and electron transport chain complex I function (NDUFV3). The muscle mitochondrial glycine cleavage system (GCS) was identified as critically involved in RA disease activity improvements given upregulation of multiple GCS genes at baseline, while GLDC was significantly downregulated following HIIT. CONCLUSION: In the absence of physical activity, RA inflammatory disease activity is associated with transcriptional remodeling of skeletal muscle metabolism. Following exercise training, the greatest improvements in disease activity occur in older, more inflamed, and less fit persons with RA. These exercise training-induced immunomodulatory changes may occur via reprogramming muscle bioenergetic and amino acid/protein homeostatic pathways. TRIAL REGISTRATION: ClinicalTrials.gov , NCT02528344 . Registered on 19 August 2015.

Vitamin D Analogues and Coronary Calcification in CKD Stages 3 and 4: A Randomized Controlled Trial of Calcitriol Versus Paricalcitol.

RATIONALE & OBJECTIVE: Mineral and bone disorder in chronic kidney disease (CKD) is associated with progression of coronary artery calcification (CAC). Mineral and bone disorder often is treated with calcitriol and other vitamin D receptor activators, including paricalcitol, agents that may have differential effects on calcium, phosphate, and parathyroid hormone levels. Accordingly, we investigated whether these agents have differential effects on CAC progression in patients with CKD. STUDY DESIGN: Randomized, double-concealed, 48-week clinical trial. SETTING & PARTICIPANTS: CKD stage 3 or 4 with secondary hyperparathyroidism with CAC score > 0 and no prior treatment with activated vitamin D. INTERVENTION: Calcitriol versus paricalcitol. OUTCOMES: The primary outcome was log-transformed CAC change. Secondary outcomes included percent change in CAC volume, valvular calcifications, and bone mineral metabolism markers. RESULTS: Among 44 individuals randomly assigned, mean age was 65 years and mean estimated glomerular filtration rate was 27 mL/min/1.73 m2. Median CAC score was 140 (IQR, 55-277) Agatston units at baseline. There was no significant difference in CAC progression between treatment arms (P = 0.06). After adjustment for baseline CAC score (log), treatment group remains nonsignificant (P = 0.08). Further adjustment for creatinine level and/or CKD stage did not change the association. In secondary analyses adjusting for dose level of activated vitamin D, treatment group was significant (P = 0.01), and when dose level was also included in the model, the coefficient for individuals in the paricalcitol group was significantly associated with CAC progression (P = 0.02). An interaction term between dosing level and CKD stage was significant at the highest dosing level (P = 0.04). LIMITATIONS: Pilot single-center study. CONCLUSIONS: In patients with CKD with secondary hyperparathyroidism naive to activated vitamin D therapy, there was no difference in CAC or valvular progression in participants receiving calcitriol compared with paricalcitol during a 48-week period. FUNDING: Abbvie, Inc. TRIAL REGISTRATION: NCT00752102.

Effect of dairy consumption and its fat content on glycemic control and cardiovascular disease risk factors in patients with type 2 diabetes: a randomized controlled study.

BACKGROUND: Dietary Guidelines for Americans recommend the consumption of 3 servings/d of low-fat/nonfat dairy. The effects of higher dairy consumption and its fat content are unknown in patients with type 2 diabetes. OBJECTIVE: Evaluate the impact of higher consumption of high- compared with low-fat dairy on glycated hemoglobin (HbA1c), body weight, and cardiovascular disease risk factors in patients with type 2 diabetes. METHODS: We enrolled 111 subjects with type 2 diabetes (aged 58.5 ± 8.9 y, 47% females, diabetes duration 13.2 ± 8.3 y, HbA1c 8.09 ± 0.96%) who consumed <3 servings of dairy/d. We randomly assigned them into 3 groups: control group maintained baseline dairy intake, low-fat (LF) group incorporated ≥3 servings/d of LF dairy, and the high-fat (HF) group incorporated ≥3 servings/d of HF dairy. We evaluated HbA1c, body weight, BMI, body composition parameters, blood pressure (BP), lipid parameters, homeostatic model assessment of insulin resistance (HOMA-IR), and total energy and macronutrient intake at baseline, and after 12 and 24 wk. RESULTS: At 24 wk, percent energy from saturated fat increased from baseline in the HF group by 3.6%, (95% CI: 2.2, 5.1) and decreased in the LF group by -1.9% (95% CI: -3.3, -0.4). The LF group increased their percent energy from protein by 4.5% (95% CI: 2.6, 6.4), whereas the HF group decreased their percent energy from carbohydrates by -3.4% (95% CI: -0.2, -6.7). There were no differences in the mean changes in HbA1c, body weight, BMI, body composition or lipid parameters, or BP between the 3 groups at 24 wk. CONCLUSION: In patients with type 2 diabetes, increased dairy consumption to ≥3 servings/d compared with <3 servings/d, irrespective of its fat content, while maintaining energy intake has no effect on HbA1c, body weight, body composition, lipid profile, or BP. This trial was registered at clinicaltrials.gov as NCT02895867.

