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.
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.
Weight loss alone should never be your goal. Fat loss should be your goal. This can be demonstrated from the numbers. If you have 25% body fat then the weight you want to lose should come out of that 25% of body fat and not from the 75% of lean body mass. If you lose weight and most of the weight comes from your lean body mass you have not done yourself any favors.
Maximum Fat Loss
The fastest way to lose fat is to greatly reduce your carbohydrates and fat intake. Protein should never be reduced. For most people protein should be increased.
Macros for Fat Loss
There is a pretty simple set of macros for maximum body fat loss.
The recommended daily protein minimums are pretty low. I suggest much more. If you have normal kidney function that is no problem.
You need enough protein in your diet to replace the protein your body will eat up during the diet. You also need some for gluconeogenesis. Since you will be eating at a caloric deficit any extra protein won’t be a problem – it won’t turn into chocolate cake.
Protein has essential nutrients. Eating 3 grams of Leucine (found in about 30g of protein) is a good goal to hit with every protein meal. That’s around 5 ozs of skinless chicken breast.
Eat the carbs as green leafy veggies. Broccoli is a great choice for micronutrients. You don’t like the taste? Get over it. It’s good for you. And you will eventually grow to like the taste.
If you want to lose fat faster, eat less fat. If you are losing too quickly, eat more fat. The fat you eat doesn’t come off your body. The fat you don’t eat in your diet comes off your body. Any fat you eat is stored on your body very efficiently. Fat has few essential nutrients.
Even a low fat diet is still relatively high fat. The fat is just coming off your body. You can’t stay on a low fat diet forever. You have to increase your fat over time as you reach your goals.
It’s a good idea to take a couple of fish oil capsules every day to get more of the good fats.
Studies on this Diet
This is also known as a variant on the Protein Sparing Modified Fast. It is well studied and effective. The PSMF is often done at very low (20g) of fat.
Our bodies burn carbs in preference to fats. That is because we only have a limited amount of storage for carbs and we have a very high capacity for fat storage.
We are typically burning some mixture of both fat and carbs (except at extremes). The amount of carbs we are burning is strongly influenced by the amount of carbs we have eaten. If you ate nothing but carbs and ate them at an amount matching your total energy expenditure you will pretty much just burn carbs.
Since most people don’t eat in their sleep there’s some point where the carbs go down and the body starts to draw from the carb stores, aka, glycogen. That can last as long as a day or so but as the glycogen stores draw down the body starts to shift to fat burning. This is known as glycogen sparing.
On a low carb diet our fuel mixture shifts to largely fat based. At very low levels of Insulin that come with a reduction in carbohydrates, our peripheral cells resist the small amount of glucose we produce and we spare the glucose for the parts of our body which rely on glucose for fuel. This is how the low carbohydrate diet is glucose/glycogen sparing.
A high carb diet is fat sparing since it spares our body fat from being burned and reduces the amount of time that glycogen stores are being drawn down.
Isoenergetic 1000 kJ (240 kcal) servings of 38 foods separated into six food categories (fruits, bakery products, snack foods, carbohydrate-rich foods, protein-rich foods, breakfast cereals) were fed to groups of 11-13 subjects. Satiety ratings were obtained every 15 min over 120 min after which subjects were free to eat ad libitum from a standard range of foods and drinks.
A satiety index (SI) score was calculated by dividing the area under the satiety response curve (AUC) for the test food by the group mean satiety AUC for white bread and multiplying by 100.
Thus, white bread had an SI score of 100% and the SI scores of the other foods were expressed as a percentage of white bread.
The results were:
There were significant differences in satiety both within and between the six food categories. The highest SI score was produced by boiled potatoes (323 +/- 51%) which was seven-fold higher than the lowest SI score of the croissant (47 +/- 17%).
Most foods (76%) had an SI score greater than or equal to white bread.
The amount of energy eaten immediately after 120 min correlated negatively with the mean satiety AUC responses (r = -0.37, P < 0.05, n = 43) thereby supporting the subjective satiety ratings. SI scores correlated positively with the serving weight of the foods (r = 0.66, P < 0.001, n = 38) and negatively with palatability ratings (r = -0.64, P < 0.001, n = 38).
Protein, fibre, and water contents of the test foods correlated positively with SI scores (r = 0.37, P < 0.05, n = 38; r = 0.46, P < 0.01; and r = 0.64, P < 0.001; respectively) whereas fat content was negatively associated (r = -0.43, P < 0.01).
