Peter’s interest is in fat storage based on insulin levels. The study compared ad libitum to calorie restricted eating in the mice. Peter concentrated on the ad libitum eating of the mice (not being all that interested in calorie restricted diets). Peter points out that it takes insulin to store fat in subcutaneous tissues but very little insulin to store fat in visceral fat. The study put it this way:
In all WAT depots, CR markedly upregulated the expression of proteins involved in FA biosynthesis in fed rats. In visceral WAT (rWAT and eWAT), hormone-sensitive lipase (lipolytic form) phosphorylation was increased by CR under fed conditions, and decreased by CR under fasted conditions. Conversely, in sWAT, hormone-sensitive lipase phosphorylation was increased by CR under fasted conditions. CR enhanced the effect of feeding on AKT activity in sWAT (indicative of a positive effect on insulin sensitivity) but not in rWAT or eWAT. These data suggest that CR improves lipid metabolism in an insulin signaling-dependent manner in sWAT only.
As Peter puts it:
This looks very much like one of the intrinsic differences between subcutaneous adipocytes and visceral adipocytes is that visceral adipocytes maintain insulin signalling at much lower levels of plasma insulin than do subcutaneous adipocytes. You have to store calories which arrive without insulin somewhere. Looks like this is the place!
We used stable-isotope mass spectrometric methods with indirect calorimetry to establish the metabolic basis of changes in whole-body lipid balances in healthy men after consumption of 24 g alcohol.
Eight healthy subjects were studied and DNL (by mass-isotopomer distribution analysis), lipolysis (by dilution of [1,2,3,4-(13)C(4)]palmitate and [(2)H(5)]glycerol), conversion of alcohol to plasma acetate (by incorporation from [1-(13)C(1)]ethanol), and plasma acetate flux (by dilution of [1-(13)C(1)]acetate) were measured.
The fractional contribution from DNL to VLDL-triacylglycerol palmitate rose after alcohol consumption from 2 +/- 1% to 30 +/- 8%; nevertheless, the absolute rate of DNL (0.8 g/6 h) represented <5% of the ingested alcohol dose; 77 +/- 13% of the alcohol cleared from plasma was converted directly to acetate entering plasma. Acetate flux increased 2.5-fold after alcohol consumption. Adipose release of nonesterified fatty acids into plasma decreased by 53% and whole-body lipid oxidation decreased by 73%.
We conclude that the consumption of 24 g alcohol activates the hepatic DNL pathway modestly, but acetate produced in the liver and released into plasma inhibits lipolysis, alters tissue fuel selection, and represents the major quantitative fate of ingested ethanol.
It’s not so much that the alcohol itself gets turned to fat, it’s that alcohol inhibit lipolysis (fat burning).
Eleven people with type 2 diabetes (49.5 ± 2.5 years, BMI 33.6 ± 1.2 kg/m2, nine male and two female) were studied before and after 1, 4 and 8 weeks of a 2.5 MJ (600 kcal)/day diet.
Here are the results:
After 1 week of restricted energy intake, fasting plasma glucose normalised in the diabetic group (from 9.2 ± 0.4 to 5.9 ± 0.4 mmol/l; p = 0.003).
Insulin suppression of hepatic glucose output improved from 43 ± 4% to 74 ± 5% (p = 0.003 vs baseline; controls 68 ± 5%).
Hepatic triacylglycerol content fell from 12.8 ± 2.4% in the diabetic group to 2.9 ± 0.2% by week 8 (p = 0.003).
The first-phase insulin response increased during the study period (0.19 ± 0.02 to 0.46 ± 0.07 nmol min−1 m−2; p < 0.001) and approached control values (0.62 ± 0.15 nmol min−1 m−2; p = 0.42).
Maximal insulin response became supranormal at 8 weeks (1.37 ± 0.27 vs controls 1.15 ± 0.18 nmol min−1 m−2).
Pancreatic triacylglycerol decreased from 8.0 ± 1.6% to 6.2 ± 1.1% (p = 0.03).
Other interesting factoids from the study. In Type 2 diabetics:
Beta cell function declines linearly with time, and after 10 years more than 50% of individuals require insulin therapy.
Here’s the data from the study.
