Type 2 Diabetes and Prediabetes:
A New Understanding of Cause and Treatment
Bruce Latham, M.D.
Endocrine Specialists
Greenville Health System
Objectives for this presentation
- Understand the “thrifty genotype and
thrifty phenotype” hypothesis as to
the origin of insulin receptor signaling
pathway mutations in patients with type 2 diabetes
- Review the new hypothesis as to the cause of
pre-diabetes and type 2 diabetes
- Understand why bariatric surgery and extreme
diets can reverse type 2 diabetes
- Briefly review current research for diagnosis
and treatment of type 2 diabetes
Types of Diabetes
Type 1 diabetes – autoimmune destruction of
beta cells in the islets of Langerhans in
the pancreas
Type 2 diabetes – chronic hyperglycemia resulting
from insulin receptor signaling
pathway gene mutations
LADA (latent autoimmune diabetes of adulthood)
Diabetes due to pancreatic destruction
(pancreatitis, pancreatic resection)
Other genetic causes (Leprechaunism, MODY, etc)
Definition of pre-diabetes and diabetes
Pre-diabetes: Two finger stick glucoses of 100-125
HbA1c 5.7-6.4
Post glucola (2hr) glucose 140-199
Diabetes:
Two finger stick fasting glucoses
of 126 or higher
HbA1c 6.5 or higher
Post glucola (2hr) glucose >200
What causes pre-diabetes and diabetes?
Is it obesity?
Is it genetics?
Is it bad life-style?
One size does not fit all
The Paradox…
- 85 percent of diabetics are overweight
- but only 30 percent of overweight people
have type 2 diabetes
and 15 percent of type 2 diabetics
have a normal BMI
Obesity is not the cause of diabetes
To understand the cause, we need to review
insulin action
Only two organs need insulin to internalize glucose:
Skeletal muscle
Fat
The key: both are involved in energy utilization:
Skeletal muscle transforms chemical energy (glucose)
to mechanical work on a “as needed” basis.
Fat provides free fatty acids (FFA) for conversion to
ATP in mitochondria during prolonged periods of energy
need or during periods of fasting.
There are over 150 known mutations in the
insulin receptor or receptor signaling pathway
that lead to insulin resistance.
Most mutations are detrimental to the
survival of the organism.
If this is the case, why are there so
many mutations in this signaling pathway?
Hypothesis:
These mutations may have once been beneficial
to Homo sapiens
The “thrifty phenotype” hypothesis
The “thrifty genotype” hypothesis
Possible etiology of pre-diabetes and type 2 diabetes
“Thrifty genotype” hypothesis
Possible etiology of type 2 diabetes
Thrifty phenotype hypothesis
Babies with low birth weight (less than
4.3 kg, especially those less than 2.5 kg)
have a 7x higher incidence of impaired
glucose or Type II diabetes as adults than
those who were heaviest at birth.
This is thought due to poor fetal nutrition
leading to in utero genetic reprogramming
for insulin resistance to increase the
chance of surviving poor postnatal
nutrition.
These adaptations are beneficial if the individual
experiences poor nutrition postnatally
Example: very low incidence of diabetes in subSaharan Africa: poor fetal nutrition + poor postnatal
nutrition =no diabetes.
These adaptations are most detrimental if the
individual has poor fetal nutrition + good postnatal
nutrition = high incidence of diabetes, especially if
obese as an adolescent or adult
Examples:
Pima Indians
Nauru Islanders: “coca-colonization”
Europeans:
Until recently incidence was decreasing
until “glowing pixels of light” and extreme
life spans.
Patients with type 2 diabetes also have a greatly
increased risk for NASH (non-alcoholic steatosis
and hepatitis; i. e. severe fatty liver and liver failure)
In one autopsy series, obesity and/or diabetes was
found in 20 of 22 patients who died with NASH.
Prerequisites for development of pre-diabetes
and type 2 diabetes
- Insulin receptor signaling pathway gene defect
- High organ (visceral) fat (liver and pancreas)
concentrations. Subcutaneous fat not important.
High organ fat – pancreas and liver
High liver fat – leads to impaired
down-regulation of gluconeogenesis and
and glycogenolysis and later, NASH
High pancreas fat – (later) decreased insulin production
Interventional Therapies
Weight Reduction in patients without diabetes
Finnish Diabetes Prevention Study (522 subjects)
Diabetes Prevention Study (U.S.) (3243 subjects)
Patients treated with:
Regular moderate exercise (2.5-3 hrs/wk)
“Optimal” diet (low simple carbs, more dietary
fiber, less saturated fat)
7% weight loss over 3 years
58% fewer people developed type II diabetes
than in the control groups.
