Background
Type 2 diabetes (T2DM) pathogenesis revolves around chronic insulin resistance and relative beta-cell failure. The primary cause of these issues is a heavily debated topic; however, throughout this article, I will try to clarify why I believe excess bodyfat is the primary cause of T2DM. I think this makes for an interesting article considering that many people still place the blame for T2DM pathology elsewhere. I understand why people shy away from bodyfat as a causal factor, too. After all, obesity and T2DM appear largely unrelated at the population level. For example, in the United Kingdom Prospective Diabetes Study [1], which analysed the baseline characteristics of 5100 newly-diagnosed patients with T2DM, there is clearly a massive range of BMI’s among these individuals (see graph below). There is a slight tendency for people over a normal BMI to get more T2DM, as demonstrated by the rightward skew in the graph, but ~36% of T2 diabetics were not considered overweight because their BMI was <25. To add to this, based on the National Health and Nutrition Examination Survey in the United States, ~72% of people with a BMI above 40 (extremely obese) do not have T2DM [2]. It is these kinds of statistics that drive the narrative that T2DM must be a chronic disease that is caused by issues other than excess bodyfat, such as dietary sugar or the “dreaded seed oils”.
A Shift in Perspective
The problem with arguing that T2DM is mainly caused by factors other than excess bodyfat is that it misaligns with seminal research over the last 15 years or so. The first key insights that suggested bodyfat does indeed play a major part in T2DM pathology were actually from bariatric surgery; a surgical treatment to significantly reduce food intake and promote rapid weight loss. Specifically, within just days of bariatric surgery, the normalisation of glucose and reversal of T2DM is common [3]. Such dramatic results are explained by a vast drop in energy intake alongside preferential and rapid mobilisation of fat from the liver and pancreas, as quantified by various serial imaging techniques [4].
As these results were novel at the time and seemingly opposed the consensus that T2DM was chronic and irreversible, they led to a series of amazing studies conducted by Roy Taylor – Counterpoint, Counterbalance and the Diabetes Remission Clinical Trial (DiRECT) – which have since established that long-term remission of T2DM is achievable via effective diet-induced weight loss [5] [6] [7]. The first seminal dietary randomised controlled trial (RCT) was on just 11 T2 diabetics who followed a 600kcal/day diet for 8 weeks. Here, the normalisation of beta-cell function (insulin-producing cells) and hepatic (liver) insulin sensitivity in T2DM was achieved by dietary energy restriction alone. The researchers noted a concurrent reduction in pancreatic and hepatic (liver) fat during weight loss alongside an improved first-phase insulin response [5]. Although a cause and effect relationship between raised intra-organ fat levels and metabolic effects were not “proven”, the time course data following the dietary intervention study highly suggested a causal link. See below…
This initial trial was insightful yet limited by a small sample size, which created a need for the more comprehensive DiRECT trial [6]. The DiRECT trial was on a much larger group of T2 diabetics and with a much longer study duration. The intervention comprised a complete withdrawal of antidiabetic and antihypertensive drugs, total diet replacement for 3-5 months (~850kcal/day), followed by stepped food reintroduction for 2-8 weeks, and then structured support for long-term weight loss maintenance. The control group simply continued with their standard medication. After the full 12-month intervention, the results showed that T2DM remission was closely related to the degree of weight loss maintained at 12 months. Achievement of remission was apparent in 86% of participants with >15kg weight loss from baseline, and in 73% that had weight loss of >10kg or more. Essentially, the degree of weight loss was linearly associated with T2DM remission. See below..
Also, detailed metabolic tests on subgroups from this trial (intervention, n = 64; control, n = 26) were performed before and after the 12-month intervention. As seen in the graphs below, the change in bodyweight and liver fat correlated with the change in pancreatic fat. Also, pancreatic fat correlated with the change in beta-cell function (first-phase insulin response). These results confirmed and extended previous observations related to T2DM pathology [8].
To solidify the 12-month DiRECT trial findings over the long-term, a 2-year follow-up re-affirmed that sustained remission was strongly correlated to the extent of sustained weight loss [7].
There were also further insights from a defined sub-group of DiRECT participants who achieved remission at 5 months into the trial. These participants were subject to detailed metabolic tests at baseline, 5 months, 12 months, and 24 months follow-up. The interesting part of this follow-up analysis is that the subgroup (achieving remission after 5 months) were then split into ‘responders’ and ‘relapsers’ based on their diabetes status at 24 months. As shown below, the results clarified that a decrease in both hepatic and intrapancreatic fat is a prerequisite for diabetes remission. After 24 months, the ‘relapsers’ were those who had re-accumulated intra-pancreatic and intra-hepatic fat. ‘Relapsers’ also had a greater rise in the content of VLDL1-triglyceride (circulating fat produced by the liver), which suggested that the re-accumulation of liver fat led to fat spillover to the pancreas. Thus, weight-related disordered fat metabolism appears to drive both the development and reversal of T2DM [9].
The Point of No Return
To add minor nuance to the discussion so far, you may have noticed that not everyone who loses weight goes into diabetes remission. Now, it may be the case that some people may have needed to lose >15 kg for remission to occur. Still, regardless, it should also be acknowledged that reversing diabetes is only possible if the pancreatic beta cells have not surpassed what is known as the “point of no return”. This refers to the situation where diabetes has been prevalent for so long that the beta-cells are beyond reversible damage and can no longer secrete insulin adequately. As the duration of diabetes increases, it appears that beta-cells are more prone to becoming unable to return to fully differentiated and functioning beta cells.
For example, in a sub-analysis of the Counterbalance study, although ~87% of those with diabetes <4 years achieved non-diabetic fasting plasma glucose levels after acute weight loss, only ~50% of those who had diabetes for >8 years did so. These results align with recent audits of bariatric surgery metabolic outcomes. A return to normal average blood glucose levels (HbA1c) after bariatric surgery is achieved in ~62% of individuals with diabetes duration <4 years, but those with diabetes duration >8 years only achieve normal blood glucose levels in only ~26% of cases [10] [11].
Interpreting the Data and Generating Hypothesis
Based on all of the above findings, the personal fat threshold hypothesis was born. In contrast to the initial population data presented at the beginning of this article, the personal fat threshold treats everyone as individuals. It suggests that each person has a unique threshold to which excess energy can be accumulated before T2DM occurs. The threshold for energy accumulation includes subcutaneous adipose tissue storage—the safest means of fat storage—ectopic fat storage (outside of adipose tissue), and muscle glycogen storage. Thus, T2DM only develops if an individual accumulates more fat than can be stored in their metabolically (relatively) inert depots. These depots’ capacity varies considerably between individuals and is probably genetically determined, but perhaps (slightly) modifiable by few lifestyle exposures. This will be discussed in the next article.
Gaining sufficient weight to cross the personal fat threshold will trigger diabetes, whereas losing ‘excess weight’ can return people back to normal glucose tolerance. For a visual demonstration, the graph below shows three hypothetical individuals who have just been diagnosed with T2DM at different BMIs (red dots). One is obese (BMI 36), one is overweight (BMI 29), and one is normal weight (BMI 24). Here, the blue dot represents the scenario where each individual loses 15kg bodyweight and regains normal glucose metabolism. Therefore, all three crossed their personal fat threshold, above which glucose control is lost and below which it is normal. Thus, the effect of crossing the personal fat threshold is identical for any individual, regardless of what BMI the personal fat threshold lies [12].
