Glucose Regulation

The Science Behind

Revisited
Detoxification
Dr.Subtitle
Bryan Walsh
OVERVIEW
1. A Different Way to Look At Insulin
Resistance
2. How to evaluate glucose regulation
3. Clinical and Therapeutic Interventions
A New Paradigm of Insulin
Resistance: Oxidative Stress and
Cellular Defense
These findings indicate that while insulin resistance is associated
with multiple deficiencies, the most deleterious defects and the
origin of insulin resistance occur independently of IRS.

Moreover, such defects may occur as a consequence of an

alternate initial defect possibly to sustain the insulin resistant
state.
 A major advance
mitochondrial O2 is of the present
upstream of IRstudy is themuscle
in skeletal observation
and adipose
that •−

tissue.

This hypothesis is exciting for a number of reasons. For example, it

suggests that IR may be a protective mechanism, in which case
we should perhaps reconsider using therapeutic strategies to
overcome unless they also eliminate the primary defect.
 The β-cell is particularly vulnerable to glucolipotoxicity. Other
tissues, such as heart and skeletal muscle, that express the insulin-
regulated glucose transporter GLUT4 have the capacity to protect
themselves from glucolipotoxicity by developing IR, which restrains
glucose entry into cells and therefore the glucose arm of this
potentially damaging process.
The combination of high levels of glucose and FFA entry into cells will overload
the electron transfer chain with reducing equivalents resulting in mitochondrial
dysfunction and increased reactive oxygen species (ROS) production. The
increased glucose entry will also alter the malonyl-CoA/AMPK metabolic
network to favor the partitioning of the FFA toward synthesis of complex lipids,
including cholesterol and ceramide, and glucolipotoxicity, contributing to both
mitochondrial dysfunction and endoplasmic reticulum stress. The increased FFA
levels will also impede glucose oxidation, particularly at the level of pyruvate
dehydrogenase, such that glucose flux into pathways above this step, including
glycogen synthesis, the polyol and hexosamine pathways, and the production of
advanced glycation end product (AGE) precursors, are likely to be increased.
SUMMARY
• Excess oxidative stress appears to not only
precede insulin resistance, but insulin resistance
may be a defense mechanism to reduce cell
damage and the accumulation of ROS
A New Paradigm of Insulin
Resistance: Insulin Independent
Glucose Uptake
GLUCOSE EFFECTIVENESS

• Glucose Effectiveness (SG) is the capacity of

glucose to enhance its own cellular uptake and
to suppress endogenous glucose production.

• In relatively small studies, SGhas been shown to

predict future diabetes, but its contribution to
the development of diabetes remains largely
unknown.
 Glucose effectiveness (SG) is the ability of glucose per se to
stimulate its own uptake and to suppress its own production under
basal/constant insulin concentrations. In an individual, glucose
tolerance is a function of insulin secretion, insulin action and SG.
Under conditions of declining insulin secretion and action (e.g. type
2 diabetes), the degree of SG assumes increasing significance in
determining the level of glucose tolerance both in fasted and
postprandial states.
There is an assumption that apart from enhancing insulin
secretion, GLP-1 increases SG via centrally mediated action in
brain hypothalamus.
NON-INSULIN MEDIATED GLUCOSE UPTAKE
• Insulin mediated glucose uptake (IMGU), occurs only in
insulin-sensitive tissues (i.e. liver, muscle and
adipocytes).

• Non-insulin mediated glucose uptake (NIMGU), occurs in

both insulin-sensitive and non-insulin-sensitive tissues
(i.e., brain, blood cells, nerve, etc.).

• In experimental models, NIMGU has been defined

as uptake of glucose at zero insulin concentrations.

• In the fasting state NIMGU accounts for about 83%

of whole body glucose disposal
Hyperglycemia increases glucose flux into muscle cell by the
mass action effect. This effect is insulin-independent and
therefore probably occurs through GLUT1.
 Thus, the common feature for the insulin resistance induced by
obesity, inflammation and infection or hyperglycemia is enhanced
glucose transport through GLUT1 and availability for the formation
of hexosamines. These can reduce muscle GLUT4 and hexokinase II
activity leading to a decrease in insulin-mediated glucose transport.
 Chronic IL-1β infusion in rats resulted in fasting hypoglycemia and
elevated blood glucose levels in response to oral glucose.