This goes a long way to explain the Kitavan diet which is largely sweet potatoes. Can you imagine eating sweet potatoes every day as a main staple? Even though they are high carbohydrates it would be tough to over eat them.
I looked earlier (Glycogen Stores – Why does it matter?) at this study (K J Acheson Y Schutz T Bessard K Anantharaman J P Flatt E Jéquier. Glycogen storage capacity and de novo lipogenesis during massive carbohydrate overfeeding in man. The American Journal of Clinical Nutrition, Volume 48, Issue 2, 1 August 1988, Pages 240–247). The purpose of the study was to look at body glycogen stores. As part of the study they compared several diets. These diets were performed as a glycogen depletion/repletion strategy. The study shows the relatively short term weight loss on each diet (Low Carb High Fat, [overfed] High Carb Low Fat, and Protein Sparing Modified Fast diets).
Mean body weight decreased by 0.8 ± 1.4 kg during the 3 d on the restricted, high-fat, low-carbohydrate diet. After the 7 d of overfeeding the high-carbohydrate, low-fat diet (day 10), body weight had increased by 4.6 ± 1 .3 kg (ie, 5.6, 4.9, and 3.2 kg). During the 2 d on the restricted high-protein, low-energy diet (600 kcal/ d) 4.4 ± 0.9 kg were lost.
There’s an interesting book which describes the capture of frontier folks by American Indians in the frontier era. Often these captives were adopted by their Indian captors to replace family members who had died. In some cases, the captives later refused to return to European American communities when they had the opportunity. There’s a book which collects together many of their experiences (Captured by the Indians: 15 Firsthand Accounts, 1750-1870. Edited by Frederick Drimmer, 1961).
Diet Was Animal-based
The book recounts the diet of the North American Indians and the adaptation of people who were on European diets to the diets of the Indians. The Indians relied largely on animals for their food.
Differences from European Diet
The European captives seem to have suffered the equivalent of the ketogenic flu when they adapted to the Indian diet. They describe a couple of rough days at the start when they abruptly ceased to eat the European diet.
There were definite differences in diet. For example, the Europeans were used to bread at all of their meals but the Indians ate meat alone. From p 27.
This is as simple as the idea that the Indians were largely nomadic in the summer. They built shelters in the winter and stayed at those locations.
Other food they ate included:
boiled venison (p. 33)
buffalo (p. 34)
deer, bear, racoon (p. 38)
wildcat (p. 40)
fox (p. 41)
hickory nuts (p. 37)
hawthorn seeds (p. 37)
green corn (pp. 33, 41)
There are some very specific details such as this account of cooking a bear (p. 39).
For carbohydrates the women among the Indians tapped trees for sap and then concentrated the sap by heating it in bronze pots. They would dip their meat in the syrup. Here is the account of how they made syrup.
In 2005, Simpson and Raubenheimer postulated the ‘protein leverage hypothesis’ (PLH) to address the question of which nutrient (fat or carbohydrates) is responsible for obesity. The PLH idea is that like numerous other animal species, human macronutrient regulation minimizes variation in absolute protein intake. There is a lot of evidence to this effect (Martínez Steele E. Ultra-processed foods, protein leverage and energy intake in the USA. Public Health Nutr. 2018 Jan;21(1):114-124.).
The study exposed C57BL/6 mice to 29 different diets varying from 8.3% to 80% fat, 10% to 80% carbohydrate, 5% to 30% protein, and 5% to 30% sucrose. The study concluded that:
Mice regulate their food consumption primarily to meet an energy rather than a protein target, but this system can be over-ridden by hedonic factors linked to fat, but not sucrose, consumption.
The study has a cute graphic.
Examining the Graphic
An ad libitum fed lean mouse didn’t get leaner on higher protein. A lean mouse didn’t get fatter on high carbohydrates.
It took higher fat to make a mouse fatter. Interestingly the steps for fat were much larger than the steps for carbohydrates or protein. I can understand why protein would be limited but why did they limit carbohydrates to 30% maximum? Also, what were the other macros when protein was provided?
The DRI (Dietary Reference Intake) is 0.8 grams of protein per kilogram of body weight, or 0.36 grams per pound. This amounts to:
* 56 grams per day for the average sedentary man. * 46 grams per day for the average sedentary woman.
As I noted in a prior post (Overfeeding Studies) minimum protein requirements are determined by nitrogen studies which typically give standard diets with adjusted protein contents until excess nitrogen is produced in the urine. This indicates that the person is in a positive protein intake since the excess protein is being expelled as urea (nitrogen).