101.5 ± 3.4
103.7 ± 4.5
99.7 ± 4.5*
94.1 ± 4.3*
88.4 ± 4.3*†
33.4 ± 0.9
33.6 ± 1.2
32.3 ± 1.2*
30.5 ± 1.2*
28.7 ± 1.3*†
Fat mass (kg)
36.2 ± 2.7
39.0 ± 3.5
36.6 ± 3.6*
31.7 ± 3.7*
26.3 ± 4.0*
64.7 ± 3.8
64.7 ± 3.0
63.2 ± 3.1
62.4 ± 3.0*
62.1 ± 3.0*
Waist circumference (cm)
105.0 ± 1.5
107.4 ± 2.2
104.4 ± 2.2*
99.7 ± 2.4*
94.2 ± 2.5*†
Hip circumference (cm)
109.8 ± 2.4
109.5 ± 2.9
108.3 ± 2.7*
105.0 ± 2.6*
99.5 ± 2.6*†
0.96 ± 0.02
0.98 ± 0.02
0.97 ± 0.02
0.95 ± 0.01
0.95 ± 0.01
It is remarkable that the people lost mostly fat. The Fat Free Mass loss was only 2.6kg (about 6 lbs). The fat loss was 10 kg (about 22 lbs). That’s a pretty decent drop.
This was neither a Low Carb nor Low Fat diet. It was a restricted calorie diet (600 calories a day). The macros were 46.4% carbohydrate, 32.5% protein and 20.1% fat; vitamins, minerals and trace elements; 2.1 MJ/day [510 kcal/day]; Optifast; Nestlé Nutrition, Croydon, UK. This was supplemented with three portions of non-starchy vegetables such that total energy intake was about 2.5 MJ (600 kcal)/day.
It is remarkable how much fat was lost from the liver in just the first week.
Hepatic triacylglycerol content decreased by 30 ± 5% during week 1 of intervention (p < 0.001), becoming similar to control values (p = 0.75). It continued to decline throughout the intervention period to reach the normal range for non-obese individuals  (2.9 ± 0.2%; p = 0.003; Fig. 1), i.e. a total reduction of 70 ± 5%.
Most interestingly, the study after the study noted:
Following the intervention, participants gained 3.1±1.0 kg body weight over 12 weeks, but their HbA1c remained steady while the fat content of both pancreas and liver did not increase.
The conclusion matches my own hypothesis:
The data are consistent with the hypothesis that the abnormalities of insulin secretion and insulin resistance that underlie type 2 diabetes have a single, common aetiology, i.e. excess lipid accumulation in the liver and pancreas.
…a high-fructose diet in rhesus monkeys produces insulin resistance and many features of the metabolic syndrome, including central obesity, dyslipidemia, and infl ammation within a short period of time; moreover, a subset of monkeys developed type 2 diabetes
A Rhesus monkey used in the study is closer genetically to a human than the typical mouse study.
Numerous animal studies, mostly conducted in rodents, have shown that diets high in fructose produce metabolic perturbations associated with the metabolic syndrome and T2DM.
However, important metabolic differences exist between rodents and primates, particularly with respect to lipoprotein metabolism,the major site of lipogenesis (liver vs. adipose), and the physiology of thermogenesis.
Therefore, the results of metabolic studies performed in primates are substantively more applicable to human physiology and medicine than those from rodent studies, underscoring the importance of developing standardized nonhuman primate models of insulin resistance for the study of metabolic syndrome and T2DM.
Kimber Stanhope was one of the authors of this study. See her other study on Fructose (Not All [Sugar] Is Bad).
That’s a challenging question since by most tests I am not a diabetic. I no longer take diabetic meds and have good control of my blood sugars. The Type 2 Diabetes ADA Diagnosis Criteria are any of the following:
A hemoglobin A1c (HbA1c) level of 6.5% or higher; the test should be performed in a laboratory using a method that is certified by the National Glycohemoglobin Standardization Program (NGSP) and standardized or traceable to the Diabetes Control and Complications Trial (DCCT) reference assay, or
A fasting plasma glucose (FPG) level of 126 mg/dL (7 mmol/L) or higher; fasting is defined as no caloric intake for at least 8 hours, or
A 2-hour plasma glucose level of 200 mg/dL (11.1 mmol/L) or higher during a 75-g oral glucose tolerance test (OGTT), or
A random plasma glucose of 200 mg/dL (11.1 mmol/L) or higher in a patient with classic symptoms of hyperglycemia (ie, polyuria, polydipsia, polyphagia, weight loss) or hyperglycemic crisis
I have changed the bullet-ted list to a numbered list for convenience. I am on no diabetes medications to mask the results here:
My last HbA1C was 5.2 so I pass this test.
