Diabetes and Risk of Non-Hodgkin's Lymphoma

OBJECTIVE: To examine the epidemiologic association between diabetes and risk of non-Hodgkin's lymphoma (NHL). RESEARCH DESIGN AND METHODS: We searched MEDLINE for observational studies on the association between diabetes and NHL in adults using the keywords "diabetes" and "lymphoma." Prospective cohort studies that reported relative risks or standardized incidence ratios and case-control studies that reported odds ratios with 95% CIs were included. A random-effects model was used to combine results from the individual studies. RESULTS: A total of 15 manuscripts (reporting data from 5 prospective cohort and 11 case-control studies) met the inclusion criteria. Combining data from all studies, the risk ratio (RR) of developing NHL in patients with diabetes was 1.19 (95% CI 1.04–1.35). Based on prospective studies, patients with diabetes had an RR of developing NHL of 1.41 (1.07–1.88), without heterogeneity among studies (I2 = 34.3%; P > 0.10). Based on case-control studies, patients with diabetes had an RR of 1.12 (95% CI 0.95–1.31) of developing NHL compared with people without diabetes, with some heterogeneity among studies (I2 = 36.28%; P = 0.09). CONCLUSIONS: Diabetes is associated with a moderately increased risk of NHL, which is consistent with other reported associations between diabetes and malignancies. Future studies should focus on elucidating potential pathophysiologic links between diabetes and NHL.National Institutes of Health grants (R01-DK76092, R0179003, and R2178867

Response to Letter to the Editor from Dalan: "Vitamin D Supplementation for Prevention of Type 2 Diabetes Mellitus: To D or Not to D?"

We thank Rinkoo Dalan for the comments on our paper (1, 2). We agree that although the reduction in diabetes risk with vitamin D supplementation among people at high risk for diabetes appears to be moderate (~ 12% relative risk reduction compared to placebo) (3), certain individuals may derive a higher (or lower) benefit based on certain characteristics. For example, in the simplest demonstration of such heterogeneity, vitamin D supplementation reduced diabetes risk by 62% among participants in the Vitamin D and Type 2 Diabetes (D2d) study who had a baseline serum 25-hydroxyvitamin D (25[OH]D) level of less than 12 ng/mL (30 mmol/L) (2). Consistent with the focus of the scientific community on precision nutrition, we agree that we need to better understand responsiveness to vitamin D supplementation for specific outcomes of interest. The vitamin D response index is an interesting concept that reflects activation of the vitamin D receptor, and it is determined on the basis of measuring vitamin D–triggered changes in the expression of 24 target genes in peripheral blood mononuclear cells and 12 clinical and biochemical parameters (4). There are at least 2 limitations: 1) Although such an index may reflect vitamin D–induced changes in specific response parameters, these changes may not necessarily translate to clinically meaningful outcomes, such as lowering diabetes risk. 2) Low-, mid-, and high-responders are determined with statistical means within a specific cohort but that can be calculated only retrospectively; specific cutoffs to define degree of response need to be established for use in real time in research or in the clinical setting. The author also suggests that daily, steady exposure to vitamin D is preferred over intermittent exposure for optimal benefit, and we agree. In a secondary analysis from the D2d study, we reported that participants who received the active intervention (100 mcg [4000 units] of vitamin D3 daily) and maintained high 25(OH)D levels that were stable throughout the trial period had the lowest risk of diabetes, whereas participants in the placebo group who maintained similar overall 25(OH)D levels that fluctuated during follow-up did not derive significant benefit (5)

Vitamin D: beyond bone.

In recent years, vitamin D has been received increased attention due to the resurgence of vitamin D deficiency and rickets in developed countries and the identification of extraskeletal effects of vitamin D, suggesting unexpected benefits of vitamin D in health and disease, beyond bone health. The possibility of extraskeletal effects of vitamin D was first noted with the discovery of the vitamin D receptor (VDR) in tissues and cells that are not involved in maintaining mineral homeostasis and bone health, including skin, placenta, pancreas, breast, prostate and colon cancer cells, and activated T cells. However, the biological significance of the expression of the VDR in different tissues is not fully understood, and the role of vitamin D in extraskeletal health has been a matter of debate. This report summarizes recent research on the roles for vitamin D in cancer, immunity and autoimmune diseases, cardiovascular and respiratory health, pregnancy, obesity, erythropoiesis, diabetes, muscle function, and aging

Plasma 25-Hydroxyvitamin D and Progression to Diabetes in Patients at Risk for Diabetes

