About a decade ago, Michael Brownlee posited that AGEs were one of The Four Horsemen responsible for the microvascular complications of diabetes.
Thereafter, the image below (or a closely related one) appeared in at least one talk at every major diabetes conference for about 5 years. Then it faded – maybe not because it is wrong, but rather just too simplistic to be useful (similar to CICO & ELMM).
or… Circadian Meal Timing!
They say if you’re going to [intentionally] skip a meal, it should be breakfast – and hey, that’s probably the easiest meal to skip. However, a recent study showed skipping dinner FTW (well, not exactly). I’ve never seen a proper study directly comparing the effects of skipping different meals, but here are a few that come close. The findings may surprise you.
note: with the exception of Fernemark (Exhibit B), these studies are mostly macronutrient-controlled. That is, protein, fat, and carbs are similar between the groups; the only thing that differs is when they were ingested. This can be tricky and/or very nuanced in some instances, like if dinner was smaller (fewer calories) but more protein-rich, for example… but in order to include 5 relevant studies and not bore you to death, you’ll have to check the full texts for those details.
Posted in Advanced nutrition, circadian, diet, empty calories, Energy balance, fat, insulin, Protein, TPMC
Tagged body composition, calories, calories proper, carbs, diabetes, diet, energy balance, energy expenditure, fat, insulin, nutrition, obesity, protein
Pathologically low blood pressure can lead to shock & death. Angiotensin II is there to prevent that, but it does much more. A bit non-sequiter, perhaps.
This is what I call teamwork: low blood pressure detected by kidneys –> secretes renin. Angiotensinogen (liver) is cleaved by renin to Angiotensin I. Angiotensin Converting Enzyme (lungs [among other tissues]) cleaves angiotensin I into angiotensin II.
Angiotensin II increases blood volume and restores blood pressure. Good if you’ve lost a ton of blood fighting a wild beast; not good if you’re an overweight pen pusher on potato chips. ACE inhibitors reduce angiotensin II, lowering blood pressure. ACE is present in lungs probably because it deactivates bradykinin. ACE inhibitors prevent this which might contribute to one of their side effects, a persistent dry cough which makes these drugs intolerable for many. One alternative is angiotensin II receptor 1 blockers, or “ARBs.”
If anyone in pharma reads my blog (doubtful, unless they are monitoring for people to polonium-laced blow-dart), this will be their favorite post because I think ARBs are an interesting class of drugs.
If diet and weight loss are inadequate, telmisartan might be the next best thing to manage hypertension in diabetics: Telmisartan for the reduction of cardiovascular morbidity and mortality (Verdecchia et al., 2011) –> effective at reducing mortality in patients with diabetes.
Efficacy of RAS blockers on cardiovascular and renal outcomes in NIDDM (Cae & Cooper 2012) –> reduces morbidity and slows progression of renal disease (both hypertension and diabetes contribute to [irreversible] kidney damage, and frequently occur together, which makes this endpoint particularly relevant). Hyperglycemia should be managed via diet, of course, and ARBs would need to be tested in people following something other than a Western diet (although said people may not even need treatment in the first place) (just thinking out loud here. Or typing/whatever.)
But enough about blood pressure (<– boring); on to the more interesting stuff:
It started here: Chronic perfusion of angiotensin II causes cognitive dysfunctions and anxiety in mice (Duchemin et al., 2013)
Then: Candesartan prevents impairment of recall caused by repeated stress in rats (Braszko et al., 2012)
And: Anti-stress and anxiolytic effects of [candesartan] (Saavedra et al., 2005)
[Candesartan] prevents the isolation stress-induced decrease in cortical CRF1 receptor and benzodiazepine binding (Saavedra et al., 2006)
[Candesartan] ameliorates brain inflammation (Benicky et al., 2011) brain inflammation induced by chronic exposure to artificial lights causes depression-like symptoms (in mice) (probably humans, too)
Finally, a human study: Candesartan and cognitive decline in older patients with hypertension (Saxby et al., 2008)
And then there’s this: Angiotensin receptor blockers for bipolar disorder (de Gois et al., 2013)
No mechanistic stuff because, well, I have no idea how it works. On one hand, it might seem obvious that stress & anxiety can raise blood pressure, so something that lowers stress & anxiety could lower blood pressure. Candesartan appears to do both (cause <–> effect?). There are two unique properties of candesartan to note: 1) it gets into the brain; and 2) it leads to increased levels of angiotensin II (which presumably can’t do much because candesartan blocks the receptor for angiotensin II). Perhaps angiotensin II targets a different receptor? ARBs might blunt angiotensin II-induced CRH secretion, leading to anxiolysis, stress-tolerance, and pro-cognitive effects (that speculation was made possible by a thread on Avant Labs’ Forum and a few posts by Jane Plain on CRH [eg, here & here]).
Oh yeah, ARBs also prevent cafeteria diet-induced weight gain, insulin resistance, and ovulatory dysfunction [in rats] (Sagae et al., 2013). And are sympatholytic like bromocriptine (Kishi & Hirooka 2013).
“The Angiotensin-melatonin axis” (Campos et al., 2013).
just sayin’
Posted in Advanced nutrition, Bromocriptine, circadian, depression, Dopamine, insulin, mortality, vasopressin
Tagged angiotensin, blood pressure, bromocriptine, circadian rhythm, insulin, mortality
Melatonin is secreted from the pineal gland, the seat of the soul, the third eye. Pinealectomy induces circadian arrhythmia and has interesting effects on adipose tissue biology.