These observations can be explained by increased glucose transport

through GLUT1 in a fasting state, and decreased GLUT4 action
during hyperinsulinemia.
 Most studies that have shown an effect of insulin on
increasing glucose transport into muscle have used high
concentrations of insulin outside the physiological range.

Results of the experiments showed that only 15% of ingested

glucose leaves the liver over three hours. In diabetics, who are
insulin resistant, the restraining effect of insulin on hepatic glucose
production is impaired and increased glucose production causes
hyperglycemia.
Our results also emphasize the importance of the effect of insulin on
glucose production in diabetes, which has been largely ignored.
SUMMARY
• Hyperglycemia may not be due to poor glucose
disposal at the level of skeletal muscle myocytes
or adipocytes, but rather excess production of
hepatic glucose
• Questionable effects of insulin and glucose disposal
in skeletal muscle and adipocytes
 A New Paradigm of
Insulin Resistance:
The True Role of Insulin?
The effects of continuous infusions of insulin in physiologic doses on glucose
kinetics and circulating counter-regulatory hormones were determined in
normal subjects and diabetics.

With the lower insulin infusion dose, plasma insulin rose two- to threefold,
plasma glucose initially fell at a rate of 0.37±0.04 mg/min for 75 min and
stabilized at 67±3 mg/dl after 75 min. The changes in plasma glucose were
entirely a result of a fall in glucose output and subsequent return to base
line, whereas glucose uptake remained unchanged. Plasma levels of
counter- regulatory hormones showed no change from basal throughout
the insulin infusion.
 In the diabetic group, the initial fall in plasma glucose was almost entirely a
result of suppression of glucose output, which showed a twofold greater
decline (60±6%) than in controls (27±5%, P <0.01) and remained suppressed
throughout the insulin infusion. In contrast, the late stabilization in plasma
glucose was a result of a fall in glucose uptake to values 50% below basal (P <
0.001) and 39% below that observed in controls at termination of the insulin
infusion (P < 0.01).
 We conclude that (a) in the postabsorptive state, NIMGU is the major
pathway for glucose disposal for both C and NIDDM; (b) for a given glucose
level the efficiency of NIMGU (NIMGU divided by serum glucose level) is
equal in C and NIDDM, but since basal Rd is elevated in NIDDMs their
absolute basal rates of NIMGU are higher; and (c) elevated basal rates of
NIMGU in NIDDM may play a role in the pathogenesis of the late
complications of diabetes.
 In normal subjects, ∼75% of glucose disposal (Rd) under euglycemic
conditions occurs as a result of NIMGU, primarily in the central nervous
system and, to a lesser extent, in other tissues such as the splanchnic bed,
blood cells, the peripheral nerves, and skeletal muscle. Under hyperglycemic
conditions, the proportion of NIMGU occurring in skeletal muscle increases
substantially.

We found that GLP-1 resulted in an ∼15% increase in glucose

disposal.
 A New Paradigm of
Insulin Resistance:
If Not Insulin, Then
What?!?!
Glucagon and GCGRs should be considered as potential targets for treatment of
type 2 diabetes. It is expected that GCGR blockade alone, may provide clinical
benefits by reducing hyperglycemia, improving or resetting insulin sensitivity
and β-cell function, and preventing type 2 diabetic cardiovascular and renal
complications.
A NEW PARADIGM
1. Energy Excess: too many calories and/or lack of
exercise (or xenobiotics, or infection)
2. Hyperinsulinemia
3. Increased lipogenesis (fatty acid synthesis) and
TAG synthesis in pancreatic islet cells
4. Ceramide (toxic) and palmitate synthesis
and accumulation
5. Beta-cell apoptosis and alpha-cell insulin
resistance
• Decreased insulin production and elevated
glucagon production
A NEW PARADIGM
1. Overconsumption of calories and/or lack of
exercise
2. Insulin hyper-secretion
3. Increased lipogenesis (fatty acid synthesis) and
TAG synthesis in islet cells of the pancreas
4. This leads to ceramide accumulation (toxic)
5. Beta-cell apoptosis and insulin resistance in
alpha- cells
• Poor insulin production with elevated
glucagon production
CURRENT “KNOWLEDGE” OF INSULIN

