Endogenous saturated fat production in
T2D
According
to Taylor, individuals with normal muscle insulin sensitivity apportion post-meal
glucose as follows: Most of it is oxidized as energy, one fourth is stored as liver
glycogen, a third is stored in skeletal muscles, and lastly, only a tiny
portion is stored as saturated fat via de novo lipogenesis. [
Am J Physiol 1993;265:e224-229;
PNAS
2007;104:12587]
He
then contrasted this with a person who has relative muscular insulin resistance:
Muscle storage is decreased to eight percent while changes in liver storage are
not much (since this storage is affected by blood glucose levels and not by
insulin); much is still oxidized—but now, over a third is stored as saturated
fat. [
Am J Physiol
2006;284:e286-294;
PNAS
2007;104:12587]
An
implication of the de novo saturated fat synthesis, Taylor noted, is that while
nutritionists focus on the dietary control of such fat, they are unaware that the
body itself can produce an excess of it, which would help drive on TD2 and its cardiovascular
(CV) complications.
Keys to glucose control via weight loss:
liver's glucose production and fat–dependent insulin sensitivity
“The
liver produces glucose every minute of the day.” But In T2D, Taylor said that it
produces 50 percent more glucose than usual” [
JCI 1996;97:126-132;
AJP 2002;283:E275-83],
pointing out that if a patient asks, “Why is my glucose sometimes higher in the
morning when I wake up despite not eating for eight hours?” the answer is that plasma
glucose is being topped up and kept high by the liver.
“Our
work shows that the liver’s insulin sensitivity is strictly related to the
concentration of liver fat”. Modest calorie restriction for over ten weeks resulted
in around eight-kilogram weight loss, bringing about a dramatic reduction in liver
fat levels and, then—strikingly—an increased suppression of hepatic glucose
production to about nondiabetic levels, Taylor said. “Improvement in whole body
insulin sensitivity is due to the liver and not the muscle.” [
Diabetes 2005;54:603–8]
Taylor's twin liver/pancreas cycle
hypothesis of T2D etiology
The
liver’s role is central to Taylor’s proposed twin cycle hypothesis of T2D
etiology (see figure). In this hypothesis, the liver drives up basal insulin, which,
in turn, drives up the conversion of glucose to fat, eg, de novo lipogenesis,
thus, reinforcing the cycle.
The liver also lends to the pancreas cycle (right
side of figure) by elevating plasma triglycerides which tend to deposit into
ectopic sites like the pancreas. Long-term exposure of pancreatic β cells to
triglycerides suppresses their function in susceptible people. [
Diabetol 2008;51:1781–89]
Testing the hypothesis: Counterpoint study
A
way to test the two-cycle hypothesis is to control the positive calorie balance
(figure). Taylor designed the Counterpoint study, to subject participants who
were diabetic for up to four years to calorie restriction (800 kcal/day) while on
hypoglycemic medications withdrawal.
In
eight weeks, the subjects lost an average of 15.3 kg of body weight. The
researchers observed a dramatic fall in plasma glucose similar to normal levels.
Also, the study's MRI data showed that the subjects' liver fat decreased from above
10 to below 5 percent. Plasma triglycerides, HbA1c, pancreas fat, and first
phase insulin response likewise recovered. Moreover, the measured improvement
in insulin sensitivity was attributed to the liver alone, not the muscle. [
Diabetol
2011;54:2506–14] “Liver fat is not a complication of diabetes; it’s a
manifestation of overnutrition. There is still remarkable misinterpretation of
data that leads some to suggest that liver fat needs to be controlled with drugs,
when in fact it’s just a case of overnutrition.”
Counterbalance study: the follow-up to
Counterpoint
“A
question that arose was, ‘Were the Counterpoint data a reflection of true return
to the nondiabetic state, or were they just a starvation effect?”
In
the Counterbalance study, patients who had T2D for 0.5 to 24 years were monitored
while they reverted to normal diet. Taylor noted that the results supported the
durability of the regained nondiabetic state. Even for nonremitters, the liver
cycle was normalized, although beta cell unresponsiveness persisted. Remission
was reportedly dependent on T2D duration: The earlier the dietary intervention,
the more durable the return to the normal state. The ten-year CV risk score
reportedly decreased from 15 to six percent (normal). [
Diabetes Care
2016;39:808–15]
Interestingly,
a study by psychologists showed that the Counterbalance dietary intervention was
well liked by the patients, mainly because the short-term rapid weight loss
afforded them right away the normal activities of daily living, according to
Taylor. [
Diab Med
2017;34:1554–67;
Nutrients
2021;13:1465]
Primary care trial intervention and real
world studies
The
DiRECT randomized clinical trial showed that, in the primary care setting, medication
withdrawal, diet replacement, food reintroduction, and weight loss support for over
a third of T2D patients achieved long-lasting remissions at two years. As
Taylor related, the higher the sustained weight loss, the longer the remission.