OBJECTIVE To investigate the association between vitamin D status, assessed by plasma 25-hydroxyvitamin D, and risk of incident diabetes. RESEARCH DESIGN AND METHODS Prospective observational study with a mean follow-up of 2.7 years in the Diabetes Prevention Program (DPP), a multicenter trial comparing different strategies for prevention of diabetes in patients with prediabetes. We assessed the association between plasma 25-hydroxyvitamin D, measured repeatedly during follow-up, and incident diabetes in the combined placebo (n = 1,022) and intensive lifestyle (n = 1,017) randomized arms of the DPP. Variables measured at multiple study time points (25-hydroxyvitamin D, BMI, and physical activity) entered the analyses as time-varying “lagged” covariates, as the mean of the previous and current visits at which diabetes status was assessed. RESULTS After multivariate adjustment, including for the DPP intervention, participants in the highest tertile of 25-hydroxyvitamin D (median concentration, 30.1 ng/mL) had a hazard ratio of 0.72 (95% CI 0.56–0.90) for developing diabetes compared with participants in the lowest tertile (median concentration, 12.8 ng/mL). The association was in the same direction in placebo (0.70; 0.52–0.94) versus lifestyle arm (0.80; 0.54–1.17). CONCLUSIONS Higher plasma 25-hydroxyvitamin D, assessed repeatedly, was associated with lower risk of incident diabetes in high-risk patients, after adjusting for lifestyle interventions (dietary changes, increased physical activity, and weight loss) known to decrease diabetes risk. Because of the observational nature of the study, the potential association between vitamin D and diabetes needs to be confirmed in intervention studies

Effect of body composition methodology on heritability estimation of body fatness

Heritability estimates of human body fatness vary widely and the contribution of body composition methodology to this variability is unknown. The effect of body composition methodology on estimations of genetic and environmental contributions to body fatness variation was examined in 78 adult male and female monozygotic twin pairs reared apart or together. Body composition was assessed by six methods - body mass index (BMI), dual energy x-ray absorptiometry (DXA), underwater weighing (UWW), total body water (TBW), bioelectric impedance (BIA), and skinfold thickness. Body fatness was expressed as percent body fat, fat mass, and fat mass/height2 to assess the effect of body fatness expression on heritability estimates. Model-fitting multivariate analyses were used to assess the genetic and environmental components of variance. Mean BMI was 24.5 kg/m2 (range of 17.8-43.4 kg/m2). There was a significant effect of body composition methodology (p<0.001) on heritability estimates, with UWW giving the highest estimate (69%) and BIA giving the lowest estimate (47%) for fat mass/height2. Expression of body fatness as percent body fat resulted in significantly higher heritability estimates (on average 10.3% higher) compared to expression as fat mass/height2 (p=0.015). DXA and TBW methods expressing body fatness as fat mass/height2 gave the least biased heritability assessments, based on the small contribution of specific genetic factors to their genetic variance. A model combining DXA and TBW methods resulted in a relatively low FM/ht2 heritability estimate of 60%, and significant contributions of common and unique environmental factors (22% and 18%, respectively). The body fatness heritability estimate of 60% indicates a smaller contribution of genetic variance to total variance than many previous studies using less powerful research designs have indicated. The results also highlight the importance of environmental factors and possibly genotype by environmental interactions in the etiology of weight gain and the obesity epidemic.R01 AR046124 - NIAMS NIH HHS; R01 MH065322 - NIMH NIH HHS; T32 HL069772 - NHLBI NIH HHS; R21 DK078867 - NIDDK NIH HHS; R37 DA018673 - NIDA NIH HHS; R01 DK076092 - NIDDK NIH HHS; R01 DK079003 - NIDDK NIH HHS; F32 DK009747 - NIDDK NIH HHS; R01 DA018673 - NIDA NIH HH

Effects of 2-year calorie restriction on circulating levels of IGF-1, IGF-binding proteins and cortisol in nonobese men and women: A randomized clinical trial

