Does insulin resistance cause weight gain?

Written by Mike Gibbs
7 October, 2015 | 14mins read

One of the biggest questions swirling my mind over the last year has been trying to decipher which of the following is more likely:

(A) Does insulin resistance cause weight gain?
(B) Does weight gain cause insulin resistance?

The difference between these two questions may seem quite nuanced, but it is incredibly important. It changes how you might approach the treatment of type 2 diabetes as well as those with Impaired Glucose Regulation (a.k.a. ‘pre-diabetes’).

Do you specifically focus on weight loss or do you focus on the underlying insulin resistance? Do you focus on both?

In this article (a warning: this has essentially become an extended essay), I will cover 4 areas that I think are incredibly interesting when looking at these questions:

  • Professor Roy Taylor’s work at Newcastle University
  • Peter Attia’s talk on insulin resistance
  • Professor Roger Unger’s prize winning lecture
  • Slim diabetics and the exceptions

Professor Roy Taylor’s work at Newcastle University

Professor Roy Taylor is a professor of medicine and metabolism at the University of Newcastle. He and his research group have specifically focused on understanding if, and how, you can reverse type 2 diabetes. Answers to this question would also broadly apply to reversing pre-diabetes.

On the research group’s university website, they have stated that type 2 diabetes can be reversed with major weight loss:

“It has been possible to work out the basic mechanisms which lead to type 2 diabetes. Too much fat within liver and pancreas prevents normal insulin action and prevents normal insulin secretion. Both defects are reversible by substantial weight loss.”

So here we have our first interplay between weight loss and insulin function. Professor Taylor is saying that if you lose weight, then you can also return insulin action and secretion to normal.

Insulin action: When we talk about insulin action here, we’re really talking about insulin resistance i.e. proper insulin action means there is little or no insulin resistance in the body.

Insulin secretion: When we talk about insulin secretion, we’re specifically talking about the ability of the pancreatic beta cells to release insulin into the blood steam.

Before we delve further down into the insulin resistance rabbit hole, the research group highlights one further critical point. The insulin secreting function of the pancreas decreases once the fat levels go above a person’s specific fat threshold, which varies from person to person and is highly correlated with genetics and heritage (e.g. people of South Asian origin have much higher risk and have much lower fat thresholds):

“A crucial point is that individuals have different levels of tolerance of fat within liver and pancreas. Only when a person has more fat than they can cope with does type 2 diabetes develop. In other words, once a person crosses their personal fat threshold, type 2 diabetes develops. Once they successfully lose weight and go below their personal fat threshold, diabetes will disappear.”

Professor Taylor’s research paper provides an explanation for the whole cycle, which he has called the ‘Twin-cycle hypothesis’.

Before exploring this hypothesis, it’s important to highlight one quick fact about fasting blood glucose levels: Fasting blood glucose levels depend entirely on the rate that the liver produces glucose (e.g. from glycogen). However, insulin can suppress liver glucose production. As a result, fasting blood glucose levels are strongly affected by the sensitivity of the liver to insulin.

To provide a summarised version of the twin-cycle hypothesis, Professor Taylor proposes:

Twin Cycle Hypothesis

  1. Over time, a person consistently eats too much food
  2. Fat accumulates in the liver – this liver fat accumulation is particularly promoted by excess carbohydrate consumption (excess carbs are converted into fat, the term is called ‘de novo lipogenesis’) as well as any pre-existing insulin resistance from lifestyle factors or genetics.
  3. The liver slowly becomes resistant to insulin – this reduces insulin’s suppressing effect on glucose production in the liver i.e. the liver produces and releases more glucose into the blood.
  4. Over many years, higher fasting blood glucose levels result in higher base insulin levels in the blood in order to help bring the blood glucose levels back down.
  5. The elevated insulin levels further promote fat storage in the liver, which becomes a positively reinforcing cycle.
  6. Meanwhile, increased fat in the livers leads to increased export of VLDL triacylglycerol into the blood (a side note: VLDL is the precursor to LDL, which the mainstream media like to call ‘bad cholesterol’ -> following this cycle you can see that excess dietary carbs directly increases your LDL levels…quite an interesting point).
  7. Fat accumulates in the pancreas, where it impairs the ability of the pancreatic Beta cells to release a large ‘spike’ of insulin after eating a meal, causing the blood glucose levels to remain higher over the following hours after eating a meal (Professor Taylor says here: “previous studies have shown [pancreatic] fat stops insulin release”).
  8. The elevated blood glucose levels during the following hours after eating a meal result in a greater total insulin release over time.
  9. This greater insulin release has knock-on effects on the previously described cycle in the liver (bullet point 2 – 5), further driving the liver cycle to promote fat production.
  10. The cycle continues until the system is overwhelmed and full blown type 2 diabetes develops.

