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Effect of Vitamin D3 Supplementation on Acute Fracture Healing: A Phase II Screening Randomized Double-Blind Controlled Trial.
Slobogean, GP, Bzovsky, S, O'Hara, NN, Marchand, LS, Hannan, ZD, Demyanovich, HK, Connelly, DW, Adachi, JD, Thabane, L, Sprague, S
JBMR plus. 2023;7(1):e10705
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Almost half of all adult patients with fractures are vitamin D deficient. The aim of this double-blind, randomised, placebo-controlled trial was to evaluate the efficacy of different vitamin D regimens on the healing of acute tibia and femur fractures. 102 18-50-year-old patients were enrolled in the study and randomised to receive a) two high doses (150,000 IU) at time of injury and after 6 weeks, b) 4000 IU daily, c) 600 IU daily or d) placebo for 3 months. After 3 months, there were no statistically significant differences between the 3 intervention groups with respect to clinical or radiographic outcomes of fracture healing. The authors report a significantly better clinical, but not radiographic, outcome for 4000 IU per day versus placebo with a p-value of 0.15 (note: generally, to be considered statistically significant, p should be < 0.05). Similar results were observed after 12 months. There was no significant correlation between vitamin D levels and fracture healing. The authors concluded that high dose vitamin D may confer a modest benefit for fracture healing but that this requires confirmation from a larger clinical trial.
Expert Review
Conflicts of interest:
None
Take Home Message:
- The evidence base for the use of vitamin D supplements in isolation to support fracture healing is weak.
Evidence Category:
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X
A: Meta-analyses, position-stands, randomized-controlled trials (RCTs)
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B: Systematic reviews including RCTs of limited number
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C: Non-randomized trials, observational studies, narrative reviews
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D: Case-reports, evidence-based clinical findings
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E: Opinion piece, other
Summary Review:
Introduction
- Low levels of vitamin D can have negative effects on bone metabolism and healing of fractures
- Almost half of all adult fracture patients are vitamin D deficient
- The aim of this study was to evaluate the effectiveness of supplementing vitamin D3 (VD3) to improve tibia and femur fracture healing.
Methods
- Four-arm, double-blind, randomised, phase II screening, placebo-controlled trial
- 102 adult patients (aged 18-50 years) with a non-osteoporotic tibial or femoral shaft fracture were randomised into 1 of 4 treatment groups
- Just over half (56%) of participants were vitamin D3 deficient at baseline
- Intervention groups: 1) 150,000 IU VD3 loading dose at injury and at 6 weeks (high loading) plus daily placebo; 2) placebo loading doses plus 4000 IU VD3 daily (high dose); 3) placebo loading doses plus 600 IU VD3 daily (low dose); 4) placebo loading dose plus placebo daily
- Duration: 3 months intervention, further 9 months follow-up. Vitamin D levels were assessed at 6 weeks and 3 months.
Primary outcome measures at 3 months:
- Clinical assessment using the Function IndeX for Trauma (FIX-IT)
- Radiographic assessment using the Radiographic Union Score for Tibial fractures (RUST).
Secondary outcomes: as above at 6, 9 and 12 months.
Results at 3 months:
- No statistically significant difference between high loading and high dose, high and low dose or low dose and placebo for either clinical or radiological assessment (all p-values ≥0.4)
- Post-hoc analysis of any dose vs placebo showed no significant difference with either clinical or radiological assessment (all p-values ≥0.25)
- Post-hoc analysis of high dose vs placebo showed no significant difference for radiological assessment (p=0.76) whilst it was reported as statistically significant for clinical assessment with p=0.16, with a benefit of VD3 supplementation.
- Similar results were seen at 12 months with reported benefit of high dose VD3 for fracture healing with p=0.18
- Vitamin D levels improved in all 3 VD3 groups from baseline to 6 weeks
- There was no statistically significant correlation between fracture healing and vitamin D level.
Conclusion
The authors conclude that VD3 supplementation may be of modest benefit for fracture healing, but further, larger trials are needed to confirm this.
Clinical practice applications:
- When working with clients who present with a fracture, it should be noted that the evidence for benefit of vitamin D supplementation alone for fracture healing is weak.
Considerations for future research:
- Larger studies to increase the statistical power to detect smaller benefits are required
- Larger studies may also identify differences in potential benefits between patient populations with different baseline levels of vitamin D.
