Another long post...helps me clarify my understanding/thinking, so bear with me.
Since I’ve been looking into macular degeneration (I’m at risk according to 23andme), I’m guessing betacarotene itself may not be the problem, but the interaction with other snp variants that were not identified. (I’ve also been interested because both AD and AMD have the presence of amyloid β - in the plaques of the AD brain and in the drusen of AMD patients. Might there be a common mechanism/cause?)
Here goes my take on betacarotene and blood glucose regulation. Interactions between a zinc transporter gene and betacarotene influences diabetes risk.
...the strongest evidence for interaction in our data was between rs13266634, a non-synonymous coding SNP in the SLC30A8 gene and three nutrient factors, trans- and cis-β-carotene, and γ-tocopherol. SLC30A8 is expressed in pancreatic islets and localized in insulin secretory granules of islet β cells. It appears to modulate insulin secretion and storage (Chimienti et al. 2004, 2005)...Our study enabled us to hypothesize that impaired insulin secretion driven by rs13266634 may increase T2D risk if combined with high or low levels of specific nutrients.
(C is the risk allele)
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3625410/
In addition, in women, at least one study found a high incidence of a snp that decreases the ability to convert betacarotenes. So you might get high betacarotenes in your diet, but not be able to utilize them.
In double-tracer studies, 27–45% of volunteers have been classified as poor converters (19⇓ 20⇓ 21)⇓ . These individuals have a capacity to form only 9% vitamin A from β-carotene compared with those who are classified as normal converters (21)⇓ . This large interindividual difference might be caused by reduced enzymatic activity as a consequence of genetic polymorphisms in the BCMO1 gene.
Here we describe the screening of the total open reading frame of the BCMO1 coding region that led to the identification of two common nonsynonymous single nucleotide polymorphisms (R267S: rs12934922; A379V: rs7501331) with variant allele frequencies of 42 and 24%, respectively. In vitro biochemical characterization of the recombinant 267S + 379V double mutant revealed a reduced catalytic activity of BCMO1 by 57% (P<0.001). Assessment of the responsiveness to a pharmacological dose of beta-carotene in female volunteers confirmed that carriers of both the 379V and 267S + 379V variant alleles had a reduced ability to convert beta-carotene, as indicated through reduced retinyl palmitate:beta-carotene ratios in the triglyceride-rich lipoprotein fraction [-32% (P=0.005) and -69% (P=0.001), respectively] and increased fasting beta-carotene concentrations [+160% (P=0.025) and +240% (P=0.041), respectively]
rs12934922 and rs7501331 (T is the risk allele on both)
http://www.fasebj.org/content/23/4/1041.long
So, one might have higher circulating betacarotenes from good eating habits, but depending on their snps, still have problems utilizing them!
So, there might have been enough women in this nutrient intake study, with altered betacarotene metabolism, that uncovered this connection with blood glucose regulation.
Throw in the APOE4 lipid transport issues, and betacarotenes and Vitamin A might not be making it to their job sites effectively.
However, an association of vitamin A with the apo E polymorphism was found in women, with apo E2 carriers exhibiting a slightly higher concentration than other subjects (19). These results indicate an influence of the apo E polymorphism on antioxidant vitamins, which may be modulated by sex (19).
http://ajcn.nutrition.org/content/81/3/624.full
And, if possible glucose dysregulation isn't bad enough, not enough Vitamin A (derived from betacarotene or perhaps supplements) impacts amyloid deposition in our mouse friends.
http://www.ncbi.nlm.nih.gov/pubmed/22221326
http://www.ncbi.nlm.nih.gov/pubmed/24582848
Fortunately, it looks like there are clinical trials in humans underway with various retinoids.
In addition, high circulating levels of betacarotenes can have other consequences.
A puzzling finding of this study is that participants with a G allele in rs6564851 had significantly lower levels of lycopene, lutein, and zeaxanthin plasma concentrations. Lycopene, lutein and zeaxanthin are synthesized only by plants and mammals need to consume them in their diet. Because of their molecular structure, there is no reason to believe that these carotenoids are a direct target for BCMO1. However, it has been proposed that carotenoids antagonize absorption of each other, suggesting that uptake by intestinal cells is a protein-transport facilitated process.54 Thus, it may be hypothesized that, through a still-unknown mechanism, higher α- and β-carotene plasma levels directly affect absorption, cell transport, and bio-availability of other carotenoids that are not vitamin A precursors.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2668002/
And BTW, low lycopene, lutein and zeaxanthin are also a risk factor in AD (and especially in AMD - in fact they recommend supplementing these for AMD patients).
Serum lycopene, lutein and zeaxanthin, and the risk of Alzheimer's disease mortality in older adults.
http://www.ncbi.nlm.nih.gov/pubmed/24247062
So, the way I see this is that perhaps not a problem with betacarotene per se, but getting it converted so our bounty of antioxidants from food can actually do their jobs.
My guess is that the same problem, a series of folate metabolism / methylation snp variants, might be impacting the results for folate but working on that path will take more brain power than I have left tonight.