So fundamentally Professor Taylor says the development of type 2 diabetes / pre-diabetes is down to eating too much, which is further exacerbated by eating excess carbohydrates. This causes fat to accumulate in the liver and pancreas, increasing insulin resistance. Accumulation of fat in these organs both drive a positively reinforcing cycle, which continues until a person develops full blown type 2 diabetes.

Ok let’s summarise the work from Professor Taylor:

  • Fat accumulation in the liver and pancreas increases insulin resistance and prevents proper insulin secretion – this is a positively reinforcing cycle
  • Excess carbohydrate consumption promotes this fat accumulation
  • Weight loss (i.e. fat loss) reverses the overall process
  • The tolerance of fat in the liver and pancreas varies from person to person based on their ‘personal fat threshold’, one person may not be able to tolerate a BMI of over 40, while another may not be able to tolerate one over 22.

Remember our initial questions:

(A) Does insulin resistance cause weight gain?
(B) Does weight gain cause insulin resistance?

From Professor Taylor’s work it would seem that it could be either or both of these:

  • Scenario 1: A little bit of weight gain increases insulin resistance, which further drives increased weight gain, which further increases insulin resistance… and so on.
  • Scenario 2: A little bit of insulin resistance develops (due to excess carbohydrate consumption?), which drives weight gain, which further increases insulin resistance… and so on.

What came first, the chicken or the egg… ?

Peter Attia’s TED talk on insulin resistance

The next person I’d like to talk about is Peter Attia, a surgeon from the US who developed pre-diabetes many years ago and successfully managed/reversed the condition – he’s also one of the co-founders of the Nutrition Science Initiative.

He speaks about his experience, and his belief on the relationship between obesity and insulin resistance, in his TED talk.

Peter poses the question about whether it is insulin resistance which is driving obesity and weight gain:

“Most researchers believe obesity is the cause of insulin resistance. Logically, then, if you want to treat insulin resistance, you get people to lose weight, right? You treat the obesity. But what if we have it backwards? What if obesity isn’t the cause of insulin resistance at all? What if obesity is a coping mechanism for a far more sinister problem going on underneath the cell? I’m not suggesting that obesity is benign, but what I am suggesting is it may be the lesser of two metabolic evils.”

His analogy of banging your shin into a coffee table explains this:

Think of the bruise you get on your shin when you inadvertently bang your leg into the coffee table. Sure, the bruise hurts like hell, and you almost certainly don’t like the discolored look, but we all know the bruise per se is not the problem. In fact, it’s the opposite. It’s a healthy response to the trauma, all of those immune cells rushing to the site of the injury to salvage cellular debris and prevent the spread of infection to elsewhere in the body. Now, imagine we thought bruises were the problem, and we evolved a giant medical establishment and a culture around treating bruises: masking creams, painkillers, you name it, all the while ignoring the fact that people are still banging their shins into coffee tables. How much better would we be if we treated the cause — telling people to pay attention when they walk through the living room – rather than the effect? Getting the cause and the effect right makes all the difference in the world.”

So, he’s questioning whether we have the cause and effect of obesity and insulin resistance the wrong way round. What if, in most people, it’s actually insulin resistance that causes obesity, and weight gain is nothing more than a natural metabolic response to this ‘underlying epidemic’: insulin resistance.

Here’s his hypothesis on the situation:

“Now, my hypothesis, because everybody always asks me, is this. If you ask yourself, what’s a cell trying to protect itself from when it becomes insulin resistant, the answer probably isn’t too much food. It’s more likely too much glucose: blood sugar. Now, we know that refined grains and starches elevate your blood sugar in the short run, and there’s even reason to believe that sugar may lead to insulin resistance directly. So if you put these physiological processes to work, I’d hypothesize that it might be our increased intake of refined grains, sugars and starches that’s driving this epidemic of obesity and diabetes, but through insulin resistance, you see, and not necessarily through just overeating and under-exercising.

When I lost my 40 pounds a few years ago, I did it simply by restricting those things, which admittedly suggests I have a bias based on my personal experience. But that doesn’t mean my bias is wrong, and most important, all of this can be tested scientifically. But step one is accepting the possibility that our current beliefs about obesity, diabetes and insulin resistance could be wrong and therefore must be tested. I’m betting my career on this.