• Major metabolic regulator

• Facilitates entry of glucose into muscle, adipose
and several other tissues
• Increases glycogenesis
• Increases lipogenesis, decreases lipolysis
• Decreases proteolysis
• Stimulates glycolysis
• Stimulates cholesterol synthesis
• DNA, growth factors, etc.
CURRENT “KNOWLEDGE” OF INSULIN

• Intraislet insulin suppresses

glucagon!
A NEW PARADIGM
Should we continue to focus exclusively on
lowering serum glucose (with insulin)?
Recent large randomized trials looking at intensive glycemic control have
either shown no benefit (Action in Diabetes and Vascular Disease: Preterax
and Diamicron Modified Release Controlled Evaluation [ADVANCE] and
Veterans Affairs Diabetes Trial [VADT]) or increased all cause mortality
(Action to Control Cardiovascular Risk in Diabetes [ACCORD])
Evolutionary Benefit of Insulin
Resistance
The "thrifty gene" and "thrifty phenotype" hypotheses constitute the dominant
paradigm for over four decades. With an increasing understanding of the
diverse effects of impairment of the insulin signaling pathway, the existing
hypotheses are proving inadequate.

We propose a hypothesis that insulin resistance is a socio-ecological adaptation

that mediates two phenotypic transitions, (i) a transition in reproductive
strategy from "r" (large number of offspring with little investment in each) to
"K" (smaller number of offspring with more investment in each) and (ii) a
transition from "stronger to smarter" or "soldier to diplomat" i.e. from
relatively more muscle dependent to brain dependent lifestyle.
EVOLUTIONARY ORIGINS OF INSULIN RESISTANCE
• Insulin metabolism is likely to have evolved as
a mechanism of differential energy allocation
to different tissues (i.e. brain, placenta/fetus)
• Perhaps insulin resistance evolved as a socio-
ecological and socio-nutritional adaptation,
rather than thriftiness
• Alters the behavioral and reproductive strategies of
an individual
• r to K strategist and “stronger to smarter” explains
almost all physiological findings of insulin
resistance
R TO K STRATEGIST
• “r” = Rate
• Faster reproduction by large number of
offspring, investing little in each
• Favorable when opportunities for expansion, and
minimal competition
• “K” = carrying capacity of environment for species
• K strategist produces fewer offspring, but invests more
in each
• Favorable when population is close to carrying
capacity and fewer opportunities for survival
R TO K STRATEGIST
• Insulin resistance during pregnancy increases
fetal birth weight (more investment in baby)
• Insulin resistance also reduces ovulation
(PCOS), decreasing chances of additional
pregnancies

• Evidence that insulin resistance may be associated

with longevity in some animal studies, but more
study is needed
“STRONGER TO SMARTER” OR “SOLDIER TO DIPLOMAT”
• Insulin resistance may be due to a decreased
reliance on skeletal muscle utilization of glucose, to
an increased brain utilization of glucose
• Intense brain activities might increase insulin levels
and insulin receptors in neural tissue, but that level
of insulin would cause hypoglycemia elsewhere,
which is detrimental for brain function
• Perhaps peripheral insulin resistance develops to
protect against hypoglycemia in response to higher
insulin demands by the brain
Stress hyperglycemia is common in critically ill patients and appears to be a
marker of disease severity. Furthermore, both the admission as well as the
mean glucose level during the hospital stay is strongly associated with patient
outcomes. Clinicians, researchers and policy makers have assumed this
association to be causal with the widespread adoption of protocols and
programs for tight in-hospital glycemic control. However, a critical appraisal of
the literature has demonstrated that attempts at tight glycemic control in both
ICU and non-ICU patients do not improve health care outcomes.

We suggest that hyperglycemia and insulin resistance in the setting of

acute illness is an evolutionarily preserved adaptive responsive that
increases the host’s chances of survival. Furthermore, attempts to
interfere with this exceedingly complex multi-system adaptive response
may be harmful.
Following thermal injures, trauma and sepsis, non-insulin mediated
glucose uptake is increased. The majority of the increased glucose uptake
occurs in macrophage rich tissues.

These data suggest that the increased energy requirements of activated

macrophages and neutrophils during infection and tissue injury are regulated
by enhanced cellular glucose uptake related to the increased glucose diffusion
gradient and increased expression of glucose transporters.