Interventional Therapies
Weight reduction in patients without diabetes
Da Qing trial (577 subjects)
Three treatment groups: diet, exercise, or both
After 6 years, risk reduction
of developing T2DM 31%, 46%, and 42%,
respectively
(Pan XR, et.al. Diabetes Care 1997, 537-44.)
Interventional Therapies
Weight reduction in patients with
diabetes
• 11 patients with type 2 DM (age 49+/-2.5; BMI 36; 9 male
2 female). 8 non-diabetic control pts
• 600 kcal diet for 8 weeks
• Pancreatic and hepatic fat measured by MRI after 1, 4 and
8 weeks.
• Insulin suppression of hepatic glucose production,
1st phase insulin response measured
Lim KG et. al. Reversal of type 2 diabetes: normalisation of beta cell function in association with decreased pancreas and liver
triacylglycerol. Diabetologia (2011) 54:2506–2514
Interventional Therapies
Weight reduction in patients with
diabetes
Results
• After 1 week, fasting plasma glucose normalized
• Insulin suppression of hepatic glucose improved from
43% to 74%.
• Hepatic triacylglycerol fell from 12% to 2.9%
• 1st phase pancreatic insulin response improved from
.19 nmol/min/m to .46 nmol/min/m.
• Maximal insulin response became supranormal at
8 weeks (1.36 vs. 1.15 nmol/min/m controls)
• Pancreatic triacylglycerol decreased from 8 to 6.2
nmol/min/m
Interventional Therapies
Weight reduction in patients with
diabetes
Bariatric surgery
136 studies; 22094 patients. 18% men, 72% women
-Mean age 39 years; mean BMI 46.9 (range 32.368.8)
-Gastric banding, gastric bypass, gastroplasty,
biliopancreatic diversion or duodenal switch
Operative mortality .1% for restrictive procedures,
.5% for gastric bypass, 1.1% for biliopancreatic
diversion or duodenal switch
(Buchwald, et. al. JAMA 292, Oct. 13, 2004)
Interventional Therapies
Weight Reduction
Bariatric surgery
Diabetes completely resolved in 76.8%;
resolved or improved in 86%.
Hyperlipidemia improved in 70%.
Hypertension resolved in 62% or resolved
or improved in 78.5%
Sleep apnea resolved in 86% and resolved
or improved in 83%.
Interventional Therapies
Current Research
2, 4, dinitrophenol
• Blocks oxidative phosphorylation in mitochondria
• Causes “runaway” consumption of hepatic fat –
conversion to heat rather than to ATP
• Once used for weight loss; banned in the 1930’s
due to deaths from severe hyperthermia
• Still abused by some athletes today to promote rapid
weight loss
In the Zucker diabetic rat, can treatment with
small amounts of 2,4 dinitrophenol reverse diabetes?
When given in very small amounts to these rats,
it caused a
• 40% reduction in fasting glucose
• 50% reduction in plasma insulin concentration
• 90% reduction in hepatic diacylglycerol (fatty acids)
Perry RJ, et.al. Science. 2015 Mar 13;347(6227):1253-6.
What is the concentration of pancreatic and hepatic fat
that is associated with the onset of type 2 diabetes?
So, how does this new information influence
day to day treatment algorithms of type 2
diabetes?
Diabetes treatment algorithms are rapidly changing…
First, metformin
(inhibits hepatic gluconeogenesis;
weight neutral)
Then…what?
Older therapies:
Insulin injections
Sulfonylurea oral agents
often cause weight gain – leading to
increased insulin resistance
Interventional Therapies
Newer diabetic medications which cause weight loss:
GLP-1 agonists: exenatide (Byetta), liraglutide
(Victoza), dulaglutide (Trulicity), etc.
SGLT 2 inhibitors: dapagliflozin (Farxiga),
canagliflozin (Invokana), empagliflozin
(Jardiance)
Take Home Points
• Obesity itself does not cause type 2 diabetes.
• Type 2 diabetes is the result of an insulin receptor
or receptor pathway mutation in some individuals,
present from birth.
• It is the combination of the mutation – along with visceral
fat – that may lead to type 2 diabetes.
• The visceral fat content needed to cause type 2 diabetes is
not yet known.
• Weight loss and exercise can prevent and may reverse
diabetes in some if not most individuals.
Take Home Points
Prediabetes and type 2 diabetes are diseases of our times.
The rapid change in human culture from hunter-gatherers to the
agricultural age, and now the industrial age has made a once
apparently beneficial mutation in our genetic code a detriment.
Because of the rapid nature of our cultural change,
we as a species have not had time to adapt to our
new environment. Since those of us in western societies
no longer eat or exercise as our distant ancestors did,
this mutation has left many at risk for cardiovascular
disease and type II diabetes.