Clinical Quickies (May-June 2016)

1. Is Melatonin Safe for People with Dysglycemia or Pre- Diabetes?

ABSTRACT: Type 2 diabetes (T2D) is a global pandemic. Genome- wide association studies (GWASs) have identified >100 genetic vari- ants associated with the disease, including a common variant in the melatonin receptor 1 b gene (MTNR1B). Here, we demonstrate in- creased MTNR1B expression in human islets from risk G-allele carri- ers, which likely leads to a reduction in insulin release, increasing T2D risk. Accordingly, in insulin-secreting cells, melatonin reduced cAMP levels, and MTNR1B overexpression exaggerated the inhibition of insulin release exerted by melatonin. Conversely, mice with a disrup- tion of the receptor secreted more insulin. Melatonin treatment in a human recall-by-genotype study reduced insulin secretion and raised glucose levels more extensively in risk G-allele carriers.Thus, our data support a model where enhanced melatonin signaling in islets reduces insulin secretion, leading to hyperglycemia and greater future risk of T2D.The findings also imply that melatonin physiologically serves to inhibit nocturnal insulin release.

Tuomi T, et al. Increased Melatonin Signaling Is a Risk Factor for Type 2 Diabetes. Cell Metab. 2016 May 11. pii: S1550-4131(16)30160-7. doi: 10.1016/j.cmet.2016.04.009. [Epub ahead of print]

Notes: A study published in 2011 actually showed melatonin improves sleep and HbA1c in Type 2 diabetics. Garfinkel D, et al. Efficacy and safety of prolonged-release melatonin in
insomnia patients with diabetes: a randomized, double-blind, crossover study.

Diabetes Metab Syndr Obes. 2011; 4: 307–313.

2. Vitamin D Supplementation May Benefit Hypertensive Patients with Vitamin D Deficiency

ABSTRACT: Increasing evidence describes a possible interplay be- tween vitamin D insufficiency with increased aldosterone.The authors sought to evaluate the effect of vitamin D supplementation on plasma aldosterone concentration (PAC) in patients with hypertension and 25-hydroxyvitamin D[25(OH)D] insufficiency. The Styrian Vitamin D Hypertension Trial was a single-center, double-blind, placebo-con- trolled randomized clinical trial conducted from 2011 to 2014.Two hundred patients with arterial hypertension and 25(OH)D levels <30 ng/mL were enrolled. Study participants were randomized to receive either 2800 IU of vitamin D3 or placebo.The present investigation is a post hoc analysis using analysis of covariance adjusting for baseline differences.A total of 188 participants (mean±standard deviation age, 60.1±11.3 years; 47% women; 25(OH)D, 21.2±5.6 ng/mL) completed the trial. Mean differences between baseline and follow-up PAC in the control and intervention arm were +3.3 ng/dL and +0.9 ng/dL, respec- tively (P=.04).The findings indicate that vitamin D3 supplementation significantly decreases PAC in patients with arterial hypertension and 25(OH)D insufficiency.

Grübler MR, et al. Effects of Vitamin D Supplementation on Plasma Aldosterone and Renin-A Randomized Placebo-Controlled Trial. J Clin Hypertens (Greenwich). 2016 Apr 21. doi: 10.1111/jch.12825. [Epub ahead of print]

3. White Button Mushroom Powder Shows Promise in Reducing Disease Progression in Patients with Prostate Cancer

BACKGROUND: Each year in the United States, nearly 50,000 prostate cancer patients exhibit a rise in prostate-specific antigen (PSA) levels, which can indicate disease recurrence. For patients with biochemically recurrent prostate cancer, we evaluated the effects of white button mushroom (WBM) powder on serum PSA levels and determined the tolerability and biological activity of WBM. 

METHODS: Patients with continuously rising PSA levels were en- rolled in the study. Dose escalation was conducted in cohorts of 6; this ensured that no more than 1 patient per cohort experienced dose-limiting toxicity (DLT).The primary objective was to evaluate

treatment feasibility and associated toxicity. The secondary objectives were to determine WBM’s effect on serum PSA/androgen levels; myeloid-derived suppressor cells (MDSCs); and cytokine levels. 