Abstract
Nearly half of adult fracture patients are vitamin D deficient (serum 25-hydroxyvitamin D [25(OH)D] levels <20 ng/mL). Many surgeons advocate prescribing vitamin D supplements to improve fracture healing outcomes; however, data supporting the effectiveness of vitamin D3 supplements to improve acute fracture healing are lacking. We tested the effectiveness of vitamin D3 supplementation for improving tibia and femur fracture healing. We conducted a single-center, double-blinded phase II screening randomized controlled trial with a 12-month follow-up. Patients aged 18-50 years receiving an intramedullary nail for a tibia or femoral shaft fracture were randomized 1:1:1:1 to receive (i) 150,000 IU loading dose vitamin D3 at injury and 6 weeks (n = 27); (ii) 4000 IU vitamin D3 daily (n = 24); (iii) 600 IU vitamin D3 daily (n = 24); or (iv) placebo (n = 27). Primary outcomes were clinical fracture healing (Function IndeX for Trauma [FIX-IT]) and radiographic fracture healing (Radiographic Union Score for Tibial fractures [RUST]) at 3 months. One hundred two patients with a mean age of 29 years (standard deviation 8) were randomized. The majority were male (69%), and 56% were vitamin D3 deficient at baseline. Ninety-nine patients completed the 3-month follow-up. In our prespecified comparisons, no clinically important or statistically significant differences were detected in RUST or FIX-IT scores between groups when measured at 3 months and over 12 months. However, in a post hoc comparison, high doses of vitamin D3 were associated with improved clinical fracture healing relative to placebo at 3 months (mean difference [MD] 0.90, 80% confidence interval [CI], 0.08 to 1.79; p = 0.16) and within 12 months (MD 0.89, 80% CI, 0.05 to 1.74; p = 0.18). The study was designed to identify potential evidence to support the effectiveness of vitamin D3 supplementation in improving acute fracture healing. Vitamin D3 supplementation, particularly high doses, might modestly improve acute tibia or femoral shaft fracture healing in healthy adults, but confirmatory studies are required. The Vita-Shock trial was awarded the Orthopaedic Trauma Association's (OTA) Bovill Award in 2020. This award is presented annually to the authors of the most outstanding OTA Annual Meeting scientific paper. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.
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A Low ω-6 to ω-3 PUFA Ratio (n-6:n-3 PUFA) Diet to Treat Fatty Liver Disease in Obese Youth.
Van Name, MA, Savoye, M, Chick, JM, Galuppo, BT, Feldstein, AE, Pierpont, B, Johnson, C, Shabanova, V, Ekong, U, Valentino, PL, et al
The Journal of nutrition. 2020;150(9):2314-2321
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Non-alcoholic fatty liver disease (NAFLD) is characterised by the accumulation of fat in the liver of people who drink very little or no alcohol. NAFLD is a common problem in children with obesity and diet is a contributory factor. Recent research has suggested that the Western diet and its high omega-6 and low omega-3 fat intakes may lead to the development of NAFLD. This quasi-experimental study of twenty children with obesity and NAFLD aimed to determine whether 12 weeks of low omega-6: omega-3 ratio diet affected liver fat content. The results showed that the diet did not affect weight loss but still significantly decreased liver fat content, with one third of the participants returning their liver fat content to normal. In lieu of weight loss, improvements were also observed in markers for liver function, diabetes and blood cholesterol. Interestingly those who carry a certain gene increasing their risk of developing NAFLD, showed greater improvements in liver fat percentage and liver function. It was concluded that in the absence of weight loss, a diet high in omega-3 and low in omega-6 improves fatty liver disease, risk factors for heart disease and has the potential to revert liver fat content to normal levels. This study could be used by healthcare professionals to recommend a low omega-6:omega-3 diet in children with obesity and NAFLD.