A Randomized, Placebo-Controlled Double-Blind Trial of a Closed-Loop Glucagon System for Postbariatric Hypoglycemia.

BACKGROUND: Postbariatric hypoglycemia (PBH) can threaten safety and reduce quality of life. Current therapies are incompletely effective. METHODS: Patients with PBH were enrolled in a double-blind, placebo-controlled, crossover trial to evaluate a closed-loop glucose-responsive automated glucagon delivery system designed to reduce severe hypoglycemia. A hypoglycemia detection and mitigation algorithm was embedded in the artificial pancreas system connected to a continuous glucose monitor (CGM, Dexcom) driving a patch infusion pump (Insulet) filled with liquid investigational glucagon (Xeris) or placebo (vehicle). Sensor/plasma glucose responses to mixed meal were assessed during 2 study visits. The system delivered up to 2 doses of study drug (300/150 µg glucagon or equal-volume vehicle) if triggered by the algorithm. Rescue dextrose was given for plasma glucose <55 mg/dL or neuroglycopenia. RESULTS: Twelve participants (11 females/1 male, age 52 ± 2, 8 ± 1 years postsurgery, mean ± SEM) completed all visits. Predictive hypoglycemia alerts prompted automated drug delivery postmeal, when sensor glucose was 114 ± 7 vs 121 ± 5 mg/dL (P = .39). Seven participants required rescue glucose after vehicle but not glucagon (P = .008). Five participants had severe hypoglycemia (<55 mg/dL) after vehicle but not glucagon (P = .03). Nadir plasma glucose was higher with glucagon vs vehicle (67 ± 3 vs 59 ± 2 mg/dL, P = .004). Plasma glucagon rose after glucagon delivery (1231 ± 187 vs 16 ± 1 pg/mL at 30 minutes, P = .001). No rebound hyperglycemia occurred. Transient infusion site discomfort was reported with both glucagon (n = 11/12) and vehicle (n = 10/12). No other adverse events were observed. CONCLUSION: A CGM-guided closed-loop rescue system can detect imminent hypoglycemia and deliver glucagon, reducing severe hypoglycemia in PBH. CLINICAL TRIALS REGISTRATION: NCT03255629.

Effect of diabetes-specific nutrition formulas on satiety and hunger hormones in patients with type 2 diabetes.

OBJECTIVES: Diabetes-specific nutritional formulas (DSNFs) are frequently used by patients with type 2 diabetes (T2D) as part of nutrition therapy to improve glycemic control and reduce body weight. However, their effects on hunger and satiety hormones when compared to an isocaloric standardized breakfast are not fully understood. This study aims to evaluate the postprandial effects of two DSNFs-Glucerna (GL) and Ultra Glucose Control (UGC)-versus oatmeal on selected satiety and hunger hormones. METHOD: After an overnight fast, 22 patients with T2D (mean age 62.3 ± 6.8 years, A1C 6.8 ± 0.7%, body weight 97.4 ± 21.3 kg, and BMI 33.2 ± 5.9 kg/m²) were given 200 kcal of each meal on three separate days. Blood samples for amylin, cholecystokinin (CCK), ghrelin, glucagon, leptin, and peptide-YY (PYY) were collected at baseline and 30, 60, 90, 120, 180, and 240 min after the start of each meal. Incremental area under the curve (iAUC0-240) for each hormone was calculated. RESULTS: iAUC0-240 for glucagon and PYY were significantly higher after GL and UGC than after oatmeal (p < 0.001 for both). No difference was observed between the three meals on postprandial amylin, CCK, ghrelin, and leptin hormones. CONCLUSIONS: Intake of DSNFs significantly increases secretion of PYY and glucagon, two important satiety hormones. While subjective satiety was not directly evaluated, the increased effect on satiety hormones may partially explain the mechanism of body weight loss associated with DSNF use.

Frequency of self-monitoring of blood glucose in relation to weight loss and A1C during intensive multidisciplinary weight management in patients with type 2 diabetes and obesity.

