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How excess dietary saturated fats induce insulin resistance

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  • Maui Memory Clinic

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Excess dietary saturated fatty acids can increase the risk of and progression of type 2 diabetes. We will explore the mechanisms by which excess saturated fatty acids can reduce insulin sensitivity, suppress insulin production of beta cells through glucolipotoxicity, raise blood glucose, and lessen energy production in cells. Higher dietary saturated fatty acids, especially palmitic acid, can reduce the number of insulin receptors to approximately one-half of their normal number. This contributes to hyperinsulinemia, elevated blood glucose, and reduced mitochondrial energy production. Higher dietary saturated fatty acids also interfere with the signaling between the insulin receptor and the glucose transporter. This reduces the amount of glucose that can enter the cell and increases the risk of elevated blood glucose. Excess dietary saturated fatty acids have been found to suppress insulin production of beta cells and also to stimulate apoptosis of beta cells. Higher dietary saturated fatty acids can reduce the ability of the cells to produce glycogen from glucose, thus lowering energy storage. Finally, higher dietary saturated fatty acids can reduce mitochondrial energy production. Conclusion: Reducing dietary saturated fatty acids may help clear blood of excess glucose in type 2 diabetes.
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International Journal of
Translational Science
REVIEW
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Int J Transl Sci. 2021;1(1):4
How excess dietary saturated fats induce insulin resistance
Director of Nutritional Neuroscience, Maui Memory Clinic, USA
Steve Blake* and Dustin Rudolph
Introduction
Type 2 diabetes has become increasingly more prevalent among
the general population, leading to signicant morbidity and
mortality for those diagnosed, not to mention the undue nancial
burden it puts on both patients and the healthcare system. We
set out to identify the role of dietary saturated fatty acids in the
pathogenesis of type 2 diabetes. Reduction of excess dietary
saturated fatty acids may be an underutilized treatment for type 2
diabetes mellitus.
Excess dietary saturated fatty acids increase insulin resistance,
raise blood sugar levels, and decrease cellular energy production
via multiple mechanisms. Excess saturated fatty acids interfere
with the transport of glucose molecules into skeletal muscle cells
by reducing the total number of insulin receptors available on the
cellular membrane by up to one-half. Excess saturated fatty acids
can also disrupt the cellular signaling cascade responsible for
glucose transport into the cell at the following junctions: insulin
receptor substrate phosphorylation, phosphatidylinositol-3-kinase
phosphorylation, protein kinase-B phosphorylation, and transport
of the glucose transporter-4 to the cellular membrane. This can
result in insulin resistance, increased blood glucose levels, and
decreased glycogen synthesis. Palmitic acid has been shown
to have the strongest eect in reducing insulin sensitivity and
decreasing glycogen synthesis.
Excess circulating levels of free saturated fatty acids lead to
glucolipotoxicity-induced beta cell insulin resistance and beta cell
apoptosis and subsequent drops in pancreatic insulin production.
Excessive intake of animal fats can increase circulating free
saturated fatty acids, decreasing insulin production by up to
30-60%. Also, increased abdominal fat can be released as free
saturated fatty acids into the portal bloodstream, reducing insulin
production due to beta cell apoptosis.
Saturated fatty acids interfere with glucose transport
into cells by insulin
Insulin promotes glucose uptake in insulin-responsive tissues
including liver cells, muscle cells, and adipose tissue. Insulin
stimulates a cascade of signaling processes initiated by the binding
of insulin to the protruding α-subunit of the insulin receptor on the
outer leaf (the plasma side) of the cellular membrane.
1. Insulin binding to the insulin receptor, a transmembrane
protein, elicits activation of the β-subunit of the insulin
receptor inside the cell.
2. Once activated, the β-subunit of the insulin receptor attracts
the insulin receptor substrate, which docks onto the insulin
receptor. Saturated fatty acids inhibit activation (tyrosine
phosphorylation) of the insulin receptor substrate.
3. The insulin receptor substrate then activates
phosphatidylinositol-3-kinase. Phosphatidylinositol-3-
kinase is associated with almost all of the metabolic actions
of insulin [1]. Excess saturated fatty acids can inhibit
phosphatidylinositol-3-kinase phosphorylation [2].
4. Phosphatidylinositol-3-kinase then phosphorylates protein
kinase B. Excess saturated fatty acids can decrease protein
kinase-B activation [3].