RESULTS: Thirty-six patients were treated; no DLTs were en- countered. The overall PSA re- sponse rate was 11%.Two patients receiving 8 and 14 g/d demon- strated complete response (CR): their PSA declined to undetect- able levels that continued for 49

and 30 months.Two patients who received 8 and 12 g/d experienced partial response (PR). After 3 months of therapy, 13 (36%) patients experienced some PSA decrease below baseline. Patients with CR and PR demonstrated higher levels of baseline interleukin-15 than nonresponders; for this group, we observed therapy-associated de- clines in MDSCs.

CONCLUSIONS: Therapy with WBM appears to both impact PSA levels and modulate the biology of biochemically recurrent prostate cancer by decreasing immunosuppressive factors.
Twardowski P, et al. A phase I trial of mushroom powder in patients with biochemically recurrent prostate cancer: Roles of cytokines and myeloid-derived suppressor cells for Agaricus bisporus-induced pros- tate-specific antigen responses. Cancer. 2015 Sep 1;121(17):2942- 50. doi: 10.1002/cncr.29421. Epub 2015 May 18.

4. Low-Normal Level of Vitamin B12 Is Not Sufficient to Prevent Further Mental Decline

BACKGROUND: Low-normal concentrations of vitamin B-12 (VitB12) may be associated with worse cognition. However, previ- ous evidence has been mixed, and the underlying mechanisms remain unclear.

OBJECTIVE: We determined whether serum VitB12 concentra- tions within the normal range were linked to memory functions and

related neuronal structures in patients with mild cognitive impair- ment (MCI).
DESIGN: In a cross-sectional design, we assessed 100 amnestic MCI patients (52 women; age range: 50-80 y) with low- and high- normal VitB12 concentration (median split: 304 pmol/L) for memory functions with the use of the Auditory Verbal Learning Test. MRI was performed at 3 tesla (n= 86) for the estimation of the volume and microstructure of the hippocampus and its subfields as indicated by the mean diffusivity on diffusion-weighted images. With the use of a mediation analysis, we examined whether the relation between VitB12 and memory performance was partially explained by volume or microstructure.

RESULTS: MCI patients with low-normal VitB12 showed a sig- nificantly poorer learning ability (P= 0.014) and recognition perfor- mance (P= 0.008) than did patients with high-normalVitB12.Also,the microstructure integrity of the hippocampus was lower in patients with low-normal VitB12, mainly in the cornu ammonis 4 and den- tate gyrus region (P= 0.029), which partially mediated the effect of VitB12 on memory performance (32-48%). Adjustments for age, sex, education, apolipoprotein E e4 status, and total homocysteine, folate, and creatinine did not attenuate the effects.

CONCLUSIONS: Low VitB12 concentrations within the normal range are associated with poorer memory performance, which is an effect that is partially mediated by the reduced microstructural in- tegrity of the hippocampus. Future interventional trials are needed to assess whether supplementation of VitB12 may improve cognition in MCI patients even in the absence of clinically manifested VitB12 deficiency.

Köbe T, et al. Vitamin B-12 concentration, memory performance, and hippocampal structure in patients with mild cognitive impair- ment. Am J Clin Nutr. 2016 Apr;103(4):1045-54. doi: 10.3945/ ajcn.115.116970. Epub 2016 Feb 24.

5. Vitamin D Helps Women With Menstrual Cramps And Vitamin D Deficiency

ABSTRACT: Dysmenorrhea is common among women of repro- ductive age.This study aim was to investigate the effect of vitamin D (vit D) supplementation in treatment of primary dysmenorrhea with vit D deficiency. A randomized double-blind placebo-controlled clini- cal trial was conducted on 60 women with primary dysmenorrhea and vit D deficiency referred to our clinic at Arash Women’s Hospital from September 2013 to December 2014. Eligible women were ran- domly assigned into treatment and control groups (30 in each group). Individuals in the treatment group received 50 000 IU oral vit D and the control group received placebo weekly for eight weeks.After two months of treatment, there was a significant difference in serum vit D concentration between the two groups (p < 0.001). Pain severity decreased significantly in treatment group after eight weeks of treat- ment.There was a significant difference in pain intensity between the two groups after eight weeks of treatment and one month after the end of treatment (p < 0.001 for both).A weekly high dose (50 000 IU) oral vit D supplementation for eight weeks in patients with primary dysmenorrhea and vit D deficiency could improve pain intensity. 

Moini A, et al. The effect of vitamin D on primary dysmenorhea with vitamin D deficiency: a randomized double-blind con- trolled clinical trial. Gynecol Endocrinol. 2016 Jun;32(6):502-5. doi: 10.3109/09513590.2015.1136617. Epub 2016 May 5.