Iatrogenic normalization of blood glucose may therefore impair immune

and cerebral function at a time of crises.
Here we hypothesize that insulin resistance promotes glucose availability for the
inflammatory response in the defense against starvation, disease and trauma
and to promote growth during lactation, pregnancy, puberty and cancer, and in
situations where the organism prepares itself for migration or hibernation. This
mechanism is evolutionarily well preserved in multiple species, including the
human organism. It is also likely that in other insulin resistance states like
chronic inflammatory illnesses (chronic obstructive pulmonary disease,
rheumatoid arthritis etc.), insulin resistance is initially beneficial in promoting
the inflammatory response and healing.
This beneficial role of insulin resistance has consequences for treatment and
research. Forcing glucose into oxidative pathways by liberal administration of
insulin deprives the organism of glucose for synthetic and anti-oxidative
pathways, which is actually suggested by recent findings showing that in ICU
patients late initiation of parenteral nutrition was associated with lower
insulin infusion rates, faster recovery and fewer complications.
Insulin resistance increases glucose availability for brain metabolism. It also
increases salt and water retention and sympathetic tone and induces
endothelial dysfunction, favoring an increase in blood pressure, obviously
beneficial when trauma occurs. Similarly, the increased coagulability and
decreased fibrinolysis associated with insulin resistance are defensive
mechanisms against bleeding.
But more important is that insulin resistance favors obesity, protecting against
starvation, and obesity contributes to a proinflammatory state through the
secretion of several cytokines, contributing to the defense against infection,
and possibly to the development of functional hyperandrogenism and PCOS.
SUMMARY
• Oxidative stress  mitochondrial dysfunction 
insulin resistance
• Inflammation  ceramide (DAG) accumulation
 mitochondrial dysfunction, ER stress and
insulin resistance
• Energy excess  ROS  insulin resistance as a
defense mechanism
• Hyperglycemia appears to be less about glucose
uptake/disposal and more about glucose
production
• Insulin less involved in glucose disposal, more
involved in the suppression of glucagon.
Glycemic Variability – End of the
A1C Era?
GLYCEMIC VARIABILITY
GLYCEMIC VARIABILITY
GLYCEMIC VARIABILITY
• Increased oxidative stress
• Increases oxidative stress in adipocytes leading
to less adiponectin and more resistin (highly
pro- inflammatory)
• Hypoglycemic tendencies
• Inflammation
• Decreased brown adipocyte thermogenesis
• Association between obesity and glycemic
variability
• Decreased HRV (women)
• Micro- and macrovascular complications
• Mood, depression, and poor quality of life
Patients with similar mean glucose or glycosylated hemoglobin (HbA1c)
values can have markedly different daily glucose profiles, with differences
both in number and duration of glucose excursions.

In vitro, animal and human studies in experimental settings consistently

report a deleterious effect of intermittent high glucose, either larger than or
as large as constant high glucose, despite less total glucose exposure.

In comparison to the long-acting analog insulin glargine, the glucagon-like

peptide-1 receptor agonist exenatide reduced glucose variability with a
similar reduction in HbA1c.
In this study, we have been able to show that oscillating glucose, over a
period of 24 h, is more damaging to endothelial function than stable
constant high glucose. This is true not only when a subject is exposed to the
same total amount of glucose for 24 h (i.e., 10 mmol/l clamp) but even
when the total amount is higher (i.e., 15 mmol/l clamp). Finally, data
suggest that oxidative stress plays a key role in all of these phenomena.
The role of glucose variability from peaks to nadirs is less documented, but
there are many reasons to think that both upward (postprandial) and
downward (interprandial) acute fluctuations of glucose around a mean
value activate the oxidative stress.

As a consequence, it is strongly suggested that a global antidiabetic

strategy should be aimed at reducing to a minimum the different
components of dysglycemia (i.e., A1C, fasting and postprandial glucose, as
well as glucose variability).

All the therapeutic agents that act on postprandial glucose excursions seem
of particular interest for reducing the latter parameter (i.e., the glucose
instability).