Abstract
BACKGROUND Recent literature suggests that the Western diet's imbalance between high ω-6 (n-6) and low ω-3 (n-3) PUFA intake contributes to fatty liver disease in obese youth. OBJECTIVES We tested whether 12 wk of a low n-6:n-3 PUFA ratio (4:1) normocaloric diet mitigates fatty liver and whether the patatin-like containing domain phospholipase 3 (PNPLA3) rs738409 variant affects the response. METHODS In a single-arm unblinded study, obese youth 9-19 y of age with nonalcoholic fatty liver disease were treated with a normocaloric low n-6:n-3 PUFA ratio diet for 12 wk. The primary outcome was change in hepatic fat fraction (HFF%), measured by abdominal MRI. Metabolic parameters included alanine aminotransferase (ALT), lipids, measures of insulin sensitivity, and plasma oxidized linoleic acid metabolites (OXLAMs). Outcomes were also analyzed by PNPLA3 rs738409 genotype. Wilcoxon's signed rank test, the Mann-Whitney U test, and covariance pattern modeling were used. RESULTS Twenty obese adolescents (median age: 13.3 y; IQR: 10.5-16.4 y) were enrolled and 17 completed the study. After 12 wk of dietary intervention, HFF% decreased by 25.8% (P = 0.009) despite stable weight. We observed a 34.4% reduction in ALT (P = 0.001), 21.9% reduction in triglycerides (P = 0.046), 3.28% reduction in LDL cholesterol (P = 0.071), and a 26.3% improvement in whole body insulin sensitivity (P = 0.032). The OXLAMs 9-hydroxy-octadecandienoic acid (9-HODE) (P = 0.011), 13-HODE (P = 0.007), and 9-oxo-octadecadienoic acid (9-oxoODE) (P = 0.024) decreased after 12 wk. HFF% declined in both the not-at-risk (CC/CG) and at-risk (GG) PNPLA3 rs738409 genotype groups, with significant (P = 0.016) HFF% reduction in the GG group. Changes in 9-HODE (P = 0.023), 9-oxoODE (P = 0.009), and 13-oxoODE (P = 0.003) differed between the 2 genotype groups over time. CONCLUSIONS These data suggest that, independently of weight loss, a low n-6:n-3 PUFA diet ameliorates the metabolic phenotype of adolescents with fatty liver disease and that response to this diet is modulated by the PNPLA3 rs738409 genotype.This trial was registered at clinicaltrials.gov as NCT01556113.
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Insulin resistance drives hepatic de novo lipogenesis in nonalcoholic fatty liver disease.
Smith, GI, Shankaran, M, Yoshino, M, Schweitzer, GG, Chondronikola, M, Beals, JW, Okunade, AL, Patterson, BW, Nyangau, E, Field, T, et al
The Journal of clinical investigation. 2020;130(3):1453-1460
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Non-alcoholic fatty liver disease (NAFLD) is a common complication of obesity and is associated with multiorgan insulin resistance, dyslipidaemia and an increased risk of diabetes and coronary heart disease. The aims of this study were to (a) determine hepatic de novo lipogenesis (DNL) [the liver’s biochemical process of synthesising fatty acids] in 3 distinct cohorts, (b) determine the relationships among hepatic DNL and intrahepatic [within the liver] triglyceride (IHTG) content, and (c) determine the effect of moderate (10%) weight loss. This study is a cross-sectional study which included a total of 67 men and women (mean age: 39 ± 1 years; 14 men and 53 women). Results highlight the importance of DNL in the pathogenesis of hepatic steatosis [build up of fats in the liver] and suggest that increases in daily 24-hour plasma glucose and insulin concentrations are major drivers of increased DNL in individuals with obesity and NAFLD. Additionally, moderate (10%) weight loss caused a marked decrease in both hepatic DNL and IHTG content. Authors conclude that increases in circulating glucose and insulin promote hepatic DNL in individuals with NAFLD. Whereas an improvement in insulin sensitivity and a decrease in hepatic DNL, are potentially important contributors to the decline in IHTG content associated with moderate weight loss.
