The RCT That Will Never Happen

Here’s the Randomized Control Trial that I really want to see.

Take a lot of Type 2 Diabetics with BMIs in the obese range. Split them into two groups who are pair matched. Start one of the groups on Low Carb / High Fat diet and leave the control group on their customary Standard American Diet (SAD). Treat all of them with the standard of care as it is at the time. Track them for 40 years and look at the outcomes. Don’t just track some of the benchmarks like LDL cholesterol. Track all of their results including all-cause mortality. 

It won’t happen for too many reasons. And it doesn’t take a belief in conspiracy theories to figure out why. Perhaps the biggest reason is nobody makes money with Low Carb/High Fat and a study with sufficient statistical power would be very expensive.

In the meanwhile, we are all n=1. And none of us have 40 years. And no point in looking for the RCT above since it’s never going to happen. It would have had to start before anyone knew the right questions to ask.

How Low to Go?

I’ve done somewhere around 50 grams of carbohydrates a day (30 grams when subtracting out fiber) for the past year. And my blood sugar control has been great. I’ve wondered how low someone has to go (or stay) in order to control Type 2 Diabetes. Certainly, the weight loss I’ve had (120 lbs) is a part of the solution. Being at a low body fat percentage now (7.5% per BodPod) has to help as well. My weight has been stable for 6 months now as well which means I’ve not lost or gained any weight – I was at 164.7 lbs when I took the BodPod test and today I weighed 163.7 lbs (close enough). My coffee consumption (which helps in weight loss for sure) is higher than ever before but I’m trying to keep the caffeine down by mixing in mostly decaf coffee. 

So all of this begs the question of how many grams of carbs I could tolerate. Now, I am not going to be testing this anytime soon. I find the advantages of being low carb just way too easy (see above for the results). I did find a study that might provide at least a partial answer to the question of how many grams of carbs can keep someone in remission from Diabetes.

The answer is in this 2009 study (Haimoto H, Sasakabe T, Wakai K, Umegaki H. Effects of a low-carbohydrate diet on glycemic control in outpatients with severe type 2 diabetes. Nutr Metab (Lond). 2009 May 6;6:21).

Now, I wouldn’t even call this diet at 30% of calories from carbohydrates a “Low Carbohydrate” by any definition that I would recognize but it has interesting results. One of the things that was interesting is that the study was done on severe diabetics (HbA1c levels of 9.0% or above). This is not a group of new diabetics nor were the participants young. They were a pretty good representative of Type 2 Diabetics with poor blood sugar control. The participants:

were instructed to follow a low-carbohydrate diet (1852 kcal; %CHO:fat:protein = 30:44:20) for 6 months in an outpatient clinic and were followed to assess their HbA1c levels, body mass index and doses of antidiabetic drugs.

The results were really good. Many of the participants got off their medications and:

HbA1c levels decreased sharply from a baseline of 10.9 ± 1.6% to 7.8 ± 1.5% at 3 months and to 7.4 ± 1.4% at 6 months.

These are similar to the results I got with the Low Carbohydrate diet when I got to an HbA1c level of 6.4. They are not as good as the results I got over the last couple of years with even lower levels of carbohydrates plus intermittent fasting.

In spite of being on a fairly low calorie diet (1852 kcal) they didn’t lose much weight. This group also didn’t seem to be all that obese since their BMI was around 24 (top end of “normal” weight).

Body mass index decreased slightly from baseline (23.8 ± 3.3) to 6months (23.5 ± 3.4).

So, if you are “normal” weight and diagnosed as diabetic then dropping from the Standard American Diet (SAD) 50% of calories from carbohydrates to 30% might give as good of control as exogenous Insulin without the long term increase in insulin resistance that comes along with Insulin therapy.

There was one telling outlier in the data.

One female patient had an increased physical activity level during the study period in spite of our instructions. However, her increase in physical activity was no more than one hour of walking per day, four days a week. She had implemented an 11%-carbohydrate diet without any anti-diabetic drug, and her HbA1c level decreased from 14.4% at baseline to 6.1% after 3 months and had been maintained at 5.5% after 6 months.

Insulin Glucagon Glucose

Here’s a fun watch that is of interest to diabetics. And nerds.