6. Melatonin is More Tolerable and As Effective As Ami- triptyline in Migraine Prevention

INTRODUCTION: Melatonin has been studied in headache dis- orders.Amitriptyline is efficacious for migraine prevention, but its un- favourable side effect profile limits its use.

METHODS: A randomised, double-blind, placebo-controlled study was carried out. Men and women, aged 18-65 years, with migraine with or without aura, experiencing 2-8 attacks per month, were enrolled. After a 4-week baseline phase, 196 participants were ran- domised to placebo, amitriptyline 25 mg or melatonin 3 mg, and 178 took a study medication and were followed for 3 months (12 weeks). The primary outcome was the number of migraine headache days per month at baseline versus last month. Secondary end points were responder rate, migraine intensity, duration and analgesic use. Toler- ability was also compared between groups.

RESULTS: Mean headache frequency reduction was 2.7 migraine headache days in the melatonin group, 2.2 for amitriptyline and 1.1 for placebo. Melatonin significantly reduced headache frequency compared with placebo (p=0.009), but not to amitriptyline (p=0.19). Melatonin was superior to amitriptyline in the percentage of patients with a greater than 50% reduction in migraine frequency. Melatonin was better tolerated than amitriptyline.Weight loss was found in themelatonin group, a slight weight gain in placebo and significantly for amitriptyline users.

CONCLUSIONS: Melatonin 3 mg is better than placebo for mi- graine prevention, more tolerable than amitriptyline and as effective as amitriptyline 25 mg.
Gonçalves AL, et al. Randomised clinical trial comparing melatonin 3 mg, amitriptyline 25 mg and placebo for migraine prevention. J Neurol Neurosurg Psychiatry. 2016 May 10. pii: jnnp-2016-313458. doi: 10.1136/jnnp-2016-313458. [Epub ahead of print]

7. Vitamin D Supplementation Eliminates Asymptomatic Bacterial Vaginosis

BACKGROUND & OBJECTIVES: Bacterial vaginosis (BV) is the most prevalent vaginal infection in women of reproductive age group which has been found to be associated with vitamin D defi- ciency.The purpose of this study was to investigate the effectiveness of the administration of 2000 IU/day edible vitamin D for 15 wk to eliminate asymptomatic BV among reproductive age women with vi- tamin D deficiency.

METHODS: A total of 208 women with asymptomatic BV, who were found to be eligible after interviews and laboratory tests, were randomly assigned to a control group (n=106) or an intervention group (n=105). They used vitamin D drops daily for 105 days. Vaginal and blood samples were taken before and after the second interven- tion using identical methods (Nugent score for BV diagnosis, serum 25-hydroxyvitamin D for vitamin D determination).

RESULTS: The cure rate of asymptomatic BV was 63.5 per cent in the intervention and 19.2 per cent in the control group (P <0.001). The results showed that being unmarried (P=0.02), being passive smoker (P<0.001), and being in the luteal phase of a menstrual cycle during sampling (P=0.01) were significantly associated with post-in- tervention BV positive results.After these elements were controlled, the odds of BV positive results in the control group was 10.8 times more than in the intervention group (P<0.001). 

INTERPRETATION & CONCLUSIONS: Among women in reproductive age group with vitamin D deficiency, the administration of 2000 IU/day edible vitamin D was effective in eliminating asymp- tomatic BV.This treatment could be useful in preventing the symp- toms and side effects of BV.
Taheri M, et al. Treatment of vitamin D deficiency is an effective method in the elimination of asymptomatic bacterial vaginosis: A placebo-controlled randomized clinical trial. Indian J Med Res. 2015 Jun;141(6):799-806. doi: 10.4103/0971-

7. Nicotinamide Riboside Looks Promising for Improving Blood Sugar Control, Fatty Liver, and Preventing Peripheral Nerve Damage.

