Archive for the ‘diabetes’ Category
a post to send you to sleep, or not
Häggström, Mikael (2014). “Medical gallery of Mikael Häggström
Canto: Anything interesting you’ve learned lately?
Jacinta: Well, there’s so much, it’s hard to keep track of it all, before it slides down the slippery slope into a past of fragmented memories.
Canto: A pasta of memories? That’s food for thought. I know you’ve been reading up on sleep, among all your other heavy reading. Tell me.
Jacinta: Yes, I’ve been reading up on feminism and misogyny as you know, which is mostly depressing, but this sciencey but very accessible book, Why we sleep by Matthew Walker, is not so much depressing as worrisome, for those of us whose sleep patterns are all over the place, like mine. He’s a big-time sleep researcher, and what he says about sleep deprivation is all bad – even for a wee bit of it.
Canto: So, those dreams of doing away with sleep, of zapping your brain for a few seconds to provide the instant reinvigoration that sleep takes eight hours of wasteful oblivion to achieve, allowing us that much more time to ruin the biosphere and all, or just to read more books and shit, those dreams are just a waste of sleep?
Jacinta: No zapping will ever replace the complexity of sleep, with all its REMness and non-REMness, let Mr Walker assure you. Sleep is a restorative and builder, which has complexly evolved with the complex evolution of our brains and bodies. And by ‘our’ I don’t just mean humans, but every complex or not-so complex evolved organism. They all sleep.
Canto: Well, there are many questions here. You’ve mentioned REM sleep, which I think has something to do with dreaming – your eyes, presumably under their lids, are rapidly moving about. Why? It doesn’t sound healthy.
Jacinta: They’re responding to brain signals, and it’s perfectly normal. More specifically, they seem to be responding to the brain’s changing visual representations while dreaming. They used electrodes in the brain to discover this – which sounds Frankensteinish but in this case they were patients with epilepsy preparing to have very invasive treatment to stop their seizures. They looked at activity in the medial temporal lobe, a region deep in the brain which includes the hippocampus and amygdala, and is involved in encoding and consolidating memories, and found fairly clear-cut connections between that activity and patients’ eye movements.
Canto: But how could they ‘see’ the eye movements?
Jacinta: Oh god, I don’t know, for now I’m more interested in sleep deprivation, which raises concerns for everything from diabetes to Alzheimer’s. And, although I haven’t measured anything carefully, my guess is that I average 6 to 7 hours’ sleep a night, and I need to amp that up.
Canto: And you’ve recently been diagnosed as pre-diabetic, so do you think more sleep can help with that? It’s usually pretty strongly correlated with diet isn’t it?
Jacinta: Less time sleeping, more time for eating, Walker writes. I’m certainly trying to lose weight, but only by eating less. I think my diet’s not too bad, less wine though. And I suppose if I slept more, which is easier said than done, I wouldn’t eat so much. I’ve found in the past that just reducing the quantity of food I ingest, without changing its make-up – in other words, being more disciplined – can take the weight off quite quickly. The key is to make it life-long.
Canto: More fibre is good, I think. For the microbiome.
Jacinta: So type 2 diabetes is generally about blood sugar levels and their regulation, or lack thereof. In a healthy person, eating a meal adds glucose to the blood, which triggers the hormone insulin, produced in the pancreas, to somehow bring about cellular absorption of the glucose as an energy source. In the case of diabetes, there’s usually a break-down in the cellular response to the insulin signal, I think, and so you become hyperglycaemic – not that this has ever happened to me, so far.
Canto: So how does this relate to lack of sleep, apart from giving you more time to guzzle sugar?
Jacinta: Walker describes a series of studies, independent from each other, in different continents, which found high rates of type 2 diabetes in people who reported sleeping for less than six hours a night on a regular basis. They controlled for other factors such as obesity, alcohol use, smoking etcetera. But of course correlation isn’t causation so they investigated further. They conducted experiments with a bunch of healthy people – no blood glucose problems or signs of diabetes. Firstly, they mildly tortured them – they permitted them only four hours of sleep per night over six straight nights. Then they tested their ability to absorb glucose, and found a 40% reduction in that ability. This would immediately classify them as pre-diabetic, and these studies, I’m assured, have been replicated numerous times.
Canto: That sounds incredible. And these guinea pigs quickly recovered? Or are they now full-blown diabetics? Doesn’t sound like mild torture to me. And do they know why a week’s sleep deprivation had such a dramatic effect?