Objective: We evaluated the relationship between frequency of self-monitoring of blood glucose (SMBG) and body weight, A1C, and cardiovascular risk factors in patients with type 2 diabetes (T2D) and obesity enrolled in a 12-week intensive multidisciplinary weight management (IMWM) program. Research design and methods: We conducted a retrospective analysis of 42 patients who electronically uploaded their SMBG data over 12 weeks of an IMWM program and divided them into tertiles based on their average frequency of SMBG per day. Mean (range) SMBG frequencies were 2.3 (1.1-2.9) times/day, 3.4 (3-3.9) times/day, and 5 (4-7.7) times/day in the lowest, middle, and highest tertiles, respectively. Anthropometric and metabolic parameters were measured at baseline and after 12 weeks of intervention. Results: Participants in the highest tertile achieved a median change (IQR) in body weight of -10.4 kg (-7.6 to -14.4 kg) compared with -8.3 kg (-5.2 to -12.2 kg), and -6.9 kg (-4.2 to -8.9 kg) in the middle and lowest tertiles, respectively (p=0.018 for trend). Participants in the highest tertile had a median change (IQR) in A1C of -1.25% (-0.6 to -3.1%) compared with -0.8% (-0.3% to -2%) and -0.5% (-0.2% to -1.2%) in the middle and lowest tertiles, respectively (p=0.048 for trend). The association between change in body weight and SMBG frequency remained significant after adjusting for age, sex, baseline body mass index, diabetes duration, and use of insulin therapy. Conclusions: Increased frequency of SMBG during IMWM is associated with significantly better weight loss and improvement of A1C in patients with T2D and obesity. These findings may suggest future clinical recommendations aimed at increasing SMBG frequency to achieve the most favorable outcomes.

Plasma FGF-19 Levels are Increased in Patients with Post-Bariatric Hypoglycemia.

BACKGROUND: Hypoglycemia is an increasingly recognized complication of bariatric surgery. Mechanisms contributing to glucose lowering remain incompletely understood. We aimed to identify differentially abundant plasma proteins in patients with post-bariatric hypoglycemia (PBH) after Roux-en-Y gastric bypass (RYGB), compared to asymptomatic post-RYGB. METHODS: Proteomic analysis of blood samples collected after overnight fast and mixed meal challenge in individuals with PBH, asymptomatic RYGB, severe obesity, or overweight recruited from outpatient hypoglycemia or bariatric clinics. RESULTS: The top-ranking differentially abundant protein at 120 min after mixed meal was fibroblast growth factor 19 (FGF-19), an intestinally derived hormone regulated by bile acid-FXR signaling; levels were 2.4-fold higher in PBH vs. asymptomatic post-RYGB (mean + SEM, 1094 ± 141 vs. 428 ± 45, P < 0.001, FDR < 0.01). FGF-19 ELISA confirmed 3.5-fold higher concentrations in PBH versus asymptomatic (360 ± 70 vs. 103 ± 18, P = 0.025). To explore potential links between increased FGF-19 and GLP-1, residual samples from other human studies in which GLP-1 was modulated were assayed. FGF-19 levels did not change in response to infusion of GLP-1 and PYY in overweight/obese individuals. Infusion of the GLP-1 receptor antagonist exendin 9-39 in recently operated asymptomatic post-RYGB did not alter FGF-19 levels after mixed meal. By contrast, GLP-1 receptor antagonist infusion yielded a significant increase in FGF-19 levels after oral glucose in individuals with PBH. While plasma bile acids did not differ between PBH and asymptomatic post-RYGB, these data suggest unique interrelationships between GLP-1 and FGF-19 in PBH. CONCLUSIONS: Taken together, these data support FGF-19 as a potential contributor to insulin-independent pathways driving postprandial hypoglycemia in PBH.

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).

Characterization of periodontitis in people with type 1 diabetes of 50 years or longer duration.

