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Effect of intratrial mean 25(OH)D concentration on diabetes risk, by race and weight: an ancillary analysis in the D2d study.
Chatterjee, R, Davenport, CA, Vickery, EM, Johnson, KC, Kashyap, SR, LeBlanc, ES, Nelson, J, Dagogo-Jack, S, Pittas, AG, Hughes, BD, et al
The American journal of clinical nutrition. 2023;(1):59-67
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BACKGROUND Higher serum 25-hydroxyvitamin D [25(OH)D] is associated with lower type 2 diabetes risk. 25(OH)D varies due to skin pigmentation and weight. OBJECTIVES This analysis aims to determine whether the effect of vitamin D differs among people of color and those with overweight/obesity (who have higher diabetes risk) compared with individuals who are White or have normal weight. METHODS The D2d study is a randomized clinical trial in people with prediabetes that tested the effects of daily vitamin D3 4000 IU vs. placebo on diabetes risk (median followup 2.5 y). We compared baseline and intratrial mean 25(OH)D concentrations, defined as the mean of all available annual 25(OH)D values, among groups defined by self-reported race and body mass index (BMI). We used Cox proportional hazards models to assess the associations between intratrial mean 25(OH)D and diabetes risk by race- and BMI-based groups. RESULTS Asian (n=130), Black (n=616), and White (n=1616) participants were included. Both baseline and intratrial mean 25(OH)D concentrations differed significantly by race groups (both P < 0.001) and were lower in Asian and Black vs. White participants, and in those with higher vs. lower BMI adjusted for race (both P < 0.001). Compared with those with lower concentrations, Black and White participants with intratrial mean 25(OH)D ≥ 40 ng/mL had significantly reduced diabetes risk [HR (95% CI): Black: 0.51 (0.29, 0.92); White: 0.42 (0.30, 0.60)] and with a similar reduction in diabetes risk among Asian participants: 0.39 (0.14, 1.11). Compared with those with lower concentrations, participants with baseline BMI < 40 kg/m2 who achieved intratrial mean 25(OH)D concentrations ≥ 40 ng/mL had a significantly reduced diabetes risk. There was no statistically significant interaction between intratrial 25(OH)D and race or between intratrial 25(OH)D and BMI on diabetes risk. CONCLUSIONS Among people with prediabetes, particularly for Black and White race groups and those with BMI < 40 kg/m2, the optimal 25(OH)D concentration may be ≥ 40 ng/mL to optimize diabetes-prevention efforts. This trial was registered at clinicaltrials.gov as NCT01942694.
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Diagnosis and management of post-bariatric surgery hypoglycemia.
Alkhaled, L, Al-Kurd, A, Butsch, WS, Kashyap, SR, Aminian, A
Expert review of endocrinology & metabolism. 2023;(6):459-468
Abstract
INTRODUCTION While bariatric surgery remains the most effective treatment for obesity that allows substantial weight loss with improvement and possibly remission of obesity-associated comorbidities, some postoperative complications may occur. Managing physicians need to be familiar with the common problems to ensure timely and effective management. Of these complications, postoperative hypoglycemia is an increasingly recognized complication of bariatric surgery that remains underreported and underdiagnosed. AREA COVERED This article highlights the importance of identifying hypoglycemia in patients with a history of bariatric surgery, reviews pathophysiology and addresses available nutritional, pharmacological and surgical management options. Systemic evaluation including careful history taking, confirmation of hypoglycemia and biochemical assessment is essential to establish accurate diagnosis. Understanding the weight-dependent and weight-independent mechanisms of improved postoperative glycemic control can provide better insight into the causes of the exaggerated responses that lead to postoperative hypoglycemia. EXPERT OPINION Management of post-operative hypoglycemia can be challenging and requires a multidisciplinary approach. While dietary modification is the mainstay of treatment for most patients, some patients may benefit from pharmacotherapy (e.g. GLP-1 receptor antagonist); Surgery (e.g. reversal of gastric bypass) is reserved for unresponsive severe cases. Additional research is needed to understand the underlying pathophysiology with a primary aim in optimizing diagnostics and treatment options.