[
Lancet Diabetes Endocrinol 2019;7:344]
In
a follow-up to DiRECT, for participants who regained weight and relapsed, their
liver fat, plasma triglyceride, and first phase insulin profiles also reverted
back to diabetic levels. [
Cell
Metab 2020;31:233–49]
A
longer study Taylor cited showed that the DiRECT intervention at five years led
to an average weight loss of 6.1 kg, with 13 percent in remission. While there
were only few participants still in remission, they were those who had avoided
regaining weight far longer—a remarkable feat when compared with current
routine treatment. [
Lancet
Diabetes Endocrinol 2024;12:233–46]
“Any
weight gain–related relapse is linked to pre-existing T2D risk, such as insulin
resistance in the muscles, which has never changed.” He branded the common belief
“achieving rapid weight loss makes one at a higher risk of rapidly gaining
weight” irrational as the newly attained lower body weight requires lower
dietary requirements.
In
the real world setting (ie, no experimental intervention), Taylor showed that diet
restriction and weight loss–mediated remission is achievable, based on the
first-year data from England's National Health Service (NHS) Type 2 Diabetes Path
to Remission (NHS T2DR) program, although the rate of remission was lower than
those found in research studies. [
Lancet Diabetes Endocrinol 2024;12:653-63]
Lowering the Filipino BMI cutoff due to incidence of low-BMI TD2
“In
the US, among individuals with body mass indices (BMI) below 25 kg/m², Filipino Americans are
said to have thrice the T2D susceptibility of those with white European ancestry.” [
Can J Pub Health 2017;108:e36–42]
Moreover,
Taylor mentioned one study that determined the optimal Filipino BMI cutoff for
cardiometabolic diseases to be 23 rather than the usual 25kg/m². [Pagsisihan et
al. Presented at Asia Oceana Congress of Endocrinology, Philippines, 2014]
Results
of a long-term American study on the link of T2D to nurses’ obesity also appear
to mirror the above study. “The relative risk of getting T2D surprisingly increased
four-fold when the nurses' BMIs increased from below 23 to between 23 to 25
kg/m². [
N Engl J Med 2001;345:790–797]
Taylor
suggested that the BMI cutoff for Filipinos, who are in general more
susceptible, should even be lower, at 21 kg/m², but he qualified that further work is needed to
validate his opinion. A study he cited to support a lower Filipino cutoff is the
UK Prospective Diabetes Study. The study's population bell distribution curve of
diabetics across BMIs showed that many of them fell within the normal BMI range.
He reiterated that T2D is primarily not caused by obesity, but the latter
increases the likelihood of the disease. Hypothetically, “if the diabetics in
this population curve were to lose 15 kg of body weight, they, including those
with normal BMI, would have achieved remission.” [
Clinical Science 2015;128:405–10]
So,
can normal-BMI diabetic individuals achieve remission through weight loss? To
test this hypothesis, ReTUNE study’s one-year data showed that in “T2D
individuals with BMIs 21 to 27 kg/m², 70 percent remission was achieved at an average threshold of
6.5 percent weight loss.” [
Clinical Science 2023;137:1333–46;
Diabetol
2021;51:24]
He
stressed that persons with T2DM should be treated as individuals and not with
cutoffs from epidemiology, as the latter is only a guide. “Personal fat thresholds
may vary individually and among different ethnic groups.”
Simplifying everything for use in the
clinics
“If
a patient asks, ‘What’s causing my diabetes?’ the answer is that basically one
is eating a little bit more than what one requires for energy to maintain the body
for many years. Despite claims that T2D has heterogeneous causes, T2D in genetically
diverse individuals is still tightly linked with overnutrition, as consistently
borne out by epidemiological data.”
The
genetic diversity notwithstanding, overnutrition leads to T2DM in genetically
susceptible individuals. That is, as Taylor explained, overnutrition drives two
underlying genetic risks: the tendency to exceed subcutaneous fat capacity and
the susceptibility of β cells to fat exposure—if either overnutrition or any of
these two genetic risks is absent in genetically predisposed groups such as
Filipinos, T2D does not happen.
An
implication of this process, he said, is that one can be obese without having T2D
if β cell susceptibility is absent. Hence, obesity is not synonymous with diabetes.
In the US and the UK, many obese individuals (eg, BMI above 40) of Caucasian
origin don’t have T2D. [
Lancet
Diabetes Endocrinol 2024;664–73]
Hammering home the durable effects of
remission
To
reiterate the impact of weight loss on TD2 remission on the long term, Taylor
cited again the DiRECT extension study’s five-year data, which showed better health
status for the intervention group, halving the rate of serious adverse events
when compared with routine care. [
Lancet Diabetes Endocrinol
2024;12:233–46]
How
about at an even longer period? Taylor offered the Look AHEAD trial, which demonstrated
that remission arising from lifestyle intervention for 12 years conferred substantially
lower incidence of CV and chronic kidney diseases when compared with
remission-free individuals. [
Diabetol 2024;67:459–69]
Final thoughts
“If
a person has gained weight in life and has true T2D, they are too heavy for
their own constitution. Weight loss is the answer. Taking this message to the
clinic allows one to shape therapy for the individual patient. Not everyone can
undergo procedures or take medicines to get the same benefits. In terms of
medical advance, this is the way of conferring future health.”