Revisiting our initial questions:

(A) Does insulin resistance cause weight gain?
(B) Does weight gain cause insulin resistance?

Peter Attia is firmly in the (A) camp: insulin resistance causes weight gain. He’s dedicated his career to answering this question through the Nutrition Science Initiative (NuSI).

I like his summary at the end of his talk: “I don’t know how this journey is going to end, but this much seems clear to me, at least: We can’t keep blaming our overweight and diabetic patients like I did. Most of them actually want to do the right thing, but they have to know what that is, and it’s got to work.”

Professor Roger Unger’s prize winning lecture

Time to put a potential spanner in the works – this comes from Professor Roger Unger, a professor who has dedicated much of his career in elucidating “the roles of insulin and glucagon in the regulation of normal blood glucose homeostasis and in the pathogenesis of diabetes”.

Professor Roger Unger’s 2014 prize winning lecture blows open the whole diabetes debate by providing a substantial amount of evidence that it is glucagon‘s action, not insulin, which is crucial to the pathogenesis of type 2 diabetes (and type 1 diabetes).

To quote him: “Glucagon action is required for type 2 diabetes… the way to stop this disease is to block glucagon action”.

Let’s explore this in a little more detail:

  • In healthy individuals – following consumption of a meal (‘postprandial’), the body releases a large spike of insulin in reaction to the spike in blood glucose levels. This normal spike in insulin is associated with a significant suppression in blood glucagon levels. The high insulin levels and low glucagon levels essentially tell the liver to “suck up glucose and store this as glycogen”.
  • In type 2 diabetics, the postprandial insulin spike in response to elevated blood glucose levels is not seen. Instead, a gradual and sustained rise in insulin levels is seen over time. Associated with this, the normal suppression of glucagon levels does not occur. As a result, high levels of glucagon remain in the blood. This essentially tells the liver: “don’t store glucose, keep producing it from stored glycogen”. This is the exact opposite thing that you want to happen directly after consuming a meal that has already elevated your blood glucose levels.

So why is glucagon not being suppressed in type 2 diabetics after they eat a high glucose meal?

Professor Unger proposes that it is a result of insulin resistance in the pancreatic alpha cells. In normal situations, insulin acts on the alpha cells to suppress further glucagon release. When the alpha cells are insulin resistant, this suppression doesn’t happen. This effect is further compounded by the lack of the postprandial insulin spike in type 2 diabetics (remember we also covered this when exploring Professor Taylor’s work above, in point 7: “Fat in the pancreas impairs the ability of the pancreatic beta cells to release a large ‘spike’ of insulin after eating a meal”).

OK – so the pancreatic alpha cells become insulin resistant, but how does this happen?

Here we return to the common theme that has been running through the work of many the above research groups: pancreatic fat levels.

We explored earlier that Professor Taylor proposed that increased pancreatic fat levels impairs pancreatic beta cell function. Professor Unger provides a mechanism for this effect:

  • Increased fat levels in the pancreas results in an increased accumulation of ceramide (which is toxic) in the pancreas, with two major consequences:
  • (1) Ceramide kills pancreatic beta cells
  • (2) It causes insulin resistance in alpha cells

So now we have a possible explanation for the mechanism for why the postprandial insulin release is suppressed in type 2 diabetics (due to beta cell death), as well as why glucagon release is not suppressed (alpha cell insulin resistance).

Professor Unger goes on to highlight some elegant experiments which demonstrate that the “glucagon receptor is required for dietary obesity and type 2 diabetes“. When removing the glucagon receptor from mice, these mice do not develop type 2 diabetes or insulin resistance.

So what’s Professor Unger’s proposed pathway to type 2 diabetes?

  1. Fundamentally, you have to overeat
  2. In a normal person, this will lead to hyperinsulinemia (excess levels of insulin in the blood relative to blood glucose levels)
  3. Glucagon is an enabler of hyperinsulinemia, without glucagon action you do not get hyperinsulinemia
  4. Hyperinsulinemia increases ceramide production
  5. Ceramide accumulates in excess fatty tissue, including the pancreatic islet cells
  6. Ceramide causes beta cell death, suppressing postprandial insulin spikes
  7. Ceramide causes alpha cell insulin resistance, preventing the normal suppression of glucagon by insulin

He concludes that in 1962 he saw eye-to-eye with Professor Rolf Luft (1914-2007) on the insulinocentric concept of diabetes, whereby the symptoms of diabetes could be explained by the lack of insulin. Professor Unger wonders whether Professor Luft would see eye-to-eye with him now on the glucagonocentric concept of diabetes, where the symptoms of diabetes can be explained by glucagon excess in the absence of insulin.