Jacinta: Ha, well, Walker doesn’t mention the afterlife of the experimental subjects, but I’m assuming normality came bounding back after they recovered their sleep. As to the mechanism of action, Walker describes two options – sleep loss may have blocked the release of insulin by the pancreas, providing no signal for cell absorption to take place, or it may have interfered with the released insulin’s message to the cells. And though it seems that sleep loss probably had an effect on both, it was clear from biopsies taken from subjects that it was the latter, the cells’ lack of response to insulin, their ‘refusal’ to take up the blood glucose, that was the principal problem.
Canto: Just looking at the Sleep Foundation website, and they seem to get things the other way round, that diabetics are suffering from sleep loss. I must say, that, off the top of my head, I’d find being pre-diabetic easier to manage than my sleep behaviour. I mean, I can imagine changing my diet and exercise habits easily enough, but my sleep habits not so much. How do you turn off your brain?
Jacinta: Well, Mr Walker has some suggestions on that, which we’ll explore next time. And by the way, there seems to be tons of videos and websites providing knowledge and advice on the issue, which always makes me feel superfluous to requirements as a human being…
Canto: Well, try not to lose sleep over it.
References
Why we sleep, by Matthew Walker, 2017
https://www.sciencealert.com/scientists-have-worked-out-why-your-eyes-move-when-you-re-dreaming
https://en.wikipedia.org/wiki/Sleep_deprivation
https://www.sleepfoundation.org/physical-health/lack-of-sleep-and-diabetes
covid-19, more on fructose, vitamin D, treatments and the vagaries of testing
Canto: Ok, so note that in the graphic from the previous post, Australia is third highest in the group of 31 countries studied for caloric intake from sweeteners, but we don’t use HFCS much at all.
Jacinta: It might be a misleading graphic too. You might be forgiven for thinking that it somehow shows the USA as the most unhealthy, sweet-toothy country on the list, and Australia in third position, but since we’re more concerned here with links between fructose and covid-19 co-morbidities such as obesity, diabetes, cardiovascular problems and oxidative stress, the graphic doesn’t tell us much.
Canto: Yes so I found on this indexmundi site a list of 195 countries – and that’s all of them – showing prevalence of diabetes 1 and 2. That’s to say, the percentage of the adult population (from 20 to 79) that is diabetic. The USA ranks 43rd on that list, and Australia is down at 137th, level with Finland and Japan. But the site doesn’t name sources, and provides an end-note on the unreliability of much evidence: ‘National health authorities differ widely in capacity and willingness to collect or report information’. I should also add that though the USA is 43rd, the only other major nations above them are just about every Middle Eastern country, Pakistan, South Africa, Egypt, Sudan and Mexico. Make of that what you will.
Jacinta: Let’s avoid that rabbit hole, and return to medcram update 83, which briefly describes vitamin D3 (cholecalciferol) metabolism. This may involve a bit of repetition but that’s rarely a bad thing for us. So the D3 that we absorb or ingest goes to the liver and is hydroxylased at the 25th position (25-OH), but it doesn’t become activated until it’s again hydroxylased at the first position by the kidney (1,25-diOH, aka 1,25 dihydroxy vitamin D). And there’s another enzyme that can convert the vitamin to inactive forms.
Canto: With that, Dr Seheult looks at another article from 2013 which describes a rat study that indicates that if fed on a high fructose diet, lactating rats suffered reduced rates of active intestinal calcium transport and active vitamin D. Or, more, accurately I think, they didn’t get the increased rates and levels that would be expected during lactation. So, because calcium is essential for skeletal growth, the study says ‘our discovery may explain findings that excessive consumption of sweeteners compromises bone integrity in children’.
Jacinta: Interesting, and I presume that means consumption by the mother during pregnancy. Anyway, in more detail, what they found was that increased fructose intake inhibited the enzyme that converted vitamin D into the active form in the kidney, and promoted the enzyme responsible for the inactive forms. Disturbing, as Seheult says, for the excessive fructose in American diets, which may consequently affect calcium and vitamin D levels, though that would surely require more research.
Canto: Well, the same group released more research in 2014 which found that chronic high fructose intake in calcium-sufficient rodents (rats and mice) reduced their active vitamin D levels. And a 2015 study from Iran looked at something different but again having to do with effects on enzymes and metabolism. They looked at S-methyl cysteine (SMC), and this recalls the investigation of N-acetyl cysteine (NAC) a few updates ago. Found naturally in garlic and onions, SMC is described as a hydrophilic cysteine-containing compound, which they investigated for its putative effects against oxidative stress and inflammation. So they induced oxidative stress in rats via a high-fructose diet over 8 weeks and then dosed them with SMC. Results from the high fructose diet were – here goes – increased blood levels of glucose, insulin, malondialdehyde, and tumour necrosis factor-alpha.