Young-onset calorie restriction (CR) in rodents decreases serum IGF-1 concentration and increases serum corticosterone levels, which have been hypothesized to play major roles in mediating its anticancer and anti-aging effects. However, little is known on the effects of CR on the IGF-1 system and cortisol in humans. To test the sustained effects of CR on these key hormonal adaptations, we performed a multicenter randomized trial of a 2-year 25% CR intervention in 218 nonobese (body mass index between 22 and 27.8 kg m(-2) ) young and middle-aged (20-50 years age range) men and women. Average CR during the first 6 months was 19.5 ± 0.8% and 9.1 ± 0.7% over the next 18 months of the study. Weight loss averaged 7.6 ± 0.3 kg over the 2-years period of which 71% was fat mass loss (P < 0.0001). Average CR during the CR caused a significant 21% increase in serum IGFBP-1 and a 42% reduction in IGF-1:IGFBP-1 ratio at 2 years (P < 0.008), but did not change IGF-1 and IGF-1:IGFBP-3 ratio levels. Serum cortisol concentrations were slightly but significantly increased by CR at 1 year only (P = 0.003). Calorie restriction had no effect on serum concentrations of PDGF-AB and TGFβ-1. We conclude, on the basis of the present and previous findings, that, in contrast to rodents, humans do not respond to CR with a decrease in serum IGF-1 concentration or with a sustained and biological relevant increase in serum cortisol. However, long-term CR in humans significantly and persistently increases serum IGFBP-1 concentration

Vitamin D Supplementation and Prevention of Type 2 Diabetes

BACKGROUND Observational studies support an association between a low blood 25-hydroxyvitamin D level and the risk of type 2 diabetes. However, whether vitamin D supplementation lowers the risk of diabetes is unknown. METHODS We randomly assigned adults who met at least two of three glycemic criteria for prediabetes (fasting plasma glucose level, 100 to 125 mg per deciliter; plasma glucose level 2 hours after a 75-g oral glucose load, 140 to 199 mg per deciliter; and glycated hemoglobin level, 5.7 to 6.4%) and no diagnostic criteria for diabetes to receive 4000 IU per day of vitamin D3 or placebo, regardless of the baseline serum 25-hydroxyvitamin D level. The primary outcome in this time-to-event analysis was new-onset diabetes, and the trial design was event-driven, with a target number of diabetes events of 508. RESULTS A total of 2423 participants underwent randomization (1211 to the vitamin D group and 1212 to the placebo group). By month 24, the mean serum 25-hydroxyvitamin D level in the vitamin D group was 54.3 ng per milliliter (from 27.7 ng per milliliter at baseline), as compared with 28.8 ng per milliliter in the placebo group (from 28.2 ng per milliliter at baseline). After a median follow-up of 2.5 years, the primary outcome of diabetes occurred in 293 participants in the vitamin D group and 323 in the placebo group (9.39 and 10.66 events per 100 person-years, respectively). The hazard ratio for vitamin D as compared with placebo was 0.88 (95% confidence interval, 0.75 to 1.04; P = 0.12). The incidence of adverse events did not differ significantly between the two groups. CONCLUSIONS Among persons at high risk for type 2 diabetes not selected for vitamin D insufficiency, vitamin D3 supplementation at a dose of 4000 IU per day did not result in a significantly lower risk of diabetes than placebo. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; D2d ClinicalTrials.gov number, NCT01942694.

Vitamin D Supplementation and Prevention of Type 2 Diabetes

BACKGROUND Observational studies support an association between a low blood 25-hydroxyvitamin D level and the risk of type 2 diabetes. However, whether vitamin D supplementation lowers the risk of diabetes is unknown. METHODS We randomly assigned adults who met at least two of three glycemic criteria for prediabetes (fasting plasma glucose level, 100 to 125 mg per deciliter; plasma glucose level 2 hours after a 75-g oral glucose load, 140 to 199 mg per deciliter; and glycated hemoglobin level, 5.7 to 6.4%) and no diagnostic criteria for diabetes to receive 4000 IU per day of vitamin D3 or placebo, regardless of the baseline serum 25-hydroxyvitamin D level. The primary outcome in this time-to-event analysis was new-onset diabetes, and the trial design was event-driven, with a target number of diabetes events of 508. RESULTS A total of 2423 participants underwent randomization (1211 to the vitamin D group and 1212 to the placebo group). By month 24, the mean serum 25-hydroxyvitamin D level in the vitamin D group was 54.3 ng per milliliter (from 27.7 ng per milliliter at baseline), as compared with 28.8 ng per milliliter in the placebo group (from 28.2 ng per milliliter at baseline). After a median follow-up of 2.5 years, the primary outcome of diabetes occurred in 293 participants in the vitamin D group and 323 in the placebo group (9.39 and 10.66 events per 100 person-years, respectively). The hazard ratio for vitamin D as compared with placebo was 0.88 (95% confidence interval, 0.75 to 1.04; P = 0.12). The incidence of adverse events did not differ significantly between the two groups. CONCLUSIONS Among persons at high risk for type 2 diabetes not selected for vitamin D insufficiency, vitamin D3 supplementation at a dose of 4000 IU per day did not result in a significantly lower risk of diabetes than placebo. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; D2d ClinicalTrials.gov number, NCT01942694.