The dietary supplement industry has estimated sales of over $30 billion in the US and over $100 billion globally. Many consumers believe that dietary supplements are safer and possibly more effective than drugs to treat diabetes. The sheer volume of the literature in this space makes compiling them into one review challenging, so much so that primarily narrative reviews currently exist. By applying the interactive database supplied by the Office of Dietary Supplements at the National Institutes of Health, we identified the top 100 ingredients that appeared most often in dietary supplement products. One-hundred different keyword searches using the ingredient name and the word diabetes were performed using a program developed to automatically scrape PubMed. Each search was retained in a separate Excel spreadsheet, which was then reviewed for inclusion or exclusion. The studies that met the inclusion criteria were evaluated for effect of reducing and controlling diabetes. The PubMed scrape resulted in 6217 studies. For each keyword search only the most recent 100 were retained, which refined the total to 1823 studies. Of these 425 met the screening criteria. The ingredients, fiber, selenium and zinc had the most studies associated with improvement in diabetes. Several popular supplement ingredients (phosphorus, pantothenic acid, calcium, magnesium, glutamine, isoleucine, tyrosine, choline, and creatine monohydrate) did not result in any studies meeting our screening criteria. Our study demonstrates how to automate reviews to filter and collapse literature in content areas that have an enormous volume of studies. The aggregated set of studies suggest there is little clinical evidence for the use of dietary supplements to reduce or control diabetes.

β-Hydroxy-β-methylbutyrate (HMB), a leucine metabolite, can increase skeletal muscle size and function. However, HMB may be less effective at improving muscle function in people with insufficient Vitamin D3 (25-OH-D < 30 ng/mL) which is common in middle-aged and older adults. Therefore, we tested the hypothesis that combining HMB plus Vitamin D3 (HMB + D) supplementation would improve skeletal muscle size, composition, and function in middle-aged women. In a double-blinded fashion, women (53 ± 1 yrs, 26 ± 1 kg/m2, n = 43) were randomized to take placebo or HMB + D (3 g Calcium HMB + 2000 IU D per day) during 12 weeks of sedentary behavior (SED) or resistance exercise training (RET). On average, participants entered the study Vitamin D3 insufficient while HMB + D increased 25-OH-D to sufficient levels after 8 and 12 weeks. In SED, HMB + D prevented the loss of arm lean mass observed with placebo. HMB + D increased muscle volume and decreased intermuscular adipose tissue (IMAT) volume in the thigh compared to placebo but did not change muscle function. In RET, 12-weeks of HMB + D decreased IMAT compared to placebo but did not influence the increase in skeletal muscle volume or function. In summary, HMB + D decreased IMAT independent of exercise status and may prevent the loss or increase muscle size in a small cohort of sedentary middle-aged women. These results lend support to conduct a longer duration study with greater sample size to determine the validity of the observed positive effects of HMB + D on IMAT and skeletal muscle in a small cohort of middle-aged women.