The problem is the standard diet is used for the baseline which includes carbohydrates. In the standard diet glucose needs are completely met from carbohydrates. In a Low Carb diet glucose needs come from fat and protein in the diet (via GNG).
So how should we determine if those are adequate levels for a person on a low carb diet? Protein Sparing Modified Fasts (PSMF) are low carb diets which also are low fat. They are typically higher levels of protein with the intent of preserving Lean Body Mass (LBM) in the face of a high caloric deficit. There is a study which determined the Protein needs via nitrogen balance on the PSMF diet (Bruce R Bistrian, George L Blackburn, Jean-Pierre Flatt, Jack Sizer, Nevin S Scrimshaw, Mindy Sherman. Nitrogen Metabolism and Insulin Requirements in Obese Diabetic Adults on a Protein-Sparing Modified Fast. Diabetes Jun 1976, 25 (6) 494-504).
In the three patients who had extensive nitrogen-balance studies, balance could be maintained chronically by 1.3 gm. protein per kilogram IBW, despite the gross caloric inadequacy of the diet.
This seems like a reasonable approximation for the minimal protein needs on a Low Carbohydrate Diet. The number 1.3g/kg of body weight is significantly more than 0.8g/kg of body weight. A 200 lb (100kg) person would need to eat a minimum of 130g of protein a day.
More recently, the overall contribution of dietary amino acids to glucose homeostasis received further support on the basis of quantitative evaluations of hepatic glucose production. Jungas et al. provided an elegant argument that amino acids serve as a primary fuel for the liver and the primary carbon source for hepatic GNG. Other investigators extended this thinking with the findings that endogenous glucose production in the liver is a critical factor in maintenance of blood glucose. After an overnight fast, GNG provides 70% of hepatic glucose release, with amino acids serving as the principal carbon source. These studies provide further evidence for a linkage between dietary protein and glucose homeostasis.
…a diet with low carbohydrates and increased protein would reduce the role of insulin in managing acute changes in blood glucose and maximize the liver’s role in regulating blood glucose through hepatic GNG.
We need additional protein in a low carb diet to provide the substrate for GNG.
There are quite a few interesting overfeeding studies. The typical format of these studies is to take subjects and first determine the caloric intake to keep them in energy balance (weight stable). The study will then increase one of the three macronutrients (fat, carbohydrate or protein) and then look at the effects. Often studied are fat accumulation, body composition changes or blood lipids. The change is then attributed to the changed macronutrient.
Both fat and carbs are shown to increase weight and make body composition worse. Protein has been shown to not increase weight and increased protein improves body composition.
The problem I have with the study methodology is that the changes can’t all be attributed to the increased macronutrient alone since the increased macronutrients interacts with the other baseline macronutrients.
Take as an example a baseline diet which provides 25% of calories from protein, 50% from carbohydrates and 25% from fat. For a 2000 calorie a day person that’s 500 calories from protein (125g), 1000 calories from carbohydrates (250g) and 500 calories from fat (55.6g).
Adding 500 calories a day of fat, for instance would change the fat from 500 calories to 1000 calories (111g) while leaving the carbohydrates and protein at the same amounts. So if there’s an increase in body fat how much of a change in body fat can be attributed to the fat alone? How much of the increase in weight is due to the interaction between fat and, say, carbohydrates? Perhaps there’s a carbohydrate/fat limit where if you exceed the amount of carbs/fat it causes much more fat storage due to the combination of the two?
Low Carb Diet Reduces the Variables
The Low Carb Diet essentially reduces the three [macronutrient] variables to two. The calories from carbohydrates are typically 5% on a very low carb diet. So the only two macronutrients left are protein and fat. Yet, even this is no guarantee for weight loss. There are people (think Jimmy Moore) who eat on the very low protein and high fat end. There are others (think Ted Naiman) who eat on the higher protein and lower fat end.
Clearly, what Jimmy is doing isn’t working well for Jimmy and what Ted is doing is working quite well for Ted. Jimmy is an n=1 for overeating fat. Ted is an n=1 for eating more protein. However, Ted controls for total calories and Jimmy seems to have no clue how many calories he eats in a particular day.
The difference may be exercise. It may be diet. I have a hard time finding a picture of a higher protein advocate who looks like Jimmy but I can find plenty of keto personalities who eat a lot of fat and look more like Jimmy (the Two Keto Dudes comes to mind).
A Fear of Protein?
