Jessica A. Alvarez

Role of Vitamin D in Insulin Secretion and Insulin Sensitivity for Glucose Homeostasis

Vitamin D functions are not limited to skeletal health benefits and may extend to preservation of insulin secretion and insulin sensitivity. This review summarizes the literature related to potential vitamin D influences on glucose homeostasis and insulin sensitivity. Cross-sectional data provide some evidence that circulating 25-hydroxyvitamin D (25(OH)D) is inversely associated with insulin resistance, although direct measurements of insulin sensitivity are required for confirmation. Reported associations with insulin secretion, however, are contradictory. Available prospective studies support a protective influence of high 25(OH)D concentrations on type 2 diabetes mellitus risk. There is a general lack of consistency in vitamin D intervention outcomes on insulin secretion and sensitivity, likely due to differences in subject populations, length of interventions, and forms of vitamin D supplementation. Vitamin D receptor gene polymorphisms and vitamin D interactions with the insulin like growth factor system may further influence glucose homeostasis. The ambiguity of optimal vitamin D dosing regimens and optimal therapeutic concentrations of serum 25(OH)D limit available intervention studies. Future studies, including cross-sectional and prospective, should be performed in populations at high risk for both vitamin D deficiency and type 2 diabetes mellitus. Well-designed, placebo-controlled, randomized intervention studies are required to establish a true protective influence of vitamin D on glucose homeostasis.

Threshold for Effects of Vitamin D Deficiency on Glucose Metabolism in Obese Female African-American Adolescents

CONTEXTnVitamin D status can influence insulin resistance.nnnOBJECTIVEnThe aim of the study was to determine the prevalence of vitamin D deficiency in obese African-American (AA) adolescent females in a southeastern latitude and to determine the relationship of 25-hydroxyvitamin D [25(OH)D] with insulin and glucose dynamics.nnnDESIGNnWe conducted a cross-sectional study in a University Childrens Hospital.nnnMETHODSnSerum 25(OH)D, fasting glucose, PTH, serum calcium, serum lipids, serum transaminases, and C-reactive protein were assessed. Indices of insulin sensitivity and resistance were determined from an oral glucose tolerance test. Subjects were classified as vitamin D deficient or sufficient, based on the traditional vitamin D deficiency definition [serum 25(OH)D <20 ng/ml] and also by a lower 25(OH)D cut-point of 15 ng/ml or less.nnnRESULTSnA total of 51 AA adolescent females (body mass index, 43.3 +/- 9.9 kg/m(2); age, 14 +/- 2 yr) were studied. Serum 25(OH)D concentrations were 20 ng/ml or less in 78.4% and 15 ng/ml or less in 60.8% of subjects. There were no significant group differences in the metabolic outcomes when subjects were classified using the traditional vitamin D deficiency definition. The Matsuda index of insulin sensitivity was significantly lower (P = 0.02), and insulin area under the curve was significantly higher (P = 0.04) in subjects with 25(OH)D concentrations of 15 ng/ml or less vs. those with higher concentrations.nnnCONCLUSIONSnVitamin D deficiency is highly prevalent in obese, AA female adolescents and may promote insulin resistance. Our data suggest that a 25(OH)D concentration of 15 ng/ml or less may be the threshold by which vitamin D deficiency confers negative effects on insulin sensitivity.

Serum 25-hydroxyvitamin D and parathyroid hormone are independent determinants of whole-body insulin sensitivity in women and may contribute to lower insulin sensitivity in African Americans