My fasting plasma glucose is less than 100 typically so I pass this test.
I have not had an OGTT (more on this to follow).
I have none of the symptoms of hyperglycemia at all and I have had no blood sugar measurements of 200 or higher (or anywhere near that level) since I started Low Carb.
Oral Glucose Tolerance Test (OGTT)
I don’t know if I would pass an OGTT or not. I assume I would fail such at test in spite of losing 120 lbs, etc. The reason I assume I would fail is that I think part of being on a Low Carb ketogenic diet is that my body has developed peripheral insulin resistance.
After 8 wk of consuming chow or KD, caloric intake after peripheral or central insulin and insulin and glucose levels after a glucose challenge were assessed. In a separate group of rats, glucose and insulin responses to either a low- or high-carbohydrate test meal were measured. Finally, rats maintained on KD were switched back to a chow diet, and insulin sensitivity and glucose tolerance were evaluated to determine whether the effects of KD were reversible.
That answers the test that I would want to do to determine if I would pass an OGTT. What happened to the mice?
Maintenance on KD resulted in decreased sensitivity to peripheral insulin and impaired glucose tolerance.
So after 8 weeks of not eating carbohydrates the mice had trouble eating carbohydrates. Not much of a surprise there. It would take a deeper dive to see how much worse their PIR and IGT became.
Furthermore, consumption of a high-carbohydrate meal in rats that habitually consumed KD induced significantly greater insulin and glucose levels for an extended period of time, as compared with chow-fed controls.
So the mice over-reacted to carbohydrate meals by producing more glucose and insulin.
Responsivity to central insulin was heightened in KD rats and associated with increased expression levels of insulin receptor mRNA.
Not sure how to understand that if the mice were more insulin resistant. But was this effect a permanent change or was it temporary and a side effect of the diet itself?
Finally, returning to a chow diet rapidly reversed the effects of KD on insulin sensitivity and glucose tolerance. These data suggest that maintenance on KD negatively affects glucose homeostasis, an effect that is rapidly reversed upon cessation of the diet.
Although 8 weeks isn’t that long to a human it’s a long time to a mouse. I don’t know the scaling factor but it’s reasonable to assume it is years rather than the two months of the study.
So, if someone is concerned about whether or not they would pass an OGTT it seems like they probably could stop the ketogenic diet for some time (weeks maybe?) and then take the test. Most of us who do LC / Keto won’t be trying it anytime soon.
The fact is your doctor is not going to order an OGTT for you if you don’t fail one or more of the other numbers. In fact, if you fail the fasting blood sugar test the doctor might order you an HbA1C test for confirmation. And then, depending on other factors, may just decide to keep an eye on it.
Five of the 15 gene variants associated with overweight, obesity and/or morbid obesity. Per allele ORs ranged from 1.15-1.20 for overweight, 1.10-1.25 for obesity, and 1.41-1.46 for morbid obesity. Five of the 15 variants moreover associated with increased measures of adiposity.
BDNF rs4923461 displayed a borderline BMI-dependent protective effect on type 2 diabetes (0.87 (0.78-0.96, p = 0.008)), whereas SH2B1 rs7498665 associated with nominally BMI-independent increased risk of type 2 diabetes (1.16 (1.07-1.27, p = 7.8×10(-4))).
The information that you’ll receive with your AncestryDNA raw data will include the ‘rs’ ID where possible, chromosome, and the base pair position on the human reference genome (GRCh37). The genotype (the observed alleles at each position) will be provided on the forward strand. The raw DNA data provided has passed the AncestryDNA data quality filters.
An example of raw DNA data looks like:
It looks like from my data that ancestry.com tests about half of these genes. That’s unfortunate from a health perspective. Maybe the select other genes which are more genetically heritable?
There’s a common definition of the word “obese”. We think of people who are really fat as being obese. I was one of them.
What is Obesity?