Jacinta: Okay so the increased insulin is presumably a reaction to the increased glucose. Its role is to absorb excess blood glucose, and too much of it can result in hypoglycaemia, low serum glucose levels. Malondialdehyde (MDA) is described as a marker for oxidative stress, so it’s not good. Tumour necrosis factor (TNF or TNFα) is a ‘multifunctional cytokine’, and although cytokines (types of proteins) perform many vital functions, the cytokine storm that appears to be associated with oxidative stress and covid-19 is a bad thing.
Canto: But there were also decreased levels of glutathione (GSH), glutathione peroxidase (GPx) and catalase as a result of this fructose diet, and Seheult talked about these enzymes and such as important in reducing oxidative stress. However, the SMC dosing improved antioxidant enzyme activities and reduced levels of glucose, insulin and TNFα.
Jacinta: So this SNC seems another promising antioxidant treatment. Meanwhile, watch your sugar intake, especially with fructose. More studies required of course, but I suppose there are ethical issues involved in fattening up and inducing oxidative stress on human subjects with a high fructose diet. Okay updates 84 and 85 deal with questions that hospitalised covid-19 patients might want answered, so we’re going to skip those or we’ll never catch up on these updates. With update 86 they’re into the second half of June and noticing a resurgence of the virus. So at the Johns Hopkins site they’ve ‘working to fill the void of publicly accessible covid-19 testing data’, because without testing you obviously can’t work out the numbers.
Canto: But more than testing itself, the turnaround of results is a problem. A young woman was just on the tube saying it took three weeks to get her test results, which renders the test useless. And another person on the tube reported that she’d tested positive, felt generally okay or asymptomatic, then tested negative, after which she came down with a heavy case replete with many of the covid-19 symptoms, and then tested positive again. How can this happen?
Jacinta: It’s still a mysterious virus, but to return to the update and Johns Hopkins, they’re generally looking at US data, but I’m interested in understanding the testing process and how well it maps the prevalence of this virus. The website has a graphic which shows the fairly rapid rise in daily testing from March through to June (with a drop-off from mid-June, when perhaps they thought it was more under control), and the number of positive daily tests, which hasn’t of course risen so much, so that the percentage of positive test results has gradually fallen. The WHO recommends that the percentage of positive tests, the positive percentage rate (PPR), in nations or states where there’s widespread testing, should be under 5% for at least fourteen days before those states can start ‘relaxing’, but I’ve read different, more flexible recommendations elsewhere from health authorities, so it seems still a matter of educated guesswork with an unpredictable pandemic.
Canto: For the different US states, looking at the figures now in mid-August, the figures are weird. Washington has a PPR of 100% (?!) and are testing 1 in every 10,000, so it seems they’re only testing those they know are positive? That’s top of the list and bottom is North Carolina with a PPR of -13.1, and yes that’s a minus, and they’re testing -.09 in every thousand, and I’ve no idea what that means.
Jacinta: But most states’ figures are clear enough. New York is at 0.8% PPR with over 4 tests per 1000, which is good, but Nevada, Idaho and Florida are at over 16% PPR, each with around 1.5 tests per 1000, and that’s obviously a problem. An indication of the lack of centralised control of the situation – it’s hard to compare data from state to state. Anyway, the key, some say, is to scale the testing to the size of the epidemic in that nation/state, not to the state’s population – but how can you do that when you’re using the testing to determine the size of the epidemic?
Canto: Well presumably if nobody is reporting unusual, covid-like symptoms, as is the case here in South Australia, you don’t need to spend so much time, money and energy on testing. Not the case in the USA. Anyway, in this update, Dr Seheult noted, as we have been, that the case numbers for covid-19 are increasing, but the death rate is decreasing slightly, or at least levelling off. Possibly a result of more testing combined with better treatment. They may also be catching weaker levels of the virus due to measures put in place. But there’s no evidence as yet that the virus itself has become less potent, and this seems unlikely.
Jacinta: And speaking of treatments, the steroid dexamethasone is apparently reducing mortality by as much as 35% for covid-19 patients on ventilation, according to a WHO preliminary report of work done at Oxford. It’s only good for those with severe hypoxia and associated problems though, but its a cheap, off-patent medication which can be added to the box of tricks for ICUs, once the data is confirmed.