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Indices of hepatic steatosis and fibrosis in prediabetes and association with diabetes development in the vitamin D and type 2 diabetes study.
Corbin, KD, Pittas, AG, Desouza, C, Grdinovac, KK, Herzig, KH, Kashyap, SR, Kim, SH, Nelson, J, Rasouli, N, Vickery, EM, et al
Journal of diabetes and its complications. 2023;(6):108475
Abstract
AIMS: Non-alcoholic fatty liver disease (NAFLD) is a common comorbidity that leads to poor outcomes in people at high risk for development of type 2 diabetes (T2D). Vitamin D is a possible mediator. In the vitamin D and type 2 diabetes study (D2d), we investigated the relationship of baseline indices of NAFLD with incident T2D and whether the effect of vitamin D on diabetes was modified by NAFLD. METHODS Cross-sectional associations of indices of NAFLD with glycemia and vitamin D status were assessed in 3972 individuals screened for the D2d study. In those with prediabetes randomized to vitamin D or placebo (n = 2423), we examined longitudinal associations of NAFLD indices with incident T2D. We used validated non-invasive scores to assess steatosis [(hepatic steatosis index (HSI); NAFLD-liver fat score (NAFLD-LFS)] and advanced fibrosis [fibrosis-4 (FIB-4) index; AST to Platelet Ratio Index (APRI)]. RESULTS Eighty-five percent of screened participants had likely steatosis by HSI and 71 % by NAFLD-LFS; 3 % were likely to have advanced fibrosis by FIB-4 and 1.2 % by APRI. FIB-4 indicated that 20.4 % of individuals require further follow up to assess liver health. Steatosis and fibrosis scores were higher among participants with worse glycemia. The NAFLD-LFS and APRI predicted development of diabetes (hazard ratios [95%CI] 1.35 [1.07, 1.70]; P = 0.012) and 2.36 (1.23, 4.54; P = 0.010), respectively). The effect of vitamin D on diabetes risk was not modified by baseline NAFLD indices. Individuals with likely steatosis had a smaller increase in serum 25-hydroxyvitamin D level in response to vitamin D than those without steatosis. CONCLUSIONS The predicted high prevalence of steatosis, the need for further fibrosis workup, and the relationship between liver health and incident T2D suggest that routine screening with clinically accessible scores may be an important strategy to reduce disease burden.
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The effect of vitamin D supplementation on cardiovascular risk in patients with prediabetes: A secondary analysis of the D2d study.
Desouza, C, Chatterjee, R, Vickery, EM, Nelson, J, Johnson, KC, Kashyap, SR, Lewis, MR, Margolis, K, Pratley, R, Rasouli, N, et al
Journal of diabetes and its complications. 2022;(8):108230
Abstract
AIMS: Low blood 25(OH)D level is associated with increased cardiovascular disease (CVD) risk. Additionally, individuals with prediabetes are at higher risk for CVD than individuals with normoglycemia. We investigated the effects of vitamin D supplementation on CVD outcomes in the vitamin D and type 2 diabetes (D2d) study, a large trial among adults with prediabetes. METHODS 2423 participants were randomized to 4000 IU/day of vitamin D3 or placebo and followed for median 3.0 years for new-onset diabetes. In pre-specified secondary analyses, we examined the effect of vitamin D supplementation on composite Major Adverse Cardiovascular Events (MACE); expanded MACE (MACE + revascularization); atherosclerotic CVD (ASCVD) risk score; and individual CVD risk factors (blood pressure, lipids, high-sensitivity C-reactive protein). Cox models compared hazard ratios (HR) between the two groups on MACE and expanded MACE. RESULTS Mean age was 60 years, 45 % were women, 13 % had history of CVD. Twenty-one participants assigned to vitamin D and 12 participants assigned to placebo met the MACE outcome (HR 1.81, 95%CI 0.89 to 3.69). There were 27 expanded MACE outcomes in each group (HR 1.02, 95%CI, 0.59 to 1.76). There were no significant differences between vitamin D and placebo in individual CVD risk factors, but change in ASCVD risk score favored the vitamin D group (-0.45 %, 95%CI -0.75 to -0.15). CONCLUSIONS In people with prediabetes not selected for vitamin D insufficiency and with intermediate CVD risk, vitamin D supplementation did not decrease MACE but had a small favorable effect on ASCVD risk score. TRIAL REGISTRATION D2d ClinicalTrials.gov number, NCT01942694, prospectively registered September 16, 2013.