Particular attention should be paid to such emerging therapeutic agents as

the glucagon-like peptide 1 agonists and the dipeptidyl peptidase (DPP)-IV
inhibitors that act through the incretin pathway.
Subjects with a GA/A1c ratio >/=2.8 and FCPR index <3.0 showed the
greatest SD and longest durations of hypoglycaemia, while those with a
GA/A1c ratio
<2.8 and FCPR index >/= 3.0 had smaller SDs and little sign of
hypoglycaemia.
UTILITY OF GLYCOMARK?
In multivariable logistic regression analysis, the HbA1c values did not indicate
a predictive value for the prevalence of CAD. In contrast, the 1,5-AG levels
were still an independent predictor of CAD (adjusted odds ratio 0.96, 95%
confidence interval 0.93-0.99, P = 0.0097). Serum 1,5-AG is superior to HbA1c
for predicting CAD prevalence in patients without diabetes mellitus.
Even moderate elevations in HbA(1c) substantially lower 1,5-AG, suggesting
that it can be most discriminating in identifying patients with excessive
postprandial glucose excursions at HbA(1c) levels that approach the upper
end of the normal range.
1,5-AG is not only correlated with basal insulin sensitivity and secretion,
but also closely associated with early-phase insulin secretion in Chinese
patients with newly diagnosed type 2 diabetes mellitus.
Therapeutic
Interventions
• Should we seek to increase glucose disposal and
lower fasting glucose A1C?
INCREASE GLUCOSE DISPOSAL?
• Lipoic Acid - GLUT-4
• Chromium - insulin receptors
• Cinnamon - insulin receptors
• Banaba leaf - decreases hepatic
gluconeogenesis, insulin-like glucose transport,
ppar-alpha (liver), ppar-gamma (adipose)
• Berberine - AMPK, insulin receptors, inducing
glycolysis, promoting glucagon peptide-1
release, inhibiting DPP-4, inhibiting hepatic
gluconeogenesis
• Myricetin - IRS-1, PI3-Kinase, GLUT 4
(Post receptor insulin signaling)
• Gymnema - reducing glucose absorption,
regenerates beta cells, endogenous
insulin production
• Fish oil - insulin sensitivity in skeletal muscle
• Nopal - high soluble fiber and pectin,
intestinal glucose absorption,
• Salacia Oblong - alpha-glucosidase inhibitor,
ppar- alpha
• Green Tea - upregulates glycogenesis,
downregulate glycogenolysis, protects
against glycation,
• Bilberry - insulin sensitivity
• American Ginseng - insulin sensitivity
• Glucomannan - water-soluble dietary
fiber, glucose absorption
• Bitter Melon - structurally similar to
insulin
• Vanadium - mimics insulin
• Holy Basil - increases insulin secretion
• Fenugreek - stimulates insulin secretion
THERAPEUTIC GOALS
1. Increase GLP-1 2.Support mitochondrial
• Suppresses
glucagon biogenesis and function
• Increases  Reduce oxidative
insulin stress
production
• Decreases B-cell 3.Improve insulin secretion
apoptosis and sensitivity
• Increases B-cell
proliferation 4. Suppress glucagon
• Decreases gastric
emptying 5. Optimize bile
• Increases satiety
• Increases
INCREASE GLUCOSE DISPOSAL
1. Exercise
• Decreases NAD+/NADH ratio intracellularly
• Increases GLUT-4 translocation in skeletal muscle
• Supports insulin sensitivity
• Increases mitochondrial function and biogenesis
• Increases glucose intracellular utilization and
thus increasing glucose into the cell isn’t a bad
thing
THERAPEUTIC GOALS
1. Increase GLP-1 2.Support mitochondrial
• Suppresses
glucagon biogenesis and function
• Increases  Reduce oxidative
insulin stress
production
• Decreases B-cell 3.Improve insulin secretion
apoptosis and sensitivity
• Increases B-cell
proliferation 4. Suppress glucagon
• Decreases gastric
emptying 5. Optimize bile
• Increases satiety
• Increases
INCREASE GLP-1