Jimmy and others have been afraid of protein with the fear that eating protein causes the protein to turn to chocolate cake (Jimmy is infamous for making the comparison to chocolate cake at one point). I’ve looked at this subject in many posts in this BLOG (Protein does not turn into chocolate cake).
Ted says he spends most of his day trying to convince diabetics that they should eat more protein. It is true that protein does raise blood sugar by a small amount in a diabetic but the benefits outweigh that small rise and if a person is not a diabetic protein will lower blood sugar (Glucose Response to Protein).
Problem with Protein Studies
Protein studies are used to determine protein requirements. These studies look at nitrogen balance which is either negative (the person isn’t getting enough nitrogen from their diet) or positive (the person is getting enough nitrogen from their diet).
The problem is that protein studies are based on so-called “balanced” diets where carbohydrates are available to make the amount of glucose required by the body (Low Carbs and Gluconeogenesis). These studies don’t include the effects of gluconeogenesis (GNG). If you are eating low carb then protein provides the substrate materials (from your diet) for (GNG). For diabetics their body is already really good at making glucose via GNG (Gluconeogenesis – Later Thoughts).
If you barely eat enough protein to meet the minimum (nitrogen replacement) requirements then your body will get it’s GNG needs from fat. Suppose that the body requires 120g of carbohydrates per day for the brain and other essential organs. If you eat 20g of carbohydrates a day that’s 100 short. If half the protein gets converted to glucose and your body requires 200g of protein to provide that glucose. (Note these are very rough numbers but the idea applies).
So, if you are on a low carbohydrate diet you need more protein than just your replacement needs. You also need protein to meet your GNG needs.
Many Ways to Lose Weight
There are quite a few ways to lose weight. Most of them involve eating less calories than you burn. You can lose weight with Low Fat or Low Carb diets. You can even lose weight with a Low Protein diet. All of these work if you are at a caloric deficit. High fat and high carbs at the same time don’t work at the same time unless your goal is weight gain.
Also, there’s an interaction with the macronutrient type. Some macronutrients encourage fat gain. Truthfully, fat is always stored easily as fat – but only accumulates in a caloric surplus. You burn off what you eat if you are in fat balance. If you eat less fat you lose body fat. If you eat more fat you will gain body fat.
Even people who eat a carnivore diet are eating a large portion of their calories as fat. As an example: Ribeye Steak from Walmart has 22g of protein and 20g of fat in an 4 oz serving. That’s 88 calories from protein and 180 calories from fat. Or 33% of calories from protein and 67% of calories from fat.
Consuming large amounts of fat is unavoidable in the weight maintenance portion of Low Carb diets. There’s a top limit on the amount of protein that you can/should eat. As an example, if you are eating 1 g of protein per lb of body weight and you weigh 200 lbs that’s 200 gram of protein or 800 calories. The rest of your daily caloric needs will then come from fat. If you are eating 2000 calories a day that’s 1200 calories from fat.
The problem is that many people, like Jimmy Moore, eat at a maintenance or higher level of calories and macros when they need to be in a weight loss phase. Jimmy eats low protein and carbs so it’s not protein or carbs that are making Jimmy fat. The extra fat that Jimmy eats accumulates as fat when he eats more calories from fat regardless of whether he avoids carbohydrates or not. Fat doesn’t magically vanish when you eat it and it doesn’t require much energy to store -it is about 95% efficient to store fat (Eat Too Much Fat – Get Fat).
Maximizing Weight Loss
The only way for someone like Jimmy to lose weight is to get enough protein and limit dietary fat. If Jimmy has a goal weight of 200 lbs he should eat 200 grams of protein spread over four meals a day of 50 grams per meal (Protein Gurus – Part 2). That maximizes Muscle Protein Synthesis and provides enough substrate to maintain his blood glucose. Jimmy should then eat enough fat to cover the amount he won’t be eating from his body. Jimmy has at least 100 lbs of fat mass and could easily have a 3000 calories a day deficit. It wouldn’t be at all pleasant but he could do it.
If you want to find out what you can do on a maximum fat loss diet, check out our Keto calculator.
Improved Overfeeding Studies
So how would you improve an overfeeding study? I would isolate the macronutrients and absolutely minimize the other macronutrients. Do a lean protein study (essentially a PSMF study) with variable protein levels. I’d do a carbohydrate variation study with minimal protein and fat. I’d do a fat level study with minimal carbs and protein. All of them in isolation. Wouldn’t be a very balanced diet at 90%, 5%, 5%. Couldn’t be too long a term. May not pass ethics boards. But it could tease out the interactions between the macronutrients.