Abstract
BACKGROUNDAn increase in intrahepatic triglyceride (IHTG) is the hallmark feature of nonalcoholic fatty liver disease (NAFLD) and is decreased by weight loss. Hepatic de novo lipogenesis (DNL) contributes to steatosis in individuals with NAFLD. The physiological factors that stimulate hepatic DNL and the effect of weight loss on hepatic DNL are not clear.METHODSHepatic DNL, 24-hour integrated plasma insulin and glucose concentrations, and both liver and whole-body insulin sensitivity were determined in individuals who were lean (n = 14), obese with normal IHTG content (n = 26), or obese with NAFLD (n = 27). Hepatic DNL was assessed using the deuterated water method corrected for the potential confounding contribution of adipose tissue DNL. Liver and whole-body insulin sensitivity was assessed using the hyperinsulinemic-euglycemic clamp procedure in conjunction with glucose tracer infusion. Six subjects in the obese-NAFLD group were also evaluated before and after a diet-induced weight loss of 10%.RESULTSThe contribution of hepatic DNL to IHTG-palmitate was 11%, 19%, and 38% in the lean, obese, and obese-NAFLD groups, respectively. Hepatic DNL was inversely correlated with hepatic and whole-body insulin sensitivity, but directly correlated with 24-hour plasma glucose and insulin concentrations. Weight loss decreased IHTG content, in conjunction with a decrease in hepatic DNL and 24-hour plasma glucose and insulin concentrations.CONCLUSIONSThese data suggest hepatic DNL is an important regulator of IHTG content and that increases in circulating glucose and insulin stimulate hepatic DNL in individuals with NAFLD. Weight loss decreased IHTG content, at least in part, by decreasing hepatic DNL.TRIAL REGISTRATIONClinicalTrials.gov NCT02706262.FUNDINGThis study was supported by NIH grants DK56341 (Nutrition Obesity Research Center), DK20579 (Diabetes Research Center), DK52574 (Digestive Disease Research Center), and RR024992 (Clinical and Translational Science Award), and by grants from the Academy of Nutrition and Dietetics Foundation, the College of Natural Resources of UCB, and the Pershing Square Foundation.
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Daily Intake of Fermented Milk Containing Lactobacillus casei Shirota (Lcs) Modulates Systemic and Upper Airways Immune/Inflammatory Responses in Marathon Runners.
Vaisberg, M, Paixão, V, Almeida, EB, Santos, JMB, Foster, R, Rossi, M, Pithon-Curi, TC, Gorjão, R, Momesso, CM, Andrade, MS, et al
Nutrients. 2019;11(7)
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Athletes undergoing high-intensity efforts show increased incidence of upper respiratory tract infections (URTI), both in the context of competitions and during strenuous training. The aim of this study was to evaluate the influence of the daily intake of fermented milk (containing Lactobacillus casei Shirota) on the systemic and upper airway immune/inflammatory responses before and after a race in marathon runners who previously reported upper respiratory symptoms (URS) after an exhaustive physical exercise session. The study is a double-blind randomised clinical study which recruited 42 male amateur marathon runners with an average age of 39 years. The participants were randomly separated into two groups: Lactobacillus casei Shirota group (n=20) or the placebo group (n=22). Results indicate that daily ingestion of fermented milk (containing Lactobacillus casei Shirota) was able to control both immunological and inflammatory responses in the blood and also in the upper airways mucosal of amateurs´ runners after a marathon. Authors conclude that Lactobacillus casei Shirota is able to modulate the systemic and airways immune responses post-marathon, presenting protective effects.
Abstract
BACKGROUND Although Lactobacillus casei Shirota (LcS) can benefit the immune status, the effects of LcS in the immune/inflammatory responses of marathon runners has never been evaluated. Therefore, here we evaluated the effect of daily ingestion of fermented milk containing or not LcS in the systemic and upper airway immune/inflammatory responses before and after a marathon. METHODS Forty-two male marathon runners ingested a fermented milk containing 40 billion of LcS/day (LcS group, n = 20) or placebo (unfermented milk, n = 22) during 30 days pre-marathon. Immune/inflammatory parameters in nasal mucosa and serum, as well as concentrations of secretory IgA (SIgA) and antimicrobial peptides in saliva, were evaluated before and after fermented milk ingestion, immediately, 72 h, and 14 d post-marathon. RESULTS Higher proinflammatory cytokine levels in serum and nasal mucosa, and also lower salivary levels of SIgA and antimicrobial peptides, were found immediately post-marathon in the placebo group compared to other time points and to LcS group. In opposite, higher anti-inflammatory levels and reduced neutrophil infiltration on nasal mucosa were found in the LcS group compared to other time points and to the placebo group. CONCLUSION For the first time, it is shown that LcS is able to modulate the systemic and airways immune responses post-marathon.
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Effects of Fasting on 18F-DCFPyL Uptake in Prostate Cancer Lesions and Tissues with Known High Physiologic Uptake.