BACKGROUND: Periodontitis is more common and severe in people with diabetes than the general population. We have reported in the Joslin Medalist Study that people with type 1 diabetes of ≥50 years (Medalists) may have endogenous protective factors against diabetic nephropathy and retinopathy. METHODS: In this cross-sectional study, the prevalence of periodontitis according to the Centers for Disease Control/American Academy of Periodontology classification in a subset (n = 170, mean age = 64.6 ± 6.9 years) of the Medalist cohort, and its associations to various criteria of periodontitis and diabetic complications were assessed. RESULTS: The prevalence of severe periodontitis in Medalists was only 13.5% which was lower than reported levels in diabetic patients of similar ages. Periodontal parameters, including bleeding on probing, plaque index, gingival index, and demographic traits, including male sex, chronological age, and age at diagnosis were significantly associated with severity of periodontitis, which did not associate with diabetes duration, hemoglobin A1c (HbA1c), body mass index, and lipid profiles. Random serum C-peptide levels inversely associated with severity of periodontitis (P = 0.03), lower probing depth (P = 0.0002), and clinical attachment loss (P = 0.03). Prevalence of cardiovascular diseases (CVD) and systemic inflammatory markers, plasma interleukin-6 (IL-6), and serum immunoglobulin G titer against Porphyromonas gingivalis positively associated with severity of periodontitis (P = 0.002 and 0.02, respectively). Antibody titer to P. gingivalis correlated positively and significantly with CVD, serum IL-6, and high-sensitivity C-reactive protein. CONCLUSIONS: Some Medalists could be protected from severe periodontitis even with hyperglycemia. Endogenous protective factors for periodontitis could possibly be related to residual insulin production and lower levels of chronic inflammation.

Characterization of Glycolytic Enzymes and Pyruvate Kinase M2 in Type 1 and 2 Diabetic Nephropathy.

OBJECTIVE: Elevated glycolytic enzymes in renal glomeruli correlated with preservation of renal function in the Medalist Study, individuals with ≥50 years of type 1 diabetes. Specifically, pyruvate kinase M2 (PKM2) activation protected insulin-deficient diabetic mice from hyperglycemia-induced glomerular pathology. This study aims to extend these findings in a separate cohort of individuals with type 1 and type 2 diabetes and discover new circulatory biomarkers for renal protection through proteomics and metabolomics of Medalists' plasma. We hypothesize that increased glycolytic flux and improved mitochondrial biogenesis will halt the progression of diabetic nephropathy. RESEARCH DESIGN AND METHODS: Immunoblots analyzed selected glycolytic and mitochondrial enzymes in postmortem glomeruli of non-Medalists with type 1 diabetes (n = 15), type 2 diabetes (n = 19), and no diabetes (n = 5). Plasma proteomic (SOMAscan) (n = 180) and metabolomic screens (n = 214) of Medalists with and without stage 3b chronic kidney disease (CKD) were conducted and significant markers validated by ELISA. RESULTS: Glycolytic (PKM1, PKM2, and ENO1) and mitochondrial (MTCO2) enzymes were significantly elevated in glomeruli of CKD- versus CKD+ individuals with type 2 diabetes. Medalists' plasma PKM2 correlated with estimated glomerular filtration rate (r 2 = 0.077; P = 0.0002). Several glucose and mitochondrial enzymes in circulation were upregulated with corresponding downregulation of toxic metabolites in CKD-protected Medalists. Amyloid precursor protein was also significantly upregulated, tumor necrosis factor receptors downregulated, and both confirmed by ELISA. CONCLUSIONS: Elevation of enzymes involved in the metabolism of intracellular free glucose and its metabolites in renal glomeruli is connected to preserving kidney function in both type 1 and type 2 diabetes. The renal profile of elevated glycolytic enzymes and reduced toxic glucose metabolites is reflected in the circulation, supporting their use as biomarkers for endogenous renal protective factors in people with diabetes.

Retinol binding protein 3 is increased in the retina of patients with diabetes resistant to diabetic retinopathy.

The Joslin Medalist Study characterized people affected with type 1 diabetes for 50 years or longer. More than 35% of these individuals exhibit no to mild diabetic retinopathy (DR), independent of glycemic control, suggesting the presence of endogenous protective factors against DR in a subpopulation of patients. Proteomic analysis of retina and vitreous identified retinol binding protein 3 (RBP3), a retinol transport protein secreted mainly by the photoreceptors, as elevated in Medalist patients protected from advanced DR. Mass spectrometry and protein expression analysis identified an inverse association between vitreous RBP3 concentration and DR severity. Intravitreal injection and photoreceptor-specific overexpression of RBP3 in rodents inhibited the detrimental effects of vascular endothelial growth factor (VEGF). Mechanistically, our results showed that recombinant RBP3 exerted the therapeutic effects by binding and inhibiting VEGF receptor tyrosine phosphorylation. In addition, by binding to glucose transporter 1 (GLUT1) and decreasing glucose uptake, RBP3 blocked the detrimental effects of hyperglycemia in inducing inflammatory cytokines in retinal endothelial and Müller cells. Elevated expression of photoreceptor-secreted RBP3 may have a role in protection against the progression of DR due to hyperglycemia by inhibiting glucose uptake via GLUT1 and decreasing the expression of inflammatory cytokines and VEGF.