On the Hyperlipid BLOG (Insulin glucagon and protein) examined this study (Unger RH, Cherrington AD. Glucagonocentric restructuring of diabetes: a pathophysiologic and therapeutic makeover. J Clin Invest. 2012 Jan;122(1):4-12). The study looked at Diabetes as a disorder more related to glucagon than insulin. In particular, the Hyperlipid BLOG considered the blood sugar response of a diabetic to protein. I did the same thing myself here in this BLOG several times (Glucose Response to ProteinBlood Sugar Response to Proteins and Blood Sugar Responses Compared).

The paper presents the following lines of evidence for the claim,

Here we propose that glucagon excess, rather than insulin deficiency, is the sine qua non of diabetes. We base this on the following evidence:

(a) glucagon increases hepatic glucose and ketone production, catabolic features present in insulin deficiency;

(b) hyperglucagonemia is present in every form of poorly controlled diabetes;

(c) the glucagon suppressors leptin and somatostatin suppress all catabolic manifestations of diabetes during total insulin deficiency;

(d) total β cell destruction in glucagon receptor-null mice does not cause diabetes; and (e) perfusion of normal pancreas with anti-insulin serum causes marked hyperglucagonemia.

The insight that this may not be as much an insulin issue as a glucagon issue is a powerful one which may have application with medications to control Type 2 Diabetes. If giving exogenous insulin produces problems with Insulin Resistance, giving a medication which causes the body to produce less glucagon may have an opposite effect. It may be possible to develop a medication which downregulates glucagon indefinitely.

This has been tried in a 2017 Phase I drug study (Glucagon-Blocking Drug Reduces Need for Insulin and Improves Blood Glucose Levels for Patients with Type 1 Diabetes). Here is the full paper for the study (Effect of a glucagon receptor antibody (Jeremy Pettus MD. REMD‐477) in type 1 diabetes: A randomized controlled trial).

What is the cost (in other systems in the body) if glucagon is downregulated? 

Is eating 50g of Whey Protein a good replacement for the OGTT? I think it’s a much better choice than eating 75g of glucose.

Fat Stores Where/How?

Peter at the Hyperlipid BLOG has an interesting analysis of an interesting paper on fat storage in mice (On phosphorylating AKT within visceral fat). The study he looks at is (Narita T, Kobayashi M, Itakura K, Itagawa R, Kabaya R, Sudo Y, Okita N, Higami Y. Differential response to caloric restriction of retroperitoneal, epididymal, and subcutaneous adipose tissue depots in rats.  Exp Gerontol. 2018 Apr;104:127-137). The study looked at ad lib feeding of mice and the storage of fat in three White Adipose Tissues (WAT) depots in rats: retroperitoneal (rWAT), epididymal (eWAT) and subcutaneous (sWAT).

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!

I’m still of the opinion that visceral fat is what matters the most in reversal of Type 2 Diabetes. The Low Carb diet gets insulin levels low which reduces fat in general. See this article (A Grand Unified Theory of Polyunsaturated Fatty Acid Misbehaviour in Inflammatory Disease).

This article is actionable as well (Fatty liver and its treatment).

Another Way to Reverse Diabetes

Here’s another way to reverse Type 2 Diabetes (E. L. Lim, K. G. Hollingsworth, B. S. Aribisala, M. J. Chen, J. C. Mathers, R. Taylor. Reversal of type 2 diabetes: normalisation of beta cell function in association with decreased pancreas and liver triacylglycerol. Diabetologia, October 2011, Volume 54, Issue 10, pp 2506–2514). Here were the subjects:

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−2p < 0.001) and approached control values (0.62 ± 0.15 nmol min−1 m−2p = 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.

VariableControlsBaselineWeek 1Week 4Week 8
Weight (kg)101.5 ± 3.4103.7 ± 4.599.7 ± 4.5*94.1 ± 4.3 *88.4 ± 4.3*†
BMI (kg/m2)33.4 ± 0.933.6 ± 1.232.3 ± 1.2*30.5 ± 1.2*28.7 ± 1.3*†
Fat mass (kg)36.2 ± 2.739.0 ± 3.536.6 ± 3.6 *31.7 ± 3.7 *26.3 ± 4.0*
ffm (kg)64.7 ± 3.864.7 ± 3.063.2 ± 3.162.4 ± 3.0 *62.1 ± 3.0*
Waist circumference (cm)105.0 ± 1.5107.4 ± 2.2104.4 ± 2.2*99.7 ± 2.4 *94.2 ± 2.5*†
Hip circumference (cm)109.8 ± 2.4109.5 ± 2.9108.3 ± 2.7*105.0 ± 2.6*99.5 ± 2.6*†
WHR0.96 ± 0.020.98 ± 0.020.97 ± 0.020.95 ± 0.010.95 ± 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.