Impaired mitochondrial function is associated with the loss of skeletal muscle function during aging and age‐related osteoarthritis (OA). Emerging evidence suggests Rapamycin (Rap), metformin (Met) or the combination of rapamycin plus metformin (Rap+Met) can extend lifespan and preserve skeletal muscle mass and function during aging. However, the mechanisms of action are not completely understood and have not been studied in specific models of age‐related disease. The goal of this study was to test to test the hypothesis that Rap, Met, or Rap+Met would improve skeletal muscle mitochondrial function in an animal model of naturally occurring, age‐related OA. We chose the Dunkin Hartley guinea pig because they are an outbred strain that develops naturally occurring OA by 5 months of age with a progression and pathology that highly resembles aging humans. After 5 months of age, Dunkin Hartley guinea pigs also have an age‐related decline in skeletal muscle mitochondrial protein synthesis rates. Therefore, 5‐month old Dunkin Hartley guinea pigs were fed a standard diet (Con; n=8), or a diet enriched with Rap (14ppm; n=8), Met (1000ppm, n=8) or Rap+Met (14+1000ppm; n=7) for 12‐weeks. Mitochondrial respiration and hydrogen peroxide (H2O2) emissions were evaluated in permeabilized muscle fibers from the soleus via high‐resolution respirometry and fluorometry using either a saturating bolus or titrating doses of ADP. Michaelis‐Menten kinetics was used to evaluate Vmax and ADP sensitivity. All comparisons were made to control group. In the current study, Met had no effect while Rap and Rap+Met modified skeletal muscle mitochondrial bioenergetics only when ADP was titrated but not with a saturating bolus. Specifically, Rap (P<0.05) and Rap+Met (P=0.07) increased ADP sensitivity but decreased (P<0.05) maximal complex‐I (CI) linked respiration. Rap and Rap+Met also tended to decrease mitochondrial H2O2 emissions but this trend was no longer apparent when mitochondrial H2O2 emissions were expressed relative to respiration. The decrease in CI‐linked respiration and H2O2 emissions was attributed to both a lower CI protein abundance and a decreased index of intrinsic mitochondrial function. This is the first inquiry into how lifespan extending treatments can influence skeletal muscle mitochondria in a model of age‐related OA. Further research is needed to understand if increased mitochondrial ADP sensitivity at the cost of CI‐linked maximal capacity by Rap and Rap+Met is a beneficial strategy to maintain cellular energy homeostasis during age‐related OA.

The age‐related loss of skeletal muscle mass, quality, and strength can lead to the loss of independence later in life. Beta‐hydroxy‐beta‐methylbutyrate (HMB), a leucine metabolite, can increase skeletal muscle size and function. However, emerging evidence suggests HMB may be less effective at improving muscle function in people with insufficient Vitamin D3 levels (25‐hydroxy‐Vitamin D (25‐OH‐D) <30 ng/mL,) common in middle‐aged and older adults. Therefore, our current study tested the hypothesis that combining HMB (Calcium salt) with Vitamin D3 (HMB+D) would increase skeletal muscle size, quality and function in middle aged women (53±1 yrs, 26±1 kg/m2, n=43) randomized to sedentary control (SED) or progressive resistance exercise training (RT). In a placebo‐controlled, double‐blinded fashion, women were further randomized to placebo or HMB+D (3g of HMB + 2000IU of Vitamin D3). Study enrollment and recruitment occurred before and after COVID‐19 stay at home measures. In both RT and SED, HMB+D raised circulating levels of 25‐OH‐D after 8 (33±2 ng/mL) and 12 (35±2 ng/mL) weeks to reach sufficient Vitamin D3 levels. In SED, HMB+D prevented the loss of lean arm mass observed in the placebo group (0.07±0.06 vs ‐0.19±0.06 kg; P<0.05). HMB+D also increased thigh skeletal muscle (26±13 vs ‐5±8 cm3; P<0.05) and decreased intermuscular adipose tissue (IMAT) volume (‐20±11 vs 5±6 cm3; P<0.05) compared to placebo. However, 12‐weeks of HMB+D did not change skeletal muscle function. In the RT, 12‐weeks of HMB+D decreased IMAT compared to placebo (‐22±13 vs 6±4 cm3; P<0.05) but did not influence the increase in skeletal muscle mass or function. These data show that 12‐weeks of HMB+D supplementation consistently decreased thigh IMAT volume in both SED and RT. HMB+D in sedentary middle‐aged women was beneficial for skeletal muscle size but did not lead to improved muscle function or quality. Further, HMB+D did not influence the hypertrophic or functional improvements after resistance exercise training in middle‐aged women. HMB+D may be able to help combat the age‐related loss of skeletal muscle mass in sedentary women. These results lend support to conducting a larger study for a longer duration to validate these findings as well as explore additional populations who may also benefit from HMB+D.