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Diabetes, Part 1: Disease Models

ByMalcolm Kendrick, MDJanuary 17, 2020

“Diabetes,” or to be more accurate, “diabetes mellitus,” literally means passing a large volume of sweet urine (diabetes = high volume of urine; mellitus = sweet smelling or sweet tasting).

It is a disease that was recognized and described in Roman times. In the early modern era, it was described as the “pissing evil,” a term taken from Thomas Willis’ 17th-century discourse on diabetes. The word “evil” was appropriate because shortly after the first symptoms emerged, the child — for this was primarily a disease of children — died.

The childhood form of the disease is what is now commonly known as Type 1 diabetes. The underlying mechanism is well understood, although the cause is still unknown and untreatable. In Type 1 diabetes, the insulin-producing beta cells in the pancreas are damaged or destroyed, and there is no longer sufficient insulin production.

A lack of insulin results in a significant rise in blood glucose levels, which is well known. Insulin also inhibits the release of fatty acids from adipose tissue and amino acids from muscle. Therefore, in Type 1 diabetes, fatty acids escape into the bloodstream unchecked; they are therefore termed free fatty acids (FFAs). Excess FFAs then enter the liver, where they are converted to ketone bodies.

A combination of high free fatty acids (FFAs) and ketone bodies, which are both mildly acidic, gradually lowers the pH of the blood, leading to coma and then death due to ketoacidosis. Before ketoacidosis reaches a critical point, muscle and fat are rapidly lost as the energy stores of the body are released, leading to catastrophic weight loss (cachexia).

It was not until 1936 that it was formally identified that another form of diabetes exists, primarily affecting adults. This condition initially was called adult-onset diabetes. It is now termed Type 2 diabetes. It is also possible for Type 1 diabetes to start in adulthood. This is called maturity-onset diabetes of youth (MODY).

The incidence of Type 1 diabetes has remained relatively constant over many years. However, the incidence and prevalence of Type 2 diabetes has been increasing rapidly over the last 20 or 30 years, perhaps longer, in most industrialized countries.

In Type 2 diabetes, unlike Type 1, there may be a normal secretion of insulin (In fact, there is initially, and increased secretion). However, the actions of insulin are inhibited in certain organs, primarily the liver and skeletal muscle. This means insulin is unable to maintain a blood glucose level within the normal range, thus resulting in Type 2 diabetes.

However, several stages unfold before the blood glucose level becomes high enough for Type 2 diabetes to be diagnosed. Indeed, the inhibition of insulin action may begin many years, even decades, before diabetes is formally diagnosed.

In the early stages, although the actions of insulin are inhibited, the beta cells overcome this by producing more insulin. This maintains the blood glucose levels within the normal range at all times.

The next stage is that, after a meal, the blood glucose will rise significantly higher, falling back to normal in the fasting state. This is described as impaired glucose tolerance (IGT). During diagnosis, a bolus dose of glucose is given, and blood glucose levels are measured over the next two hours or so. The glucose level spikes at about the one- to two-hour mark before returning to normal.

After this stage, the blood glucose will begin to rise above normal in the fasting state, which is called IFG (impaired fasting glucose). This is then followed by full-blown Type 2 diabetes as the blood glucose rises even higher. The move from IFG to Type 2 diabetes is generally believed to occur when the increased insulin secretion “burns out,” with the beta cells beginning to fail under the increased requirement for insulin.

Therefore, the sequence is generally considered to be:

Raised insulin → impaired glucose tolerance test (IGTT) → impaired fasting glucose (IFG) → Type 2 diabetes

However, this terminology and the diagnostic criteria have changed over time. Glucose tolerance tests are rarely performed, and diabetes is now almost universally diagnosed using HbA1c (the amount of glucose that adheres to the A1c molecule on a red blood cell). The higher the HbA1c, the higher the blood glucose level has been over a longer period of time.

Red blood cells last for around 28 days after synthesis in the bone marrow, and it is therefore recognized that the HbA1c provides a better overall record of the average blood glucose level.

The HbA1c test is now almost universally used for the diagnosis of diabetes, and the terms IGTT and IFG have mostly been replaced. Nowadays, a patient will be told they have a normal HbA1c before moving on to pre-diabetes then diabetes. In the past, pre-diabetes would have been referred to as IGTT and then IFG.

It is increasingly recognized that the health problems and complications associated with pre-diabetes are very near those found in full-blown Type 2 diabetes (1).