Low Carb?

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 [20] (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.

Giving Monkeys Diabetes

I listened to an interesting Break Nutrition podcast (Episode 13 – What happens to fructose-fed monkeys?) on a study of Rhesus Monkeys who were fed fructose meals (Bremer AA, Stanhope KL, Graham JL, Cummings BP, Wang W, Saville BR, Havel PJ. Fructose-fed rhesus monkeys: a nonhuman primate model of insulin resistance, metabolic syndrome, and type 2 diabetes. Clin Transl Sci. 2011 Aug;4(4):243-52). (Full PDF).

…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).

The charts in the study are very interesting. Gabor discusses them on the podcast.

Am I Still a Diabetic?

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:

  1. 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
  2. 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
  3. 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
  4. 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:

  1. My last HbA1C was 5.2 so I pass this test.
  2. My fasting plasma glucose is less than 100 typically so I pass this test.
  3. I have not had an OGTT (more on this to follow).
  4. 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.

Peripheral Insulin Resistance

PIR is a normal response to the ketogenic diet and happens as a response to lowered glucose availability. Here’s a mouse study which shows that Peripheral Insulin Resistance got worse under a ketogenic diet (Kinzig KP, Honors MA, Hargrave SL. Insulin sensitivity and glucose tolerance are altered by maintenance on a ketogenic diet. Endocrinology. 2010;151(7): 3105-14.). The study measured:

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.

DNA and Obesity/Diabetes

Am I Fat Because of My DNA?

There are a small number of people who may be fat due to faulty genetics (Lorenzo DN, Bennett V. Cell-autonomous adiposity through increased cell surface GLUT4 due to ankyrin-B deficiency. Proc Natl Acad Sci U S A. 2017;114(48):12743-12748.).

If not much of the fault can likely be blamed on your genes, but just how much can be? From (Sandholt CH, Vestmar MA, Bille DS, Borglykke A, Almind K, Hansen L, Sandbæk A, Lauritzen T, Witte D, Jørgensen T, Pedersen O, Hansen T. Studies of metabolic phenotypic correlates of 15 obesity associated gene variants. PLoS One. 2011;6(9)).

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))).

Another study on obesity and genetics (Gudmar Thorleifsson, G Bragi Walters[…]Kari Stefansso. Genome-wide association yields new sequence variants at seven loci that associate with measures of obesity. Nature Genetics volume 41, pages 18–24 (2009)).

Here’s another study on obesity and genetics (Sungshim Lani Park, Iona Cheng, Sarah A. Pendergrass, Anna M. Kucharska-Newton, Unhee Lim, Jose Luis Ambite, Christian P. Caberto, Kristine R. Monroe, Fredrick Schumacher, Lucia A. Hindorff, Matthew T. Oetjens, Sarah Wilson, Robert J. Goodloe, Shelly-Ann Love, Brian E. Henderson, Laurence N. Kolonel, Christopher A. Haiman, Dana C. Crawford, Kari E. North, Gerardo Heiss, Marylyn D. Ritchie, Lynne R. Wilkens, Loïc Le Marchand; Association of the FTO Obesity Risk Variant rs8050136 With Percentage of Energy Intake From Fat in Multiple Racial/Ethnic Populations: The PAGE Study, American Journal of Epidemiology, Volume 178, Issue 5, 1 September 2013, Pages 780–790).

A similar paper on genetics and Type 2 Diabetes (McCarthy MI1, Zeggini E. Genome-wide association studies in type 2 diabetes. Curr Diab Rep. 2009 Apr;9(2):164-71).