Exercise tolerance and thermoregulatory responses during cycling in boys and men.

PURPOSE: Physiological responses to exercise in the heat differ between prepubertal children and young adults. Whether these maturity-related variations imply lower exercise tolerance, inferior thermoregulation, and greater risk for heat injury in the child is uncertain. This study directly compared thermoregulatory and cardiovascular responses as well as endurance performance between prepubertal boys and adult males during steady-load cycling in moderately hot and cool ambient conditions with moderate humidity. METHODS: Eight prepubertal boys (age 11.7 +/- 0.4 yr) and eight adult men (age 31.8 +/- 2.0 yr) performed steady-load cycling to exhaustion at an intensity equivalent to approximately 65% peak V O2 in both hot (approximately 31 degrees C) and cool (approximately 19 degrees C) environments, with fluid intake ad libitum. RESULTS: Exercise duration in the heat was shorter for both groups (hot: men 30.46 +/- 8.84 min, boys 29.30 +/- 6.19 min; cold: men 42.88 +/- 11.79 min, boys 41.38 +/- 6.30 min), with no significant difference between men and boys (P > 0.05). Increases in rectal temperature, heart rate, and cardiac index were similar between groups and conditions. Stroke index, mean arterial pressure, and arterial venous oxygen difference were stable and similar in both conditions, without group differences. No significant dehydration was observed in men or boys. CONCLUSIONS: This study failed to reveal differences in exercise tolerance, thermoregulatory adaptation, or cardiovascular response to exercise in the heat between euhydrated prepubertal boys and adult men.

Innovation in medical education: a culinary coaching tele-nutrition training program.

BACKGROUND: Nutrition medical education training programs that are focused on home cooking are emerging. OBJECTIVE: This short communication describes the first synchronous tele-nutrition medical education training program using a novel Culinary Coaching (CC) model. DESIGN: Seven health coaches were trained and each coach delivered CC programs to four patients (28 total). Evaluations included:1) two questionnaires before, immediately after, and six months post training program; and 2) one questionnaire after each patient program. RESULTS: CC training significantly improved coaches' attitudes about and confidence to deliver CC from pre-program means of 3.61 and 3.65 (out of 5), respectively, to post-program means, 3.77 (p<0.01) and 3.86 (p<0.05), respectively, and remained higher 6 months after the training program (3.93, p<0.01; 3.93, p<0.05). Health coaches described a high usage of CC principles and tools through the patient programs. CONCLUSIONS: This early evidence suggests that the CC model can be successfully expanded to health coaches, thus improving nutritional care.

Depressive Symptoms at Critical Times in Youth With Type 1 Diabetes: Following Type 1 Diabetes Diagnosis and Insulin Pump Initiation.

PURPOSE: Depressive symptoms occur at various times during the life cycle in persons with type 1 diabetes. We investigated depressive symptoms prospectively in youth with new-onset type 1 diabetes and in those beginning pump therapy. METHODS: Youth with type 1 diabetes (N = 96), ages 10-17 years, completed the Children's Depression Inventory (CDI) at baseline and at 1, 6, and 12 months after diabetes onset or pump start; scores ≥13 indicated clinical elevation. The change in depressive symptoms and the association between CDI score and hemoglobin A1c (HbA1c) level were assessed over 1 year. RESULTS: The new-onset group (n = 54) had an HbA1c level of 11.4% ± 2.5%. The pump group (n = 42) had a diabetes duration of 4.1 ± 3.4 years and an HbA1c level of 8.3% ± 1.3%. The baseline median CDI was 5.0 in both groups and remained low over time (ranging from 2.0 to 3.5). Most youth (new onset 72%, pump 81%) scored <13 at all times. Those with a CDI score of ≥13 in month 1 had 9-fold (95% confidence interval: 3-28) and 11-fold (95% confidence interval: 3-38) higher risks of CDI score of ≥13 at 6 and 12 months, respectively, than those with a CDI score of <13. New-onset youth with a CDI score of ≥13 in month 1 had a higher HbA1c level at 6 months (8.3% ± 1.7%) than new-onset youth with a CDI score of <13 (7.2% ± 1.6%, p = .04). CONCLUSIONS: CDI scores over 1 year were similar in the new-onset and pump groups. Youth with elevated CDI in the first month after diagnosis or pump start were significantly more likely to have a CDI score of ≥13 at 6 or 12 months, supporting recommendations to screen for depressive symptoms because of persistence over time. Those with new-onset diabetes and depressive symptoms in the first month had higher HbA1c at 6 months; confirmatory research is needed.