Canto: Okay, next time….
References
Coronavirus Pandemic Update 83: High Fructose, Vitamin D, & Oxidative Stress in COVID-19
Coronavirus Pandemic Update 86: COVID-19 Testing & Cases Increasing but Daily Deaths Decreasing
https://www.indexmundi.com/facts/indicators/SH.STA.DIAB.ZS/rankings
https://coronavirus.jhu.edu/testing
covid-19: vitamin D, fructose and oxidative stress
So looking at the Medcram coronavirus update 82, approaching mid-June, we find that many of the monitoring websites give the impression that case rates are falling in the USA and elsewhere….
The update also looks at diabetes as a risk factor for covid-19. It discusses data from China linking mortality to blood sugar levels. Glycated haemoglobin (HbA1c) was brought up in a previous post, though there are different ways of measuring it – I’ll keep to the percentages. The normal HbA1c should be below 6%, though presumably not too far below, as can happen for diabetics that over-medicate. Your HbA1c measure tells you what your blood sugar level has been over the last two-month period, approximately. So, to quote from the study:
the researchers found an increased mortality risk associated with any form of previously undiagnosed elevated blood glucose at the time of admission among 453 patients hospitalised with laboratory-confirmed SARS-CoV2 infection
One would imagine that, with the oxidative stress that SARS-CoV2 brings on, diabetics or pre-diabetics not on medication might be more at risk than those on regular medication with a consequently relatively low HbA1c. This is the kind of association found here.
The update goes on to discuss an article on race and covid-19 mortality in England, which has a supposedly open-access National Health Service (NHS), which in fact has been subject to savage cuts from successive conservative governments. The article concludes, unsurprisingly, that BAME (i.e Black, Asian and Minority Ethnic) persons are ‘at increased risk of death from covid-19 even after adjusting for geographic region’. Suggestions for reducing these apparent inequities include ensuring adequate income protection, reducing occupational risks, reducing barriers in accessing healthcare and providing culturally and linguistically appropriate services. Of course, these problems exist within all countries with substantial immigrant populations, many of whom are more exposed to the virus than others.
Vitamin D is next revisited, with an article entitled ‘Vitamin D deficiency in Europe: pandemic?’, which was actually published back in 2016. Now I note from some of the comments on this update that there’s a lot of hype and apparent misinformation on vitamin D out there, so I want to dwell on this, for my own education.
The article refers to a Vitamin D Standardisation Program (VDSP) which has developed protocols to look at serum vitamin D data from differently-aged European populations, ‘to better quantify the prevalence of vitamin D deficiency in Europe’. So they applied these protocols to 14 different population studies, looking at serum 25-hydroxyvitamin D [25(OH)D]. Vitamin D has five different types, but the pertinent one for human health is D3, aka cholecalciferol, which is made by the skin when exposed to sunlight, and is also found in foods and supplements. D3 is hydroxylated by the liver at the ’25 position’, according to Seheult. Presumably this is a position on the D3 molecule where a hydroxyl group is added. 25(OH)D refers to the molecule after this hydroxylation, but before it becomes activated by further hydroxylation at position 1 by the kidney. So they looked at this molecule in a number of studies using ‘certified liquid chromatography – tandem mass spectrometry on biobanked sera’. Combined with other standardised serum data, data was collected from almost 56,000 patients, and the findings were that 13% of them, regardless of category, had serum levels seriously below normal, especially during the winter months. 40% were below the generally accepted norm. The problem was considerably exacerbated in dark-skinned ethnic sub-groups.
Back to 2020, and an article looking at the role of vitamin D in the prevention of covid-19 infection and mortality. It noted that ‘Vitamin D levels are severely low in the aging population especially in Spain, Italy and Switzerland’, so this is obviously a covid-19 co-morbidity factor. The article goes on to describe the mechanism of vitamin D’s action in the body, the details of which I’ll pass over, but it does involve ACE-2 and angiotensin 1,7, and also many other factors including macrophage development. With all this they raise the question of widespread vitamin D supplementation, which is apparently a hot topic beyond strictly scientific media, as mega-doses of vitamin D are being argued for on certain social media platforms, and even in the comments to this update. There are messy arguments going around about safe upper limits. Dr Seheult simply reports the article’s concern about ‘popular information channels’ spruiking the use of vitamin D3 above the generally accepted safe upper limit of 4000 international units per day. There is of course a battle here, not only in relation to vitamin D3, between those who demand proper trialling and vetting of medications and supplements and those looking for quick fixes. In any case, modest, regular dosing of the vitamin seems to be most effective.
