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Diabetes, Part 2: The Causal Role of Raised Insulin

ByMalcolm Kendrick, MDJanuary 27, 2020

Several populations in the world have extremely high levels of Type 2 diabetes (T2D). This article will discuss two of them, as they can help to further illuminate the underlying cause of T2D in the general population.

The first population to consider is the Pima people who live in the southern states of the U.S. and northern Mexico. The second group includes those with congenital generalized lipodystrophy (CGL).

The Pima people have the highest rate of obesity and diabetes of any population in the world. A. Krosnick writes:

The Pima Indians are the fattest population group in the fattest country on earth, and they have the highest prevalence of diabetes in the world. Despite unprecedented research by the National Institute of Arthritis, Diabetes and Digestive and Kidney Diseases (NIH) and good care by the Indian Health Service (IHS), the problems have grown worse since first recognized in 1963. (1)

Congenital generalized lipodystrophy (CGL) is an extremely uncommon condition, and the total population of individuals with this condition is small. However, all those with CGL will develop T2D.

While the Pima people are the most obese population in the world, those with CGL have no adipose tissue. This means they are exceptionally lean. (The term “lipodystrophy” refers to a lack of fat cells, or adipose tissue, and “generalized” means “all over the body.”)

Initially, this could suggest that the underlying mechanisms for the development of T2D in these two populations may be diametrically opposed. However, on closer examination, the basic underlying mechanisms are the same.

Looking first at the Pima: The specific early feature of this population is that, when challenged with a glucose test, they produce considerably more insulin than would be the case for the general population. As described in the paper “Exaggerated insulin secretion in Pima Indians and African-Americans but higher insulin resistance in Pima Indians compared to African-Americans and Caucasians”:

Exaggerated glucose-stimulated insulin secretion, manifested initially as an increased response to an intravenous glucose challenge, appears to be a characteristic in people with normal glucose tolerance at higher risk for diabetes. (2)

If you subject healthy young, non-obese, non-diabetic Pima people to a glucose tolerance test, they manifest an exaggerated insulin response. This means the first detectable metabolic problem in the Pima is a raised insulin level/increased insulin secretion. This runs counter to the generally accepted causal chain that leads to T2D, which is:

Excess energy consumption → obesity → insulin resistance → raised insulin levels → IGTT early (pre-diabetes) → IFG (pre-diabetes) → Type 2 diabetes

This “standard” model places a raised insulin level relatively late in the causal chain.

However, in the Pima, a raised insulin level is the first identifiable abnormality. This occurs before obesity or any other detectable form of insulin resistance. A glucose tolerance test and fasting blood glucose will be normal.

Whether this means the Pima have a degree of genetic insulin resistance that causes the early raised insulin levels in response to an impaired glucose tolerance (IGT) or they simply produce more insulin in response to glucose is not clear. However, the critical issue is that, in the Pima people, raised insulin levels precede obesity. This means their insulin resistance/raised insulin levels cannot be caused by obesity.

Instead we have two possible causal chains:

1: Raised insulin levels → obesity → insulin resistance → pre-diabetes (greater insulin resistance) → Type 2 diabetes

2: Insulin resistance → raised insulin levels → obesity → ↑insulin resistance/pre-diabetes → Type 2 diabetes

This model removes excess energy consumption from the causal chain. However, it should be emphasized that it is not possible, in any population, to gain weight if calorie input does not exceed calorie output. This is confirmed by the Pima themselves, in that those living in the U.S. have far higher levels of obesity/T2D than those living in northern Mexico. This means environmental factors clearly have a critical role to play. As Leslie Schulz et al. explain:

The much lower prevalence of type 2 diabetes and obesity in the Pima Indians in Mexico than in the U.S. indicates that even in populations genetically prone to these conditions, their development is determined mostly by environmental circumstances, thereby suggesting that type 2 diabetes is largely preventable. (3)

Leaving that point aside, the important finding from the Pima is that the raised insulin levels initiate both obesity and T2D. However, this does not make the Pima unique, apart from the fact that they are more susceptible to becoming obese and diabetic due to more extreme and early excess insulin production.

Indeed, it has been found that increased insulin production precedes obesity in all other populations. Studies that have specifically looked for raised insulin secretion as the early abnormality have shown that raised insulin levels precede pre-diabetes/metabolic syndrome by many years (4).

Moving on to those with congenital generalized lipodystrophy (CGL): In this population, obesity cannot play any role, as individuals with CGL have an absolute lack of adipose/fat tissue. Despite this, they all develop T2D. As Rebecca Brown et al. explain:

Lipodystrophy syndromes are extremely rare disorders of deficient body fat associated with potentially serious metabolic complications, including diabetes, hypertriglyceridemia, and steatohepatitis. (5)

Steatohepatitis is an excess and damaging build-up of fat in the liver. The stage before steatohepatitis is usually called non-alcoholic fatty liver disease (NAFLD).