Macronutrient Sensitivity and Genetics

My own AncestryDNA data shows an inconclusive result with one less of a carb seeker, one intermediate and one more of a carb seeker:

#ChromPositionSNP IDReliabilityGenotypePhenotypePopulationReferences
More a carbohydrate seeker
Less a carbohydrate seeker
More a carbohydrate seeker
Less a carbohydrate seeker
More a carbohydrate seeker
Less a carbohydrate seeker
More a carbohydrate seeker
Less a carbohydrate seeker
More a carbohydrate seeker
Less a carbohydrate seeker

This data is based on this study (Genome-wide meta-analysis of observational studies shows common genetic variants associated with macronutrient intake).

Signif. log(p) Effect Size / Odds Ratio






+ Strand




Trait Genes
9.4 0.22 (Fat)
[0.14-0.3] % decrease
rs838145 G G 0.46 FGF21 Dietary macronutrient intake
9 0.1 (Protein)
[0.061-0.139] % increase
rs1421085 C C 0.42 FTO Dietary macronutrient intake
6.52 0.23 (Carbohydrate)
[0.15-0.31] % increase
rs838145 G G 0.46 FGF21 Dietary macronutrient intake
6.15 0.22 (Carbohydrate)
[0.14-0.3] % increase
rs838147 A A 0.48 Intergenic Dietary macronutrient intake
5.7 0.27 (Carbohydrate)
[0.15-0.39] % increase
rs1549309 A A 0.17 Intergenic Dietary macronutrient intake
5.3 0.22 (Carbohydrate)
[0.12-0.32] % decrease
rs2840445 A A 0.27 Intergenic Dietary macronutrient intake
5.3 0.22 (Carbohydrate)
[0.12-0.32] % increase
rs8019546 A A 0.3 Intergenic Dietary macronutrient intake

AncestryDNA Raw Data Format

AncestryDNA Raw Data Format. From the site:

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 tests about half of these genes. That’s unfortunate from a health perspective. Maybe the select other genes which are more genetically heritable?

How Metformin Works

Researchers have unlocked more about how Metformin works (
Zydrune Polianskyte-Prause, Tuomas A. Tolvanen, Sonja Lindfors, Vincent Dumont, Mervi Van, Hong Wang, Surjya N. Dash, Mika Berg, Jette-Britt Naams, Laura C. Hautala, Harry Nisen, Tuomas Mirtti, Per-Henrik Groop, Kristiina Wähälä, Jukka Tienari, and Sanna Lehtonen. Metformin increases glucose uptake and acts renoprotectively by reducing SHIP2 activity. The FASEB Journal 0 0:0. 15 Oct 2018).

Metformin inhibits SHIP2 in cultured cells and in skeletal muscle and kidney of db/db mice. In SHIP2-overexpressing myotubes, metformin ameliorates reduced glucose uptake by slowing down glucose transporter 4 endocytosis. SHIP2 overexpression reduces Akt activity and enhances podocyte apoptosis, and both are restored to normal levels by metformin. SHIP2 activity is elevated in glomeruli of patients with T2D receiving nonmetformin medication, but not in patients receiving metformin, compared with people without diabetes. Furthermore, podocyte loss in kidneys of metformin-treated T2D patients is reduced compared with patients receiving nonmetformin medication.

So not only does Metformin reduce the glucose production of the liver by downregulating GNG (Joseph A. Baur and Morris J. Birnbaum, Metformin inhibits gluconeogenesis via a redox-dependent mechanism in vivo.Nature Medicinevolume 24, pages1384–1394 (2018)), it also increases the uptake of glucose in skeletal muscle and the kidneys.

Another paper on the action of Metformin (Baur JA, Birnbaum MJ. Control of gluconeogenesis by metformin: does redox trump energy charge?. Cell Metab. 2014;20(2):197-9.).

Here’s yet another paper on an effect of Metformin (Cheryl A. Collier, Clinton R. Bruce, Angela C. Smith, Gary Lopaschuk, and David J. Dyck. Metformin counters the insulin-induced suppression of fatty acid oxidation and stimulation of triacylglycerol storage in rodent skeletal muscle).

Because increased muscle lipid storage and impaired FA oxidation have been associated with insulin resistance in this tissue, the ability of metformin to reverse these abnormalities in muscle FA metabolism may be a part of the mechanism by which metformin improves glucose clearance and insulin sensitivity.

Obesity and Diabetes

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.

See (Obesity and Insulin Resistance).