Exhibit A. In 2004, Alonso-Vale and colleagues showed that 6 weeks after pinealectomy, [melatonin-deficient] rats subjected to fasting exhibited an impaired energy conservation response. That is, they lost more weight and significantly depleted their adipocytes:
Posted in circadian, empty calories, Energy balance, Leptin, melatonin, TPMC
Tagged body composition, calories, calories proper, carbs, circadian rhythm, diet, energy balance, insulin
BMAL1 and CLOCK, ‘positive’ regulators of circadian gene expression, activate transcription of the negative regulators Per, Cry, and Rev-erb. PER and CRY inhibit BMAL1 and CLOCK, whereas Rev-erb inhibits Bmal1. It is said that Rev-erb is “an important link between the positive and negative loops of the circadian clock.” You don’t really need to know any of that to follow this blog post.
Posted in Advanced nutrition, circadian, diet, Energy balance, fat, insulin, melatonin, muscle, resveratrol, TPMC, wine
Tagged body composition, calories, calories proper, circadian rhythm, energy balance, energy expenditure, fat, insulin
A randomized pilot trial of a moderate carbohydrate diet compared to a very low carbohydrate diet in overweight or obese individuals with type 2 diabetes mellitus or prediabetes (Saslow et al., 2014)
Disclaimer: this study was not ground-breaking; it was confirmation of a phenomenon that is starting to become well-known, and soon to be the status quo. That is, advising an obese diabetic patient to reduce their carb intake consistently produces better results than advising them to follow a low fat, calorie restricted diet.
The two diets:
Moderate carbohydrate diet
In their words: “Active Comparator: American Diabetes Association Diet. Participants in the American Diabetes Association (ADA) diet group will receive standard ADA advice. The diet includes high-fiber foods (such as vegetables, fruits, whole grains, and legumes), low-fat dairy products, fresh fish, and foods low in saturated fat.”
Very low carbohydrate diet
In their words: “Experimental: Low Carbohydrate Diet. Participants will be instructed to follow a low carbohydrate diet: carbohydrate intake 10-50 grams a day not including fiber. Foods permitted include: meats, poultry, fish, eggs, cheese, cream, some nuts and seeds, green leafy vegetables, and most other non-starchy vegetables. Because most individuals self-limit caloric intake, no calorie restriction will be recommended.”
Both groups were advised to maintain their usual protein intake.
Posted in Advanced nutrition, diet, Dietary fat, fat, insulin, Ketosis, muscle, Protein, TPMC
Tagged Atkins, body composition, calories, calories proper, carbs, diet, energy balance, energy expenditure, fat, insulin, ketogenic, ketosis, muscle, nutrition, obesity, protein
The control of circadian gene expression is complex, with layer upon layer of suppressors and enhancers, numerous transcription factors, and a lot of interactions. A gross oversimplification: Clock and Bmal1 are positive regulators of circadian gene expression; Per and Cry are negative (you don’t really need to know any of this).
From Birky and Bray, 2014
Some pretty cool progress has been made in examining the effects of global and tissue-specific deletion of circadian rhythm-related transcription factors. Bear with me 🙂
For example, global Bmal1 knockout mice (ie, mice that don’t express Bmal1 anywhere in their whole body. Zero Bmal1. Nil.) (Lamia et al., 2008). These mice are obese, and exhibit impaired glucose tolerance yet improved insulin sensitivity.
Posted in Advanced nutrition, angiotensin, circadian, clamp, depression, diet, Dopamine, Energy balance, insulin, melatonin, vasopressin
Tagged bipolar, body composition, calories, calories proper, carbs, circadian rhythm, depression, diet, empty calories, energy balance, energy expenditure, insulin, mania, melatonin, mortality, nutrition
Insulin secretion is attenuated by sympathetic nervous system activity; eg, via exercise. Theoretically, exercising after a meal should blunt insulin secretion and I don’t think this will lessen the benefits of exercise, but rather enhance nutrient partitioning. And this isn’t about the [mythical?] post-workout “anabolic window.”
Sympathetic innervation of pancreas: norepinephrine –> adrenergic receptor activation = decreased insulin secretion & increased lipolysis (Stich et al., 1999):
note how quickly catecholamines are cleared upon exercise cessation
Posted in Advanced nutrition, Exercise, insulin, Protein, strength, Sugar, TPMC
Tagged calories, calories proper, carbohydrates, carbs, diet, energy balance, energy expenditure, exercise, insulin, nutrition
Jane Plain recently wrote a great article about the relationship between insulin, dietary fat, and calories. There are a lot of data on this topic, which collectively suggest: context matters!
For example,
Insulin and ketone responses to ingestion of MCTs and LCTs in man. (Pi-Sunyer et al., 1969)
14 healthy subjects, overnight fasted; dose: 1g/kg.
In brief, MCTs
Posted in Advanced nutrition, coconut, Dietary fat, Energy balance, fat, insulin, Protein, TPMC
Tagged calories, calories proper, carbohydrates, carbs, diet, empty calories, energy balance, fat, insulin, nutrition, protein
Nutritional ketosis is a normal, physiological response to carbohydrate and energy restriction. A ketogenic diet
In ketoacidosis, gluconeogenesis occurs at a very high rate and the lack of insulin prevents glucose disposal in peripheral tissues. Skeletal muscle protein breakdown contributes gluconeogenic substrates, exacerbating the problem. This can cause blood glucose to reach pathological levels, exceeding 250 mg/dL.
Posted in Advanced nutrition, diet, Dietary fat, fat, insulin
Tagged carbohydrates, carbs, diet, energy balance, fat, insulin, ketoacidosis, ketogenic, ketones, ketosis, nutrition, obesity, protein, sugar