Hypertriglyceridemia is the term used to describe a very high level of very low-density lipoproteins (VLDLs, also known as triglycerides). VLDLs are the lipoproteins that move fats/triglycerides out of the liver to be transported to the rest of the body along with cholesterol. (VLDLs reduce in size as they lose fat/triglycerides, then becoming low-density lipoproteins, or LDLs.)

What is the mechanism by which those with GCL develop this spectrum of abnormalities? It is most likely because they lack the ability to store excess energy. Adipose tissue is the primary energy storage organ in the body. It is possible to store 1 million kcal of energy as fat/fatty acids, although this would represent more than 100 kg of adipose tissue.

On the other hand, the total storage capacity for glucose/glycogen is around 1,500 kcal, which is considerably less than the daily calorie intake of many people. Once this limit has been reached, excess glucose and fructose must be converted to fatty acids in the liver in a process known as de novo lipogenesis (DNL).

The fatty acids synthesized by DNL are formed into triglycerides and then packaged into VLDLs, which exit the liver. In most people, the triglycerides carried in the VLDLs are absorbed and stored in adipose tissue.

However, in those with CGL, as there is no adipose tissue available, the fatty acids in the VLDLs have nowhere to be stored (other tissues — e.g., muscle — can store fats/triglycerides, but not a great deal). Therefore, the VLDL level rises very high. “Back pressure” on the lipogenesis system means fatty acids become trapped in the liver. Unless energy consumption is reduced, NAFLD and then steatohepatitis inevitably will develop.

Equally, with de novo lipogenesis blocked, the blood glucose level will rise. This will, in turn, drive insulin levels even higher. Essentially, a state of extreme insulin resistance will rapidly develop as the energy storage systems are overloaded.

Thus, the model for the development of T2D in CGL is simple:

Energy storage systems at full capacity → insulin resistance → Type 2 diabetes

While it may not seem immediately obvious, the mechanism at work here is essentially the same as that seen with the Pima people. The key difference is that the Pima do not have lipodystrophy. This means their above-average insulin levels initially lead to enhanced energy storage/obesity. They do not develop significant insulin resistance until their adipose storage systems start to overload. This takes considerably longer in the Pima than in those with CGL.

Comparing the Pima to those with CGL, we maintain this model for CGL:

Energy storage systems at full capacity → insulin resistance → Type 2 diabetes

But in the Pima, there are two more steps prior to this:

Raised insulin levels obesity → energy storage systems at full capacity → insulin resistance → Type 2 diabetes

The only real difference in the underlying mechanism in these two populations is that the Pima take longer to develop T2D.

The general population, in turn, only differs from the Pima in that there is lower insulin production in response to food. This leads to comparatively reduced energy storage.

However, in the general population, the underlying mechanism remains the same. For example, when insulin levels are measured in children, higher fasting levels predict future risk of obesity, raised triglycerides, low HDL cholesterol, and raised blood pressure. These are abnormalities now called pre-diabetes (6).

In summary, this means that in order to prevent T2D, the challenge in all populations is to ensure insulin levels are kept to a minimum, as this is what drives obesity and T2D.

Additional Reading

KendrickMalcolm Kendrick is a family practitioner working near Manchester in England. He has a special interest in cardiovascular disease, what causes it, and what may prevent it. He has written three books: The Great Cholesterol ConDoctoring Data, and A Statin Nation. He has authored several papers in this area and lectures on the subject around the world. He also has a blog,, which stimulates lively debate on a number of different areas of medicine, mainly heart disease.

He is a member of THINCS (The International Network of Cholesterol Sceptics), which is a network of doctors and scientists who believe that cholesterol is not the main underlying cause of heart disease. He remains a proud Scotsman, whisky drinker, and failed fitness fanatic who loves a good scientific debate — in the bar.


  1. The diabetes and obesity epidemic among the Pima Indians
  2. Exaggerated insulin secretion in Pima Indians and African-Americans but higher insulin resistance in Pima Indians compared to African-Americans and Caucasians
  3. Effects of traditional and Western environments on prevalence of Type 2 diabetes in Pima Indians in Mexico and the U.S.
  4. Elevated fasting insulin predicts the future incidence of metabolic syndrome: A 5-year follow-up study
  5. The diagnosis and management of lipodystrophy syndromes: A multi-society practice guideline
  6. The role of insulin in clustering of serum lipids and blood pressure in children and adolescents. The cardiovascular risk in Young Finns Study

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