GLP-1 stimulators: • Fiber

• Pea protein • Digestion-
(250mg/kg) resistant
• EPA/DHA (1-2 grams) fiber/starch
• Bile acid • Fructans and
• Berberine (500mg BID)
• Chewing food oligofructos
• Glutamine (30 grams) e
• Quercetin • Olive leaf
Compared with 15 chews, 40 chews resulted in lower energy intake and
postprandial ghrelin concentration and higher postprandial glucagon-like
peptide 1 and cholecystokinin concentrations in both lean and obese subjects.
SUPPORT MITOCHONDRIAL FUNCTION
1. Exercise - favors healthy • PQQ Pyrroloquinoline
mitochondria and also quinone
stimulates their – 20mg
biogenesis
2. Diet - Low • NAC - reduce ROS, reverse
carbohydrate diet, mitochondrial
moderate protein, high depolarization, complexes I,
vegetable intake IV and V
(Complex III and IV) • Phospholipid replacement
3. Nutritional – lecithin or formula
Supplementatio
n
• CoQ10 – 50-
300mg
• ALA – 200-
SUPPRESS GLUCAGON
• Gamma amino butyric acid
(GABA)
• With meals
Daily GABA injections initiated 7 d before streptozotocin (STZ) treatment
prevented β-cell loss. Thus, β-cell mass was preserved, whereas α-cell mass was
reduced. Consistently, GABA-treated mice showed higher circulating insulin,
lower glucagon, nearly normal glycemia, and improved metabolic conditions,
and maintained close to normal glucose tolerance, during a period of 53 d
after STZ injections.
GABA treatment increased grafted β-cell proliferation, while decreasing
apoptosis, leading to enhanced β-cell mass. This was associated with
increased circulating human insulin and reduced glucagon levels. Importantly,
GABA administration lowered blood glucose levels and improved glucose
excursion rates.
Gamma aminobutyric acid (GABA) exerts β-cell regenerative and
immunoregulatory effects. Specifically, GABA stimulates β-cell replication,
protects β-cells against apoptosis, and attenuates insulitis. These effects result
in an enhanced functional β-cell mass and, in mice, this can reverse disease
Twelve subjects were subjected to an open-labeled, three-period trial
involving sequential oral administration of placebo, 2 g GABA once, and 2 g
GABA three times/day for 7 days, with a 7-day washout between each
period. GABA was rapidly absorbed (Tmax: 0.5 ~ 1 h) with the half-life (t1/2)
of 5 h.

GABA significantly increased circulating insulin levels in the subjects under

either fasting or fed conditions. GABA also increased glucagon levels only
under fasting conditions.

Importantly, GABA significantly decreased glycated albumin levels in

the repeated dosing period.
STEP 1 - GLYCOMARK
If Glycomark is <15 µg/mL:
1. Focus on diet – quality of food
(macronutrient ratio) and quantity of
food
2. GLP-1 stimulators (pre-meal)
1. Fish oil
2. Pea protein, glutamine
3. Quercetin
4. Bile acid support
5. MUFA
6. Chew food thoroughly
7. Olive leaf extract
*Glycomark is NOT affected by
reactive hypoglycemia
STEP 2 – HEMOGLOBIN A1C
If HbA1C is above 5.3%:
1. Exercise – skeletal muscle contraction +
steady state cardio
2. Diet – macronutrient ratio, quantity of food
• Paleo-Mediterranean
3. Supplementation
• Berberine, Alpha-lipoic acid
STEP 3 – C-PEPTIDE
If C-peptide is above 2.5* (with or without
elevated A1C):
1. Mitochondrial support
• Low carbohydrate diet
• Exercise
• CoQ10, ALA, Carnitines, NAC, Phospholipids
*Ask “what is the survival benefit” (toxin
exposure) If C-peptide is below 1.1 + elevated
A1C:
2. GABA
3. Gymnema, banaba leaf, bitter melon, vanadium,
EXAMPLES
Case #1 Case #3
• Glucose: Normal • Glucose: Normal
• Glycomark: Low • Glycomark:
• A1C: Normal Normal
• C-Peptide: Normal • A1C: High
• C-Peptide: High
Case #2
• Glucose: Normal Case #4
• Glycomark: • Glucose: Normal
Normal • Glycomark:
• A1C: Normal Normal
• C-Peptide: High • A1C: High
EXAMPLES
Case #5 Case #6
• Glucose: High • Glucose: High
• Glycomark: Low • Glycomark: Low
• A1C: High • A1C: High
• C-Peptide: High • C-Peptide: Low

Case #7 Case #8
• Glucose: Normal • Glucose: Normal
• Glycomark: • Glycomark:
Normal Normal
• A1C: Normal • A1C: High
• C-Peptide: High • C-Peptide: Low
SUMMARY
• Decrease oxidative stress and
increase/support mitochondrial function
• Support beta cell function, decrease
glucolipotoxicity, increasing proliferation, decreasing
apoptosis
• Suppress glucagon – GABA, optimize GLP-1
(gut function, bile)
• Increase glucose disposal and increase
insulin sensitivity*