Wondergem, M, van der Zant, FM, Vlottes, PW, Knol, RJJ
Journal of nuclear medicine : official publication, Society of Nuclear Medicine. 2018;59(7):1081-1084
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Prostate-specific membrane antigen (PSMA) (PSMA is a type II membrane protein)–targeted PET imaging is being increasingly applied in prostate cancer. The aim of this study was to determine the impact of fasting on 18F-DCFPyL (is a fluorine-18 labelled ligand binding specifically to PSMA) uptake in organs with known high physiologic uptake and in lesions characteristic of prostate cancer metastases. The study is a cohort study in which 50 and 48 patients were analysed in the fasting and non-fasting cohorts, respectively. Results showed that lesions characteristic of prostate cancer showed similar uptake in both the fasting and the non-fasting cohorts (number of lesions characteristic of prostate cancer totalled to 152 and 131 respectively). Authors conclude that fasting for up to 6 h before 18F-DCFPyL PET/CT does not significantly affect uptake in suspected malignant lesions but significantly lowers uptake in tissues with high physiologic uptake, such as the salivary glands, liver, and spleen.
Abstract
In the literature, a 4- to 6-h fast is recommended before a patient undergoes PET/CT with 2-(3-(1-carboxy-5-[(6-18F-fluoro-pyridine-3-carbonyl)-amino]-pentyl)-ureido)-pentanedioic acid (18F-DCFPyL); however, a scientific underpinning for this recommendation is lacking. Therefore, we performed a study to determine the impact of fasting on 18F-DCFPyL uptake. Methods: The study included 50 patients who fasted at least 6 h before 18F-DCFPyL administration and 50 patients who did not. Activity (SUVmax) was measured in lesions characteristic of prostate cancer and in normal tissues known to express high physiologic uptake. Results: Uptake in suspected lesions did not differ between the cohorts. 18F-DCFPyL uptake in the submandibular gland, liver, and spleen was significantly higher in the fasting than the nonfasting cohort. Conclusion: Our data show that fasting does not significantly affect 18F-DCFPyL uptake in suspected malignant lesions but does result in significantly lower 18F-DCFPyL uptake in tissues with high physiologic uptake. The absolute differences in uptake were relatively small; therefore, the effects of fasting on the diagnostic performance can be considered negligible.
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Vitamin D supplementation for the prevention of type 2 diabetes in overweight adults: study protocol for a randomized controlled trial.
de Courten, B, Mousa, A, Naderpoor, N, Teede, H, de Courten, MP, Scragg, R
Trials. 2015;16:335
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With the rising rates of vitamin D deficiency, identifying cost-effective, preventative strategies are imperative. Vitamin D plays a well-known role in bone mineralisation, however its protective role against chronic diseases is not very well understood. The aim of this trial is to investigate whether vitamin D supplementation will increase insulin sensitivity and secretion, as well as to determine whether vitamin D deficiency underlies the inflammatory properties associated with obesity. 50 overweight adults between 18 and 60 years old were recruited and assigned to receive either 4,000 IU vitamin D daily or identical placebo capsules for 16 weeks. This study elucidates the potential role vitamin D supplementation could have on preventing diabetes and its associated co-morbidities. It also provides comprehensive insight into the potential mechanisms of action. The authors conclude that this trial can corroborate existing knowledge while expanding the understanding on the role of vitamin D in the inflammatory response and subsequent development of disease.