Obesity has a technical definition which is somewhat arbitrary. It is a function of weight and height and is known as BMI (Body Mass Index). The US government definition is (NCHS Data Brief ■ No. 288 ■ October 2017):
Obesity: BMI was calculated as weight in kilograms divided by height in meters squared, rounded to one decimal place.
Obesity in adults was defined as a BMI of greater than or equal to 30.
BMI Weaknesses as a Metric
BMI (and obesity) does not take into account body composition such as body fat or lean body mass. Two people can have the same BMI and be technically obese and one be solid muscle with little body fat and the other have significantly more body fat.
However, for the “average” person BMI is a decent measurement of fatness.
Obesity and Health
Generally, obesity and health are inversely related but there are people who are obese (by BMI) but are healthy. There are also people who are not obese but have poor health. This observation has led to the concept of personal fat threshold (PFT). This is described in (Taylor R, Holman RR. Normal weight individuals who develop type 2 diabetes: the personal fat threshold. Clin Sci (Lond). 2015 Apr;128(7):405-10) (PDF).
Personal Fat Threshold (PFT)
The Personal Fat Threshold concept is that there’s a level of fatness which the individual can tolerate before their health is impacted. This concept is tempting but has some problems.
PFT is not all that useful in the a-priori sense. There is no objective test to see if someone is at or near their PFT. Obesity isn’t useful as a metric. Neither is body fat level.
The only use of PFT is to support the medical advice to patients of weight loss as a tool for management of Type 2 diabetes. The PFT concept doesn’t actually contribute much since it has been believed (before the PFT concept was developed) that weight loss of about 15% resolves diabetes (Reversing Diabetes with Weight Loss: Stronger Evidence, Bigger Payoff).
Until there’s an a-priori means of measuring PFT the approach seems to be not all that useful. No medical doctor can tell you that you are 10 lbs away from your PFT. The point is completely hidden until it manifests. All it says that is if you are not technically considered to be obese and you are diabetic it is because you have gone over your personal fat threshold.
PFT – My Own Experience
There are three lines of reasoning from my own experience that call into question the PFT theory.
One was from my own experience with Insulin as a Type 2 Diabetic. I put on 40 lbs in a short time when I was put on Insulin. Conversely, when I got off Insulin my weight dropped quickly. Teenage females who are Type 1 diabetics and want to lose weight are well aware of this relationship. Weight increases followed Insulin increases (Skovsø S, Damgaard J, Fels JJ, Olsen GS, Wolf XA, Rolin B, Holst JJ. Effects of insulin therapy on weight gain and fat distribution in the HF/HS-STZ rat model of type 2 diabetes. Int J Obes (Lond). 2015 Oct;39(10):1531-8). not Insulin followed weight. Eventually, stasis is reached in weight and Insulin amount – at least in the short term.
Increasing dietary carbohydrates requires pumping more Insulin. When you stop eating dietary carbohydrates you don’t have to inject extra insulin for the meal.
The second reason was the increase in Insulin that is required over time to maintain blood sugar levels. I started at about 40g of Insulin and had good blood sugar controls. By four later my weight was stable but the amount of Insulin to keep blood sugar stable kept increasing to about 120 units. More particularly, the amount of insulin to cover carbohydrate loads increased. In my own case 1 unit of Insulin could cover 15 grams of carbs when I started Insulin and by four years later 1 unit wasn’t enough to cover 8 grams. All of this was at a stable weight (after the initial gain) and the same level of carbohydrates.
A third reason is my own weight history. I was at 285 lbs and non-diabetic for years. Then I mysteriously lost 50 lbs down to 235 lbs over the course of about six months. This is a common occurrence with Type 2 diabetics (Unexplained Weight Loss and Diabetes). After six months of this unexplained weight loss, I was then diagnosed with diabetes.
Perhaps this is the body pushing back from the PFT but it does call the concept into question – or at least indicate the real issue is much more complicated. After being put on Metformin my weight stabilized at around 10 lbs higher (although Metformin is said to lower weight). As my diabetes got worse my doctor tried different medications some of which added weight and some (like Byetta) caused small weight loss. Finally, the addition of Insulin added 40 lbs to my weight.