ABSTRACT: Male C57BL/6J mice raised on high fat diet (HFD) become pre-diabetic and develop insulin resistance and sensory neuropathy.The same mice given low doses of streptozotocin are a model of type 2 diabetes (T2D), developing hyperglycemia, severe insulin resistance and diabetic peripheral neuropathy involving sensory and motor neurons. Because of suggestions that increased NAD+ metabolism might address glycemic control and be neuroprotective, we treated prediabetic
and T2D mice with nicotinamide riboside (NR) added to HFD. NR improved glucose tolerance, reduced weight gain, liver damage and the development of hepatic steatosis in predia- betic mice while protecting against sensory neuropathy. In T2D mice, NR greatly reduced non-fasting and fasting blood glucose, weight gain and hepatic steatosis while protecting against diabetic neurop- athy. The neuroprotective effect of NR could not be explained by glycemic control alone. Corneal confocal microscopy was the most sensitive measure of neurodegeneration. This assay allowed detec- tion of the protective effect of NR on small nerve structures in living mice. Quantitative metabolomics established that hepatic NADP+ and NADPH levels were significantly degraded in prediabetes and T2D but were largely protected when mice were supplemented with NR.The data justify testing of NR in human models of obesity,T2D and associated neuropathies.

Trammell S, et al. Nicotinamide Riboside Opposes Type 2 Diabetes and Neuropathy in Mice. Scientific Reports, 2016; 6: 26933 DOI: 10.1038/srep26933

8. Intranasal Oxytocin May Improve Treatment Response of PTSD Patients

The neuropeptide oxytocin (OT) has been suggest- ed as a promising pharmacological agent for medication-enhanced psychotherapy in posttraumatic stress disorder (PTSD) because of its anxiolytic and prosocial properties. We therefore investigated the behavioral and neurobiological effects of a single intranasal OT administration (40 IU) in PTSD patients. We conducted a random- ized, placebo-controlled, cross-over resting-state fMRI study in male and female police officers with (n=37, 21 males) and without PTSD (n=40, 20 males).We investigated OT administration effects on sub- jective anxiety and functional connectivity of basolateral (BLA) and centromedial (CeM) amygdala subregions with prefrontal and sa- lience processing areas. In PTSD patients, OT administration result- ed in decreased subjective anxiety and nervousness. Under placebo, male PTSD patients showed diminished right CeM to left ventro-medial prefrontal cortex (vmPFC) connectivity compared with male trauma-exposed controls, which was reinstated after OT administration.

Additionally, female PTSD patients showed enhanced right BLA to bilateral dorsal anterior cingulate cortex (dACC) connectivity com- pared with female trauma-exposed controls, which was dampened after OT administration. Although caution is warranted, our findings tentatively suggest that OT has the potential to diminish anxiety and fear expression of the amygdala in PTSD, either via increased control of the vmPFC over the CeM (males) or via de- creased salience processing of the dACC and BLA (females). Our findings add to accumulat- ing evidence that OT administration could po- tentially enhance treatment response in PTSD. Koch SB, et al. Intranasal Oxytocin Normalizes Amygdala Functional Connectivity in Posttrau- matic Stress Disorder. Neuropsychopharma- cology. 2016 Jul;41(8):2041-51. doi: 10.1038/ npp.2016.1. Epub 2016 Jan 7.

9. Vitamin D Improves Quality of Life and Symptoms of IBS Patients

BACKGROUND: Low-grade mucosal inflammation and im- mune activation are involved in the pathogenesis of irritable bowel syndrome (IBS). Furthermore, IBS symptoms are associated with a significantly higher prevalence of psychological distress, which in it- self results into an impaired quality of life (QoL).Vitamin D could ameliorate the symptoms of patients suffering from IBS through its beneficial effects on psychological factors and inflammation. 

METHODS: A total of 90 IBS patients participated in this double- blind, randomized, placebo-controlled study. Participants were ran- domly selected to receive either 50 000 IU vitamin D3 or a placebo fortnightly for a period of 6 months. Patients reported their IBS symptoms at the baseline and monthly during intervention periods.The IBS severity score system (IBSSS) and IBS-specific QoL questionnaires were used at the baseline and post intervention.

KEY RESULTS: Over the 6-month intervention period, a signifi- cantly greater improvement in IBS symptoms such as abdominal pain and distention, flatulence, rumbling, and overall gastrointestinal (GI) symptoms (except dissatisfaction with bowel habits) was observed in the patients receiving vitamin D as compared to the placebo group.The IBSSS and the IBS-QoL scores in the vitamin D group significantly im- proved compared to the placebo group postintervention (mean IBSSS score change: -53.82 ± 23.3 vs -16.85 ± 25.01, p < 0.001, respectively; mean IBS-QoL score change: 14.26 ± 3 vs 11 ± 2.34, p < 0.001, respec- tively).