What causes Type 2 diabetes?

It is clear that several different factors play a role in the development of Type 2 diabetes, with genetics being a significant factor. However, it is generally considered that obesity is the primary driver. As an article in Diabetology and Metabolic Syndrome explains:

BMI is strongly and independently associated with the risk of being diagnosed with T2D. The incremental association of BMI category on the risk of T2D is stronger for people with a higher BMI relative to people with a lower BMI. (2)

Therefore, the generally accepted model for the causation of Type 2 diabetes is that excess energy consumption first leads to obesity, which in turn creates inhibition or resistance to the effects of insulin. This resistance gradually increases until the raised insulin can no longer keep the blood glucose under control. Then, Type 2 diabetes is diagnosed, possibly or probably triggered by beta-cell burnout.

A simple model for this this would be:

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

Most experts view the progression from obesity to diabetes as an almost inevitable process. This is why we have the term “pre-diabetes,” implying a person will move from pre-diabetes to diabetes. In the past, other terms were used for the pre-diabetic state, including:

  • Insulin resistance syndrome
  • Syndrome X
  • Metabolic syndrome
  • Reaven’s syndrome

These terms have mainly fallen out of mainstream use.

Using this simple model, the standard advice to prevent diabetes is to avoid macronutrients with high caloric content, as they will more readily promote weight gain. Fats generally contain 9 calories of energy per gram, whereas proteins and carbohydrates (sugars) contain around 4 calories of energy per gram.*

Therefore, people are advised to eat carbohydrates in order to stop weight gain and thus diabetes. Another way to look at this is to use the simple model of calories in = calories out (CICO). If you eat fewer calories, you will not gain weight.

In this way of thinking, it can be argued that the underlying cause of diabetes is more likely to be excess fat consumption than excess carbohydrate consumption. Indeed, many researchers have suggested that fats, specifically saturated fatty acids, cause Type 2 diabetes. For example, a study from the University of North Carolina School of Medicine claims, “A diet high in saturated fat is a key contributor to type 2 diabetes, a major health threat worldwide” (3).

A flawed model?

It can be argued that this simple CICO concept of obesity and diabetes is significantly flawed. Instead, a strong case can be made that raised insulin levels are the underlying driver of obesity, and the probable causal chain that links diabetes and obesity is as follows:

Raised insulin levels ± insulin resistance → obesity + insulin resistance → pre-diabetes → Type 2 diabetes

In support of this, it is well known that people with diabetes who take insulin to control blood glucose will inevitably gain weight. As an article from Integrated Diabetes Services explains:

One of the most common concerns expressed by people who use insulin is that it tends to cause weight gain. In fact, research from the United Kingdom Prospective Diabetes Study (UKPDS) showed that the average person with Type-2 diabetes gained about nine pounds in their first three years of insulin use. (4)

This would be equivalent to about 32 pounds in weight gain over 10 years, with no alteration in caloric intake.

If you move away from the concept that insulin is simply the glucose-lowering hormone and instead view it as primarily an energy-storage hormone, this finding would be expected. Insulin is the most potent anabolic hormone, which, when the level is high, drives the metabolic system to store energy.

Indeed, without insulin, energy will be released rather than stored, as is seen in untreated children with Type 1 diabetes. Another way to think about this is that insulin is the obesogenic hormone. This means, if we wish to reduce both obesity and Type 2 diabetes, the most effective approach is to reduce the level of insulin in the bloodstream or find ways to reverse resistance to the effects of insulin, which will in turn lower insulin levels.

Equally, if we wish to control obesity ± diabetes, we need to control the underlying factors that increase insulin levels. The next two articles in this series will examine the “raised insulin” model of diabetes and discuss practical steps to lower insulin levels.


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, drmalcolmkendrick.org, 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.

*Editor’s note: This article originally stated that both proteins and fats contain 9 calories of energy per gram. The typographical error was pointed out by Matthew Walmsley in the article’s comments and was corrected on Jan. 23, 2020.


Notes

  1. Association between prediabetes and risk of cardiovascular disease and all cause mortality: Systematic review and meta-analysis

  2. The association of body mass index with the risk of type 2 diabetes: A case-control study nested in an electronic health records system in the United States

  3. Link between high-fat diet and type 2 diabetes clarified

  4. Insulin & weight gain: Does tighter control make you loosen your belt?

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