BACKGROUNDnCirculating 25-hydroxyvitamin D [25(OH)D] and parathyroid hormone (PTH) concentrations have been shown to be associated with insulin sensitivity; however, adiposity may confound this relation. Furthermore, African Americans (AAs) have lower insulin sensitivity and 25(OH)D concentrations than do European Americans (EAs); whether these differences are associated in a cause-and-effect manner has not been determined.nnnOBJECTIVESnThe objectives of this study were to examine the relation of 25(OH)D and PTH concentrations with whole-body insulin sensitivity and to determine whether lower 25(OH)D concentrations in AAs compared with EAs contribute to the lower insulin sensitivity of AAs relative to that of EAs.nnnDESIGNnThis was a cross-sectional study of 25 AA and 25 EA women. We determined the whole-body insulin sensitivity index (S(I)) with an intravenous glucose tolerance test and minimal modeling. Percentage body fat was determined with dual-energy X-ray absorptiometry, and intraabdominal adipose tissue (IAAT) was determined with computed tomography.nnnRESULTSnMultiple linear regression analysis indicated that 25(OH)D and PTH concentrations were independent determinants of S(I) [standardized β = 0.24 (P = 0.04) and -0.36 (P = 0.002), respectively] after adjustment for age, race, and IAAT. The mean ethnic difference in S(I) decreased from 2.70 [· 10(-4) · min⁻¹/(μIU/mL)] after adjustment for IAAT and percentage body fat to 1.80 [· 10(-4) · min⁻¹/(μIU/mL)] after further adjustment for 25(OH)D and PTH concentrations.nnnCONCLUSIONSn25(OH)D and PTH concentrations were independently associated with whole-body insulin sensitivity in a cohort of healthy women, which suggested that these variables may influence insulin sensitivity through independent mechanisms. Furthermore, ethnic differences in 25(OH)D concentrations may contribute to ethnic differences in insulin sensitivity.

Fasting and postprandial markers of inflammation in lean and overweight children

BACKGROUNDnOverweight children have greater circulating concentrations of markers of inflammation (MOI) than do lean children. Whether adiposity influences the postprandial MOI response is unknown.nnnOBJECTIVEnWe aimed to evaluate the relations of fasting and postprandial MOI with total and regional adiposity and insulin sensitivity in children.nnnDESIGNnFifty-nine children aged 7-12 y were assessed for C-reactive protein (CRP), interleukin-6 (IL-6), and soluble tumor necrosis factor receptor-2 (sTNF-R2) in the fasted state and after a mixed meal. Insulin sensitivity, body composition, and abdominal adipose tissue distribution were assessed with a frequently sampled intravenous-glucose-tolerance test, dual-energy X-ray absorptiometry, and computed tomography, respectively.nnnRESULTSnCentral adipose measures were not independently associated with fasting MOI, although they were independently inversely associated with the postprandial sTNF-R2 response (r = -0.30 to -0.37, P = 0.02-0.006). The inverse association between intraabdominal adipose tissue and the postprandial CRP response was nearly significant (r = -0.27, P = 0.05). Insulin sensitivity was not associated with fasting or postprandial CRP or sTNF-R2; however, there was a positive relation between insulin sensitivity and fasting IL-6 (r = 0.27, P = 0.03), which was attenuated after adjustment for lean body mass (r = 0.25, P = 0.08).nnnCONCLUSIONSnExcess adiposity is associated with both fasting and postprandial MOI. The postprandial MOI response may be influenced by central adiposity in children. The positive association of insulin sensitivity with IL-6 warrants further study.

Associations of Serum 25-Hydroxyvitamin D and Components of the Metabolic Syndrome in Obese Adolescent Females

Vitamin D deficiency may increase the risk for metabolic syndrome. We determined the relationship of serum 25‐hydroxyvitamin D (25(OH)D) with metabolic syndrome components in obese adolescent females and assessed whether vitamin D treatment corrects metabolic disturbances. Eighty postmenarchal adolescents (53 African American (AA) and 27 Caucasian American (CA)) were evaluated with blood pressures and fasting measurements of serum 25(OH)D, lipid profile, C‐reactive protein, alanine transaminases (ALTs) and aspartate transaminases followed by an oral glucose tolerance test. A subgroup (n = 14) of vitamin D deficient subjects were re‐evaluated following vitamin D treatment. Among all subjects, 25(OH)D was inversely associated with fasting glucose (r = −0.28, P = 0.02) and positively associated with low‐density lipoprotein (LDL) cholesterol (r = 0.31, P = 0.008), independent of race and BMI. In analyses by race, adjusted for BMI, 25(OH)D was inversely associated with fasting insulin in CA (r = −0.42, P = 0.03) but not AA (r = 0.11, P = 0.43) whereas 25(OH)D was positively associated with ALT in AA, but not CA (r = 0.29, P = 0.04 vs. r = −0.21, P = 0.32). Fasting glucose improved in vitamin D treated subgroup (from 89.07 ± 8.3 mg/dl to 84.34 ± 8.4 mg/dl, P = 0.05). A trend toward improvement in fasting glucose remained after exclusion of four subjects whose serum 25(OH)D2 did not improve following treatment (P = 0.12). In conclusion, serum 25(OH)D was inversely associated with fasting glucose, and vitamin D treatment had beneficial effects on fasting glucose. Relationships of 25(OH)D with fasting insulin and ALT were ethnic specific. The positive relationship with LDL and ALT were suggestive of possible adverse influences of vitamin D.