CONCLUSIONS & INFERENCES: Vitamin D seems to be an effective and safe option to improve QoL and symptoms of IBS. Abbasnezhad A, et al. Effect of vitamin D on gastrointestinal symp- toms and health-related quality of life in irritable bowel syndrome patients: a randomized double-blind clinical trial. Neurogastroenterol Motil. 2016 May 7. doi: 10.1111/nmo.12851. [Epub ahead of print]

10. Probiotics, Although Safe, Does Not Seem to Improve Growth in Preterm Infants

BACKGROUND & AIMS: Recent studies have suggested that the gut microflora has metabolic effects.We aimed to evaluate postnatal growth in preterm infants who received different probiotic supple- ments, and to assess the safety of probiotic administration. 

METHODS: This prospective, randomized, double-blind, controlled trial was performed at three tertiary care neonatal units. Preterm in- fants were randomly assigned to receive daily supplementation over 4-6 weeks with placebo (group C) or probiotics (group P). Group P comprised three subgroups: P1 received Bifidobacterium lactis, P2 re- ceived Bifidobacterium longum, and P3 received B. lactis and B. longum. We assessed postnatal growth during the supplementation period and up to a corrected gestational age (GA) of 41 weeks when body com- position was assessed using whole-body dual-energy X-ray absorp- tiometry. Aerobic and anaerobic blood cultures were performed on suspicion of late-onset sepsis.

RESULTS: The study comprised 199 preterm infants with a mean GA of 29.1 ± 1.4 weeks and a mean birth weight of 1173 ± 210 g, who received a placebo (group C, n = 52) or probiot- ics (group P, n = 147) from the first week of life. At the end of the supplementation period, no statistically significant differenceswere seen between the groups in relation to the mean body weight (group C = 1906 ± 23 g,group P = 1875 ± 14 g,p = 0.25),length, or head circumference.The incidence rates of necrotizing entero- colitis and late-onset sepsis were similar in the two groups.At the corrected GA of 41 weeks, there were no differences between the groups with respect to anthropometric measurements or body composition analysis.

CONCLUSIONS: Preterm infants receiving Bifidobacterium supplements did not exhibit better postnatal growth compared with those who received placebo treatment. No adverse effects were associated with probiotic administration.

Hays S, et al. Probiotics and growth in preterm infants: A ran- domized controlled trial, PREMAPRO study. Clin Nutr. 2016 Aug;35(4):802-11. doi: 10.1016/j.clnu.2015.06.006. Epub 2015 Jul 16.

11. CoQ10 Plus NADH May Reduce Post-Exercise Fa- tigue in Patients with Chronic Fatigue Syndrome 

BACKGROUND & AIMS: Chronic Fatigue Syndrome (CFS) is a complex condition, characterized by severe disabling fatigue with no known cause, no established diagnostic tests, and no universally effective treatment. Several studies have proposed symptomatic treatment with coenzyme Q10 (CoQ10) and nicotinamide adenine dinucleotide (NADH) supplementation.The primary endpoint was to assess the effect of CoQ10 plus NADH supplementation on age-predicted maximum heart rate (max HR) during a cycle er- gometer test. Secondary measures included fatigue, pain and sleep. 

METHODS: A proof-of-concept, 8-week, randomized, controlled, double-blind trial was conducted in 80 CFS patients assigned to receive either CoQ10 plus NADH supplementation or matching placebo twice daily. Maximum HR was evaluated at baseline and at end of the run-in period using an exercise test. Fatigue, pain and sleep were evaluated at baseline, and then reassessed at 4- and 8-weeks through self-reported questionnaires.

RESULTS: The CoQ10 plus NADH group showed a significant reduction in max HR during a cycle ergometer test at week 8 ver- sus baseline (P = 0.022). Perception of fatigue also showed a de- crease through all follow-up visits in active group versus placebo (P = 0.03). However, pain and sleep did not improve in the active group. Coenzyme Q10 plus NADH was generally safe and well tolerated.

CONCLUSIONS: Our results suggest that CoQ10 plus NADH supplementation for 8 weeks is safe and potentially effective in re- ducing max HR during a cycle ergometer test and also on fatigue in CFS. Further additional larger controlled trials are needed to confirm these findings.

Castro-Marrero J, et al. Effect of coenzyme Q10 plus nicotinamide adenine dinucleotide supplementation on maximum heart rate af- ter exercise testing in chronic fatigue syndrome – A randomized, controlled, double-blind trial. Clin Nutr. 2016 Aug;35(4):826-34. doi: 10.1016/j.clnu.2015.07.010. Epub 2015 Jul 17.