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Prevalence and Clinical Determinants of Obesity in Adults With Type 1 Diabetes Mellitus: A Single-Center Retrospective Observational Study.
Tsushima, Y, Zhou, K, Bena, JF, Kashyap, SR
Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists. 2022;(4):378-383
Abstract
OBJECTIVE To determine the prevalence of obesity and assess the cardiometabolic risk profile and treatments associated with obesity management in the type 1 diabetes mellitus adult population. METHODS We reviewed the records of all patients with type 1 diabetes mellitus seen in our institution's outpatient endocrinology clinic between 2015 and 2018. We stratified the patients into 4 weight categories on the basis of body mass index (BMI) (normal, overweight, obesity class I, and combined obesity class II and III) and evaluated their associated clinical characteristics and relevant medications. RESULTS Of 451 patients, 64% had a BMI of >25 kg/m2, and 25% had a BMI of ≥30 kg/m2. Over 40% of patients with a BMI of >30 kg/m2 had a history of cardiovascular disease. The off-label use of the glucagon-like peptide 1 receptor agonist was 12% and the sodium glucose cotransporter 2 inhibitor use was 5% in those with obesity. Only 2 patients were prescribed phentermine and 3 had undergone bariatric surgery. Hemoglobin A1C and low-density lipoprotein did not significantly differ between the normal weight and obesity groups. The obesity groups had significantly higher levels of median triglycerides and lower high-density lipoprotein than the normal weight group. CONCLUSION Obesity was prevalent in a population of patients with type 1 diabetes mellitus seen in a specialty clinic. Those with obesity had a higher prevalence of cardiovascular disease than their normal weight counterparts. The use of weight loss medications was scarce. Studies exploring the safety and efficacy of obesity-targeted therapy in the type 1 diabetes mellitus population are needed.
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Early Post-Renal Transplant Hyperglycemia.
Iqbal, A, Zhou, K, Kashyap, SR, Lansang, MC
The Journal of clinical endocrinology and metabolism. 2022;(2):549-562
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CONTEXT Though posttransplant diabetes mellitus (PTDM, occurring > 45 days after transplantation) and its complications are well described, early post-renal transplant hyperglycemia (EPTH) (< 45 days) similarly puts kidney transplant recipients at risk of infections, rehospitalizations, and graft failure and is not emphasized much in the literature. Proactive screening and management of EPTH is required given these consequences. OBJECTIVE The aim of this article is to promote recognition of early post-renal transplant hyperglycemia, and to summarize available information on its pathophysiology, adverse effects, and management. METHODS A PubMed search was conducted for "early post-renal transplant hyperglycemia," "immediate posttransplant hyperglycemia," "post-renal transplant diabetes," "renal transplant," "diabetes," and combinations of these terms. EPTH is associated with significant complications including acute graft failure, rehospitalizations, cardiovascular events, PTDM, and infections. CONCLUSION Patients with diabetes experience better glycemic control in end-stage renal disease (ESRD), with resurgence of hyperglycemia after kidney transplant. Patients with and without known diabetes are at risk of EPTH. Risk factors include elevated pretransplant fasting glucose, diabetes, glucocorticoids, chronic infections, and posttransplant infections. We find that EPTH increases risk of re-hospitalizations from infections (cytomegalovirus, possibly COVID-19), acute graft rejections, cardiovascular events, and PTDM. It is essential, therefore, to provide diabetes education to patients before discharge. Insulin remains the standard of care while inpatient. Close follow-up after discharge is recommended for insulin adjustment. Some agents like dipeptidyl peptidase-4 inhibitors and glucagon-like peptide-1 receptor agonists have shown promise. The tenuous kidney function in the early posttransplant period and lack of data limit the use of sodium-glucose cotransporter 2 inhibitors. There is a need for studies assessing noninsulin agents for EPTH to decrease risk of hypoglycemia associated with insulin and long-term complications of EPTH.