Abstract
BACKGROUND Despite Australia's sunny climate, low vitamin D levels are increasingly prevalent. Sun exposure is limited by long working hours, an increase in time spent indoors, and sun protection practices, and there is limited dietary vitamin D fortification. While the importance of vitamin D for bone mineralization is well known, its role as a protective agent against chronic diseases, such as type 2 diabetes and cardiovascular disease, is less understood. Observational and limited intervention studies suggest that vitamin D might improve insulin sensitivity and secretion, mainly via its anti-inflammatory properties, thereby decreasing the risk of development and progression of type 2 diabetes. The primary aim of this trial is to investigate whether improved plasma concentrations of 25-hydroxyvitamin D (25(OH)D), obtained through vitamin D supplementation, will increase insulin sensitivity and insulin secretion. A secondary aim is to determine whether these relationships are mediated by a reduction in underlying subclinical inflammation associated with obesity. METHODS/DESIGN Fifty overweight but otherwise healthy nondiabetic adults between 18 and 60 years old, with low vitamin D levels (25(OH)D < 50 nmol/l), will be randomly assigned to intervention or placebo. At baseline, participants will undergo a medical review and anthropometric measurements, including dual X-ray absorptiometry, an intravenous glucose tolerance test, muscle and fat biopsies, a hyperinsulinemic euglycemic clamp, and questionnaires assessing diet, physical activity, sun exposure, back and knee pain, and depression. The intervention group will receive a first dose of 100,000 IU followed by 4,000 IU vitamin D (cholecalciferol) daily, while the placebo group will receive apparently identical capsules, both for a period of 16 weeks. All measurements will be repeated at follow-up, with the primary outcome measure expressed as a change from baseline in insulin sensitivity and secretion for the intervention group compared with the placebo group. Secondary outcome measures will compare changes in anthropometry, cardiovascular risk factors, and inflammatory markers. DISCUSSION The trial will provide much needed clinical evidence on the impact of vitamin D supplementation on insulin resistance and secretion and its underlying mechanisms, which are relevant for the prevention and management of type 2 diabetes. TRIAL REGISTRATION Clinicaltrials.gov ID: NCT02112721 .
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Modifying influence of dietary sugar in the relationship between cortisol and visceral adipose tissue in minority youth.
Gyllenhammer, LE, Weigensberg, MJ, Spruijt-Metz, D, Allayee, H, Goran, MI, Davis, JN
Obesity (Silver Spring, Md.). 2014;22(2):474-81
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Visceral adipose tissue (VAT) is one of the strongest risk factors associated with obesity and related co-morbidities. A potential mechanism for this association involves cortisol and cortisol receptors, however the specific interaction of cortisol and diet upon fat deposition has not yet been explored in humans. The purpose of this cross-sectional study was to assess the impact of a high-fat, high-sugar diet on the association between stress and visceral fat in 165 overweight minority youth. The results of this study showed that cortisol was significantly associated with elevated VAT under conditions of high sugar intake in this population. Based on these findings, the authors conclude that dietary sugar may play a crucial role in moderating the adverse effects of cortisol.
Abstract
OBJECTIVE Cortisol has been associated with preferential visceral adipose tissue (VAT) deposition; however, findings in humans are mixed, which may be clarified when diet is considered. DESIGN AND METHODS Participants included 165 African-American and Latino, overweight adolescents (BMI% 97.2±3.2%, ages 13-18, 67% Latino, 66% female). Body composition was determined by dual energy X-ray absorptiometry, abdominal fat depots [VAT, subcutaneous (SAT)] by multiple-slice MRI, time-controlled serum sample to measure cortisol, and 2-day multi-pass 24-hour dietary recall. Linear regression analysis examined the cross-sectional relationship between cortisol, and the interaction of diet and cortisol on adiposity measures. Sex, race, age, and total body fat were a priori covariates. RESULTS There was a significant interaction between cortisol and sugar (total and added) in the prediction of VAT (P(interaction) ≤ 0.05). Amongst participants with high total or added-sugar intake, cortisol was significantly associated with VAT (ß = 0.031 P < 0.001; ß = 0.026 P < 0.001), with no relationship in low consumers of total or added-sugar. CONCLUSION Dietary sugar may play an important role in modifying the relationship between cortisol and VAT, such that cortisol is significantly associated with elevated VAT under conditions of high sugar intake.
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Reversal of cognitive decline: a novel therapeutic program.
Bredesen, DE
Aging. 2014;6(9):707-17
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Alzheimer’s Disease (AD) is estimated to affect 30 million individuals globally, with projections as high as 150 million by 2050 if no effective treatment is found. This report describes a personalised, multi-modal, therapeutic programme used with 10 individuals with various degrees of cognitive decline. The goal was to optimise metabolic parameters and lifestyle factors and was personalised based on laboratory test results. 9 out of 10 of the case study patients experienced improvement in cognitive abilities, beginning within 3-6 months of starting the programme. These effects were sustained at 2.5 year follow up. The 1 patient who did not benefit had advanced AD, in comparison to the other patients with subjective or mild cognitive decline. The authors call for a more extensive trial of the therapeutic programme.