Vitamin D intake is associated with insulin sensitivity in African American, but not European American, women.

BackgroundThe prevalence of type 2 diabetes is higher among African Americans (AA) vs European Americans (EA), independent of obesity and other known confounders. Although the reason for this disparity is not known, it is possible that relatively low levels of vitamin D among AA may contribute, as vitamin D has been positively associated with insulin sensitivity in some studies. The objective of this study was to test the hypothesis that dietary vitamin D would be associated with a robust measure of insulin sensitivity in AA and EA women.MethodsSubjects were 115 African American (AA) and 137 European American (EA) healthy, premenopausal women. Dietary intake was determined with 4-day food records; the insulin sensitivity index (SI) with a frequently-sampled intravenous glucose tolerance test and minimal modeling; the Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) with fasting insulin and glucose; and body composition with dual-energy X-ray absorptiometry.ResultsVitamin D intake was positively associated with SI (standardized β = 0.18, P = 0.05) and inversely associated with HOMA-IR (standardized β = -0.26, P = 0.007) in AA, and the relationships were independent of age, total body fat, energy intake, and % kcal from fat. Vitamin D intake was not significantly associated with indices of insulin sensitivity/resistance in EA (standardized β = 0.03, P = 0.74 and standardized β = 0.02, P = 0.85 for SI and HOMA-IR, respectively). Similar to vitamin D, dietary calcium was associated with SI and HOMA-IR among AA but not EA.ConclusionsThis study provides novel findings that dietary vitamin D and calcium were independently associated with insulin sensitivity in AA, but not EA. Promotion of these nutrients in the diet may reduce health disparities in type 2 diabetes risk among AA, although longitudinal and intervention studies are required.

Ethnic differences in glucose disposal, hepatic insulin sensitivity, and endogenous glucose production among African American and European American women

Intravenous glucose tolerance tests have demonstrated lower whole-body insulin sensitivity (S(I)) among African Americans (AA) compared with European Americans (EA). Whole-body S(I) represents both insulin-stimulated glucose disposal, primarily by skeletal muscle, and insulins suppression of endogenous glucose production (EGP) by liver. A mathematical model was recently introduced that allows for distinction between disposal and hepatic S(I). The purpose of this study was to examine specific indexes of S(I) among AA and EA women to determine whether lower whole-body S(I) in AA may be attributed to insulin action at muscle, liver, or both. Participants were 53 nondiabetic, premenopausal AA and EA women. Profiles of EGP and indexes of Disposal S(I) and Hepatic S(I) were calculated by mathematical modeling and incorporation of a stable isotope tracer ([6,6-(2)H(2)]glucose) into the intravenous glucose tolerance test. Body composition was assessed by dual-energy x-ray absorptiometry. After adjustment for percentage fat, both Disposal S(I) and Hepatic S(I) were lower among AA (P = .009 for both). Time profiles for serum insulin and EGP revealed higher peak insulin response and corresponding lower EGP among AA women compared with EA. Indexes from a recently introduced mathematical model suggest that lower whole-body S(I) among nondiabetic AA women is due to both hepatic and peripheral components. Despite lower Hepatic S(I), AA displayed lower EGP, resulting from higher postchallenge insulin levels. Future research is needed to determine the physiological basis of lower insulin sensitivity among AA and its implications for type 2 diabetes mellitus risk.