I did low carb while on Insulin but it only took my HbA1C down to 6.4. It wasn’t until I did low carb plus Intermittent Fasting that I was able to get off Insulin and my weight fell very quickly. My last HbA1C was 5.2 which is a normal non-diabetic number.
Carbohydrate Insulin Relationship
At the very least, if the PFT concept is salvageable, it needs to be modified for increasing Insulin Resistance levels. If the best treatment for diabetes is weight loss the best way for Type 2 Diabetics to lose weight is to reduce insulin levels. The best way to reduce insulin levels is to the insulin load of the diet. For a Type 2 Diabetic who is on Insulin this results in a loss of a lot of weight in a very short period of time.
The recommendation that losing 15% of body weight does not seem plausible to a diabetic like myself. I’ve lost more than 15% from my peak weight and not been able to control my diabetes. I lost weight with Low Carb by itself but not enough to get off Insulin. At it was more than 15% of weight loss. If I was told that losing 15% of my body weight would control my diabetes I would have told my doctor that I tried it and it didn’t work.
I lost much less than 15% of my weight in the beginning of Low Carb plus Intermittent Fasting and was able to get off Insulin completely. It was getting off Insulin which allowed me to lose weight. And it was reducing my body’s Insulin needs by the Low Carb diet and Intermittent Fasting which worked for me.
One explanation hypothesized for the greater weight loss on Low Carb diets is the Low Carb diet is said to have an inherent metabolic advantage. This metabolic advantage should manifest itself in a greater resting energy expenditure. The paper looked at two possible mechanisms – triglyceride cycling and glyceroneogenesis.
The critics of the Low Carb diet say that the advantage is that the comparisons aren’t done by holding protein constant. Overfeeding protein is not the same as overfeeding carbs or fat since protein stimulates 24 hour energy expenditure and fat doesn’t (Overfeeding Protein – Carnivore Diet).
Our results showed no significant weight loss, lipid, serum insulin, or glucose differences between the two diets.
The study was a decently formulated study but there were weaknesses:
Small study – only 4 subjects
No control group
Older obese females only
Very short duration (6 weeks)
Low fat didn’t get super-low (20% of calories from fat)
The Low Carb diet results in more weight loss but the study was too small to have statistical power
The good parts of the study were:
Matched total calories and protein – varying carbs and protein
Decent protein level (30% of calories)
Low carb was 5% of calories – good level
Randomized control trial
Cross-over design so the subjects ate both foods in random order
Starches and fruit were the carbohydrate choices (not jelly beans)
Deficit was relatively small (200 calories below REE which is a fairly large amount below TDEE depending on activity level)
At the end of the study they gave the participants the choice to continue on for a year. They were given the choice of the two diets and three of the four participants chose the Low Carb diet. However, the Low Carb participants raised their carbohydrate amount from 5% to 23% over the rest of the study so their weight loss partially reversed. There were several distinct advantages for the Low Carb diet.
Lipids were dramatically reduced on both diets, with a trend for greater triglyceride reduction on the VLC diet. Glucose levels were also reduced on both diets, with a trend for insulin reduction on the VLC diet
This fits my own experiences with protein and Low Carb. I’ve seen people stall for a long time and then break the stall by increasing their protein (and dropping their fat). My conclusion is that the ketogenic diet advantage does come from the higher protein intake of the diet. The diet often causes people to increase their consumption of meat which a high quality food.
This study showed that varying the protein content of several entrées consumed ad libitum did not differentially influence energy intake or affect ratings of satiety over a day. When the appearance, taste, fat content, and energy density were controlled, simply adding meat to lunch and dinner entrées to increase the protein content within commonly consumed amounts was not an effective strategy to reduce daily energy intake.
Does Calories-In and Calories-Out work on Keto? In the last 162 days I have averaged 2391 calories a day. My weight is the same at the end of these 162 days. My total energy expenditure (TDEE) is calculated at 2232 calories a day. This is only 159 calories a day from my TDEE or 7% off the calculated amount and that’s less than half the assumed measurement error in the food (typically assumed to be 15%).
So, yes, I conclude that Calories-In and Calories-Out do fairly closely match. At least in my particular case and macros.
So Why Keto?
Where Keto comes in is that I have maintained a 120 lb loss for the past 5+ months without hunger. My hormones are in balance. My insulin level is kept low. I don’t have the blood sugar roller coaster ride.