Abstract
This report describes a novel, comprehensive, and personalized therapeutic program that is based on the underlying pathogenesis of Alzheimer's disease, and which involves multiple modalities designed to achieve metabolic enhancement for neurodegeneration (MEND). The first 10 patients who have utilized this program include patients with memory loss associated with Alzheimer's disease (AD), amnestic mild cognitive impairment (aMCI), or subjective cognitive impairment (SCI). Nine of the 10 displayed subjective or objective improvement in cognition beginning within 3-6 months, with the one failure being a patient with very late stage AD. Six of the patients had had to discontinue working or were struggling with their jobs at the time of presentation, and all were able to return to work or continue working with improved performance. Improvements have been sustained, and at this time the longest patient follow-up is two and one-half years from initial treatment, with sustained and marked improvement. These results suggest that a larger, more extensive trial of this therapeutic program is warranted. The results also suggest that, at least early in the course, cognitive decline may be driven in large part by metabolic processes. Furthermore, given the failure of monotherapeutics in AD to date, the results raise the possibility that such a therapeutic system may be useful as a platform on which drugs that would fail as monotherapeutics may succeed as key components of a therapeutic system.
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Glycemic load effect on fasting and post-prandial serum glucose, insulin, IGF-1 and IGFBP-3 in a randomized, controlled feeding study.
Runchey, SS, Pollak, MN, Valsta, LM, Coronado, GD, Schwarz, Y, Breymeyer, KL, Wang, C, Wang, CY, Lampe, JW, Neuhouser, ML
European journal of clinical nutrition. 2012;66(10):1146-52
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Dietary intervention studies have shown detrimental metabolic effects of high-glycaemic load diets. The glycaemic index (GI) is the numerical classification of a particular food’s blood glucose-raising effect. The aim of this study was to evaluate the effect of a high-glycaemic load diet on circulating levels of insulin-like growth factor-1 (IGF-1) [hormone] and insulin-like growth factor-binding protein 3 (IGFBP-3) [protein] compared to a low-glycaemic load diet. The study is a randomised controlled crossover study which enrolled 84 normal weight and overweight-obese healthy individuals. The study included two 28-day weight-maintaining high- and low-glycaemic load diets. Results indicate that consumption of a low-glycaemic load diet resulted in lower post-prandial [after a meal] insulin and glucose responses and modestly lower fasting IGF-1 and IGF-1/IGFBP-3 concentrations. However, there were no observable effects of glycaemic load on insulin resistance or glucose-adjusted post-prandial insulin responses in these healthy participants. Authors conclude that further intervention studies are required in order to weigh the impact of dietary glycaemic load on risk for chronic disease.
Abstract
BACKGROUND/OBJECTIVES The effect of a low glycemic load (GL) diet on insulin-like growth factor-1 (IGF-1) concentration is still unknown but may contribute to lower chronic disease risk. We aimed to assess the impact of GL on concentrations of IGF-1 and IGF-binding protein-3 (IGFBP-3). SUBJECTS/METHODS We conducted a randomized, controlled crossover feeding trial in 84 overweight obese and normal weight healthy individuals using two 28-day weight-maintaining high- and low-GL diets. Measures were fasting and post-prandial concentrations of insulin, glucose, IGF-1 and IGFBP-3. In all 80 participants completed the study and 20 participants completed post-prandial testing by consuming a test breakfast at the end of each feeding period. We used paired t-tests for diet component and linear mixed models for biomarker analyses. RESULTS The 28-day low-GL diet led to 4% lower fasting concentrations of IGF-1 (10.6 ng/ml, P=0.04) and a 4% lower ratio of IGF-1/IGFBP-3 (0.24, P=0.01) compared with the high-GL diet. The low-GL test breakfast led to 43% and 27% lower mean post-prandial glucose and insulin responses, respectively; mean incremental areas under the curve for glucose and insulin, respectively, were 64.3±21.8 (mmol/l/240 min; P<0.01) and 2253±539 (μU/ml/240 min; P<0.01) lower following the low- compared with the high-GL test meal. There was no effect of GL on mean homeostasis model assessment for insulin resistance or on mean integrated post-prandial concentrations of glucose-adjusted insulin, IGF-1 or IGFBP-3. We did not observe modification of the dietary effect by adiposity. CONCLUSIONS Low-GL diets resulted in 43% and 27% lower post-prandial responses of glucose and insulin, respectively, and modestly lower fasting IGF-1 concentrations. Further intervention studies are needed to weigh the impact of dietary GL on risk for chronic disease.