Perception of exercise difficulty predicts weight regain in formerly overweight women

It has been previously reported that overweight and obese individuals perceive exercise as more difficult than their lean counterparts, and this difference may not be solely attributed to physiological differences. Therefore, we tested the hypothesis that individual differences in the perception of exercise difficulty during exercise, independent of concurrently measured physiological markers of exertion, are predictive of weight regain, after completion of a weight loss program. A total of 113 formerly overweight women who had previously completed a weight‐loss program to achieve a normal body weight (BMI <25 kg/m2) underwent a submaximal aerobic exercise task while measures of physiological and perceived exertion (rating of perceived exertion (RPE)) were recorded. Weight gain was assessed following a subsequent 1‐year free‐living period. Average weight regain 1 year following the intervention was 5.46 ± 3.95 kg. In regression modeling, RPE (β = 0.21, P = 0.01), but not physiological exertion (β = 0.02, P = 0.81), during the submaximal exercise task was positively associated with 1‐year weight regain following weight loss in premenopausal women, independent of measured confounding variables. The association between RPE and weight regain suggests that perception of exercise difficulty is an important predictor of weight regain following a weight‐loss intervention.

Role of Various Cytokines and Growth Factors in Pubertal Development

Historical data suggest that body composition is intricately involved in pubertal development. Progression through puberty is dependent on the interaction between the growth hormone-insulin-like growth factor-1 (GH-IGF-1) axis, reproductive and metabolic hormones as well as pro- and anti-inflammatory cytokines which induce alterations in feedback mechanisms and therefore mediate body composition and growth. Simultaneous increases in GH and IGF-1, and the concomitant changes in the hormonal milieu (i.e. reproductive hormones, testosterone and estrogen, and insulin)are the major contributors to anabolic effects seen throughout the pubertal transition, and are affected by various factors including (but not limited to) energy status and body composition. Orexigenic agents (i.e. ghrelin and leptin) also play a role at the level of the hypothalamus affecting not only energy intake, but also pubertal onset and progression. Effects of cytokines, many of which may be considered catabolic, extend beyond their traditionally viewed role involving the immune system, accompanying reproductive maturity further regulating aspects of energy and bone metabolism. As such, the signal(s) initiating the hypothalamic response that triggers puberty is likely reliant on a number of neural, metabolic and endocrine networks, all of which are at least partially influenced by pubertal growth factors, and act independently, antagonistically and/or synergistically to regulate anabolic pathways, therefore modifying body composition trajectory and growth during adolescence.

Glucose Metabolism and Diet Predict Changes in Adiposity and Fat Distribution in Weight-reduced Women

Among obesity‐prone individuals, metabolic state may interact with diet in determining body composition. We tested the hypotheses that, among 103 weight‐reduced women over 1 year, (i) insulin sensitivity would be positively associated with change in %fat; (ii) this association would be modulated by dietary glycemic load (GL); and (iii) changes in fat distribution would be related to indexes of glucose metabolism. Insulin sensitivity, glucose effectiveness, fasting and postchallenge insulin and glucose, and glucose tolerance were assessed during intravenous glucose tolerance test (IVGTT). Changes in %fat and fat distribution were examined using dual‐energy X‐ray absorptiometry and computed tomography. Dietary GL was assessed on 67 women using food records. On average, women showed a +5.3 ± 3.0% change in %fat over 1 year, with the magnitude of this change being greater in relatively insulin sensitive women (+6.0 ± 0.4%, mean ± s.e.m.) than in relatively insulin resistant women (+4.4 ± 0.4 kg; P < 0.05). Women who were relatively insulin sensitive and who consumed a higher GL diet showed a +6.8 ± 0.7% change in %fat, which was greater than those who were less insulin sensitive, regardless of diet (P < 0.05), but did not differ from women who were relatively insulin sensitive and who consumed a lower GL diet (P = 0.105). Changes in intra‐abdominal and deep subcutaneous abdominal fat were inversely associated with the postchallenge decline in serum glucose. In conclusion, greater insulin sensitivity may predispose to adiposity among weight reduced women, an effect that may be ameliorated by a lower GL diet. The potential association between indexes of glucose disposal and changes in fat distribution warrants further study.