Update 83 goes intensively into a very important and interesting health topic, which has been quite controversial and also revelatory of late; the role of fructose in our diet, and how it works in our bodies. So to refresh – which is always good for me, at least – about the issue of oxidative stress and how it is exacerbated by SARS-CoV2. So we have oxidative stress in the form of an excess of superoxide and reactive oxygen species (ROS). The SARS-CoV2 virus enters the cell via the ACE2 receptor, blocking angiotensin-converting enzyme 2 (ACE2) from converting angiotensin-2 (AT-2) to angiotensin 1,7 (AT-1,7). AT-2 promotes superoxide production, while AT-1,7 inhibits it. This problem is in addition to the effect of SARS-CoV2 itself in bringing about an increase in polymorphonuclear leukocytes (PMNs), which are white blood cells such as neutrophils, basophils and eosinophils. These also lead to increased superoxide production, and more oxidative stress. An essential feature of oxidative stress is that it can result in endothelial cell dysfunction. These cells line the vascular system that feeds the body’s major organs. This dysfunction brings about an increase in von Willibrand factor which leads to clotting and thrombosis. Recent analysis of autopsies found that covid-19 patients had nine times more lung clotting than control groups including influenza patients.
So the point of all this is that not having oxidative stress in the first place will be an important prophylactic against the virus. As Dr Seheult relates from the coalface, it’s those with a high BMI, with kidney and cardiovascular issues, and with diabetes, that seem to be at most risk of succumbing to the virus. Also, those with apparently normal HbA1c but with increased glucose were about 10 times more likely to have serious complications associated with the virus. This raises the question of diet, specifically bad diet.
We then go back to 2017 and an article, or compendium of articles, published in Nutrients. Its title is ‘fructose consumption in the development of obesity and the effects of different protocols of physical exercise on the hepatic metabolism’. So fructose is a simple sugar or monosaccharide which combines with glucose to form the disaccharide sucrose. There are two forms of fructose (and of glucose), which are enantiomers, which is to say they have opposite chirality, which gives them different reactive properties. They’e called D-fructose and L-fructose. They’re six-carbon sugars, and D-fructose is the prominent form in the body. Sucrose links together a molecule of glucose with one of fructose, so that sucrose (table sugar) is essentially 50% fructose. Fructose is added to many foods as a sweetener, particularly in the form of high fructose corn syrup (HFCS) and this has become controversial, in case you didn’t know. It’s not such as issue in Australia, where we mostly use cane sugar as a sweetener, but it features in imported processed foods, and in many sweetened drinks. So how does fructose impact on obesity and oxidative stress? To quote from the abstract of the above-named article, ‘studies indicate that fructose may be a carbohydrate with greater obesogenic potential than other sugars’. The article provides a compendium of such studies and how fructose affects glucose metabolism in the liver, adversely affects hepatocyte function and engenders inflammatory responses. It also advocates physical exercise for reduction of symptoms and as harm-minimisation practice. An experiment on rodents in which half were fed on fructose, the other half on sucrose (50% fructose, 50% glucose), the fructose-fed rodents gained more weight, and over time that extra weight involved an increase in abdominal adipose tissue and increased serum triglyceride levels:
Moreover, several studies corroborated the evidence that high fructose consumption might lead to accumulation of adipose tissue, systematic inflammation, obesity, oxidative stress and consequently insulin resistance in different tissues.
And there’s much more on the same lines, with relevant references. Dr Seheult describes other articles and studies over the last ten years identifying fructose and HFCS and their relationship to type 2 diabetes prevalence. One interesting article, which looked at HFCS alone, and surveyed diabetes on a global level, found that ‘diabetes prevalence was 20% higher in countries with higher availability of HFCS compared to countries with low availability’ and these results were adjusted for BMI, population, GDP and other factors. Greatest use of HFCS was in the USA, which of course has the highest rate of diabetes, and is leading the world in covid-19 cases.
References
Coronavirus Pandemic Update 82: Racial Disparities with COVID-19 & Vitamin D
Coronavirus Pandemic Update 83: High Fructose, Vitamin D, & Oxidative Stress in COVID-19
https://www.sciencedirect.com/science/article/pii/S0899900714001920