Once again, let’s revisit our initial questions:

(A) Does insulin resistance cause weight gain?
(B) Does weight gain cause insulin resistance?

Professor Unger proposes that it is overeating (i.e. weight gain) which first kickstarts the pathway to type 2 diabetes, but critically that the whole process is enabled by glucagon. However, he doesn’t explore further around these first steps: overeating and developing hyperinsulinemia. Could they be the other way around?

Slim diabetics and the exceptions

Before concluding, there will always be exceptions to the various hypotheses presented. One of the main exceptions being people who are slim but have type 2 diabetes. Professor Taylor highlights a few of them here:

“There are some rare forms of diabetes which may be incorrectly called type 2 diabetes:

a) Diabetes occurring after several attacks of pancreatitis is likely to be due to direct damage to the pancreas (known as ‘pancreatic diabetes’)

b) Secondly, people who are slim and are diagnosed with diabetes in their teens and twenties, with a very strong family history of diabetes, may have a genetic form (known as ‘monogenic diabetes’)

c) Thirdly, type 1 diabetes sometimes comes on slowly in adults, and these people usually require insulin therapy within a few years of diagnosis (‘slow onset type 1’)”

In addition, people who are slim with actual type 2 diabetes may simply be over their ‘personal fat threshold’ which we explored earlier in the article.

Dr Malcom Kendrick highlighted on his blog two examples of people who don’t fit the trend of:

More body fat = Higher risk of diabetes

These two populations of humans are:

  • Sumo wrestlers (incredibly fat)
  • People with Beradinelli-Siep lipodystrophy (they have almost no fat cells)

If we follow the mainstream notion that having more fat increases your risk of type 2 diabetes, then you would expect sumo wrestlers to have lots of type 2 diabetes, and people with Beradinelli-Siep lipodystrophy to have no type 2 diabetes.

In reality, the opposite occurs. When training, none of the sumo wrestlers have type 2 diabetes. Conversely, 100% of people with Beradinelli-Siep lipodystrophy have type 2 diabetes.

The explanation for this is that it is about energy partioning – sumo wrestlers train incredibly hard, and burn up their spare glycogen stores. When they eat, this glucose is quickly shuttled into their muscle and liver cells (so there is no insulin resistance to overcome). People with Beradinelli-Siep lipodystrophy have no fat cells, and so there is nowhere for the excess energy to be stored after eating a large meal, regardless of how high the blood insulin levels become (hence why insulin resistance develops).

Dr Kendrick proposes a different model for the development of type 2 diabetes:

  • You eat too much carbohydrate/sugar
  • You produce too much insulin
  • This forces your body to store fat
  • You become obese
  • At a certain point insulin resistance develops to block further weight gain
  • This resistance becomes more and more severe until…
  • You develop type 2 diabetes

This model provides an explanation for the varying types of people who have type 2 diabetes or are at risk for type 2 diabetes, varying from the seemingly slim and underweight, to those who are very overweight, including sumo wrestlers.

Dr Kendrick concludes:

“Whilst those with Beradinelli-Siep lipodystrophy cannot tell us much about diabetes and obesity in ‘normal’ people, this condition does make it very clear that diabetes (insulin resistance, high insulin and high sugar levels) is primarily an issue with energy storage and how the body goes about this storage, and the role that insulin plays. If there is somewhere for excess energy to go easily, insulin levels will not go up, and nor will blood sugar levels.”


If you’ve managed to stay with me this far you’ll agree that type 2 diabetes, and ‘pre-diabetes’, are conditions that are much more complex than the typical mainstream view of “you get fat so you get type 2 diabetes”.

From the work I’ve highlighted above, weight gain is likely to be strongly driven by insulin resistance and/or hyperinsulinaemia, coupled with glucagon action.

Regarding the development of ‘pre-diabetes’ or type 2 diabetes, there doesn’t appear to be a hard and fast rule for this. I’ve been trying to work out what comes first to initiate the whole process: a little bit of weight gain or a little bit of insulin resistance?

Fundamentally, the key factors involved with the development of these diseases appear to be excess carbohydrate consumption, insulin resistance and glucagon action. Alongside these, there are additional genetic and hereditary factors that are likely involved, such as your ‘personal fat threshold‘.

What’s the easiest one to address out of all of these without the need for drugs or other interventions? Eat fewer carbohydrates. If you’ve ever done a low carbohydrate diet, you’ll also notice that it’s nearly impossible to overeat, and weight falls off you.