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Association of prior metabolic and bariatric surgery with severity of coronavirus disease 2019 (COVID-19) in patients with obesity.
Aminian, A, Fathalizadeh, A, Tu, C, Butsch, WS, Pantalone, KM, Griebeler, ML, Kashyap, SR, Rosenthal, RJ, Burguera, B, Nissen, SE
Surgery for obesity and related diseases : official journal of the American Society for Bariatric Surgery. 2021;17(1):208-214
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A growing body of evidence indicates that patients with obesity are disproportionately affected with a severe form of SARS-CoV-2 infection and may experience resultant higher mortality. The aim of this study was to determine the association of prior metabolic surgery with severity of SARSCoV-2 infection in patients with severe obesity. This study is a retrospective, matched-cohort analysis of a prospective, observational, institutional review board–approved clinical registry of all patients tested for SARS-CoV-2 infection. The study population included a total of 363 patients, including 33 individuals who had metabolic surgery and 330 matched patients who tested positive. Results indicate that a history of metabolic surgery is associated with lower severity of SARSCoV-2 infection in patients with severe obesity, as manifested by lower risks of hospital and ICU admission. Authors conclude that prior metabolic surgery with subsequent weight loss and improvement of metabolic abnormalities could potentially reduce morbidity from SARS-CoV-2 infection.
Abstract
BACKGROUND Obesity is a risk factor for poor clinical outcomes in patients with coronavirus disease 2019 (COVID-19). OBJECTIVES To investigate the relationship between prior metabolic surgery and the severity of COVID-19 in patients with severe obesity. SETTING Cleveland Clinic Health System in the United States. METHODS Among 4365 patients who tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) between March 8, 2020 and July 22, 2020 in the Cleveland Clinic Health System, 33 patients were identified who had a prior history of metabolic surgery. The surgical patients were propensity matched 1:10 to nonsurgical patients to assemble a cohort of control patients (n = 330) with a body mass index (BMI) ≥ 40 kg/m2 at the time of SARS-CoV-2 testing. The primary endpoint was the rate of hospital admission. The exploratory endpoints included admission to the intensive care unit (ICU), need for mechanical ventilation and dialysis during index hospitalization, and mortality. After propensity score matching, outcomes were compared in univariate and multivariate regression models. RESULTS The average BMI of the surgical group was 49.1 ± 8.8 kg/m2 before metabolic surgery and was down to 37.2 ± 7.1 at the time of SARS-CoV-2 testing, compared with the control group's BMI of 46.7 ± 6.4 kg/m2. In the univariate analysis, 6 (18.2%) patients in the metabolic surgery group and 139 (42.1%) patients in the control group were admitted to the hospital (P = .013). In the multivariate analysis, a prior history of metabolic surgery was associated with a lower hospital admission rate compared with control patients with obesity (odds ratio, 0.31; 95% confidence interval, 0.11-0.88; P = .028). While none of the 4 exploratory outcomes occurred in the metabolic surgery group, 43 (13.0%) patients in the control group required ICU admission (P = .021), 22 (6.7%) required mechanical ventilation, 5 (1.5%) required dialysis, and 8 (2.4%) patients died. CONCLUSION Prior metabolic surgery with subsequent weight loss and improvement of metabolic abnormalities was associated with lower rates of hospital and ICU admission in patients with obesity who became infected with SARS-CoV-2. Confirmation of these findings will require larger studies.
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Long-Term Weight Loss Strategies for Obesity.
Kheniser, K, Saxon, DR, Kashyap, SR
The Journal of clinical endocrinology and metabolism. 2021;(7):1854-1866
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CONTEXT Obesity is a chronic disease that is difficult to manage without holistic therapy. The therapeutic armamentarium for obesity primarily consists of 4 forms of therapy: lifestyle modification (ie, diet and exercise), cognitive behavioral therapy, pharmacotherapy, and bariatric surgery. EVIDENCE ACQUISITION Evidence was consolidated from randomized controlled trials, observational studies, and meta-analyses. EVIDENCE SYNTHESIS After 2 years, lifestyle interventions can facilitate weight loss that equates to ~5%. Even though lifestyle interventions are plagued by weight regain, they can have substantial effects on type 2 diabetes and cardiovascular disease risk. Although 10-year percentage excess weight loss can surpass 50% after bariatric surgery, weight regain is likely. To mitigate weight regain, instituting a multifactorial maintenance program is imperative. Such a program can integrate diet, exercise, and pharmacotherapy. Moreover, behavioral therapy can complement a maintenance program well. CONCLUSIONS Obesity is best managed by a multidisciplinary clinical team that integrates diet, exercise, and pharmacotherapy. Bariatric surgery is needed to manage type 2 diabetes and obesity in select patients.
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Antiobesity drug therapy: An individualized and comprehensive approach.
Mauer, Y, Parker, M, Kashyap, SR
Cleveland Clinic journal of medicine. 2021;(8):440-448
Abstract
Obesity affects 42% of US adults and has a devastating impact on health. Although many patients initially lose weight with diet and exercise, long-term weight loss is difficult to achieve. Pharmacotherapy, as part of a comprehensive plan, can help patients lose weight and avoid regaining it. Choosing an antiobesity drug regimen should be an individualized, shared decision-making process that accounts for patient preferences, comorbidities, and out-of-pocket costs. We review antiobesity drugs and propose an individualized and comprehensive approach to obesity management.
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Foregut Exclusion Enhances Incretin and Insulin Secretion After Roux-en-Y Gastric Bypass in Adults With Type 2 Diabetes.
Kirwan, JP, Axelrod, CL, Kullman, EL, Malin, SK, Dantas, WS, Pergola, K, Del Rincon, JP, Brethauer, SA, Kashyap, SR, Schauer, PR
The Journal of clinical endocrinology and metabolism. 2021;(10):e4192-e4201
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INTRODUCTION Patients with type 2 diabetes experience resolution of hyperglycemia within days after Roux-en-Y gastric bypass (RYGB) surgery. This is attributed, in part, to enhanced secretion of hindgut factors following exclusion of the gastric remnant and proximal intestine during surgery. However, evidence of the mechanisms of remission remain limited due to the challenges of metabolic evaluation during the early postoperative period. The purpose of this investigation was to determine the role of foregut exclusion in the resolution of type 2 diabetes after RYGB. METHODS Patients with type 2 diabetes (n = 15) undergoing RYGB had a gastrostomy tube (G-tube) placed in their gastric remnant at time of surgery. Patients were randomized to receive a mixed meal tolerance test via oral or G-tube feeding immediately prior to and 2 weeks after surgery in a repeated measures crossover design. Plasma glucose, insulin, C-peptide, incretin responses, and indices of meal-stimulated insulin secretion and sensitivity were determined. RESULTS Body weight, fat mass, fasting glucose and insulin, and circulating lipids were significantly decreased 2 weeks after surgery. The glycemic response to feeding was reduced as a function of total area under the curve but not after adjustment for the reduction in fasting glucose. Oral feeding significantly enhanced insulin and incretin secretion after RYGB, which was entirely ablated by G-tube feeding. CONCLUSION Foregut exclusion accounts for the rise in incretin and insulin secretion but may not fully explain the early improvements in glucose metabolism after RYGB surgery.