5. Phosphorylated protein kinase B moves glucose transporter-4
vesicles from the cytoplasm to the cell membrane surface,
Abstract
Excess dietary saturated fatty acids can increase the risk of and progression of type 2 diabetes. We will explore the mechanisms by
which excess saturated fatty acids can reduce insulin sensitivity, suppress insulin production of beta cells through glucolipotoxicity,
raise blood glucose, and lessen energy production in cells. Higher dietary saturated fatty acids, especially palmitic acid, can reduce
the number of insulin receptors to approximately one-half of their normal number. This contributes to hyperinsulinemia, elevated
blood glucose, and reduced mitochondrial energy production. Higher dietary saturated fatty acids also interfere with the signaling
between the insulin receptor and the glucose transporter. This reduces the amount of glucose that can enter the cell and increases the
risk of elevated blood glucose. Excess dietary saturated fatty acids have been found to suppress insulin production of beta cells and
also to stimulate apoptosis of beta cells. Higher dietary saturated fatty acids can reduce the ability of the cells to produce glycogen
from glucose, thus lowering energy storage. Finally, higher dietary saturated fatty acids can reduce mitochondrial energy production.
Conclusion: Reducing dietary saturated fatty acids may help clear blood of excess glucose in type 2 diabetes.
Keywords: diabetes; saturated fatty acids; insulin; glucolipotoxicity; palmitic acid; insulin receptors; hyperinsulinemia; elevated
blood glucose; beta cells; glycogen; mitochondrial energy production; toll-like receptor-4
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Int J Transl Sci. 2021;1(1):4
allowing cellular glucose uptake. The mineral chromium is
involved with movement of the glucose transporter-4 to the
cell surface [4].
6. Protein kinase B also activates glycogen synthase to
stimulate glycogen synthesis from glucose inside the cell.
Glycogen synthesis is inhibited by excess saturated fatty
acids [3] (Figures 1,2).
Once an insulin molecule has docked onto the cellular receptor and
eected its action, it may be released back into the extracellular
environment, or it may be degraded by the cell. Degradation
normally involves endocytosis of the insulin-receptor complex
followed by the action of insulin degrading enzyme. Interestingly,
this same insulin-degrading enzyme clears amyloid-beta from
the brain—unless it is depleted because of hyperinsulinemia [5].
Most insulin molecules are degraded by liver cells. It has been
estimated that a typical insulin molecule is fully degraded about
71 minutes after its initial release into circulation [1].
Saturated fatty acids increase insulin resistance and
increase glucose in blood
Saturated fatty acids are associated with insulin resistance and
glucose intolerance, which are signicant risk factors for type 2
diabetes. Myristic and palmitic acids were positively associated
with fasting insulin and increased glucose in blood. Stearic acid
was associated with increased glucose, but not increased insulin
[6].
The KANWU study included 162 healthy subjects chosen at
random to receive a controlled, isoenergetic diet for 3 months
containing either a high proportion of saturated or monounsaturated
fatty acids. Insulin sensitivity was 12.5 % lower on the saturated
fatty acid diet and 8.8 % higher on the monounsaturated fatty acid
diet (p = 0.03). Insulin secretion was not aected. These eects
were only seen at a total fat intake below 37% of total energy
intake. Above that level, insulin insensitivity was seen in both
groups [7].
Excesses of total fatty acids lead to insulin resistance. Excesses
of myristic, palmitic, stearic, and oleic acids have been implicated
in interfering with the signaling between the insulin receptor and
the glucose transporter GLUT-4. Palmitic acid has been found to
be the most powerful in decreasing insulin sensitivity. Interference
has been found with the insulin receptor substrate, protein
kinase-B, and phosphatidylinositol-3-kinase [8].
Excess dietary saturated fatty acids reduce the number
of insulin receptors
Excess dietary saturated fatty acids can lead to a sustained
downregulation of the expression of the insulin receptor [2].
Excess dietary saturated fatty acids lead to a lack of the HMGA1
gene, which transcribes a high-mobility group protein. Lack of
HMGA1 can suppresses biosynthesis of the insulin receptor [8].
Palmitic acid was shown to decrease insulin receptor expression
and activity. A two-fold decrease in the number of insulin receptors
in the cellular membrane was found with excess palmitate [2].
Palmitate inhibition of insulin receptor gene expression eectively
reduced the amount of insulin receptors in skeletal muscle cells.
This is in addition to the well-known interference shown by
saturated fatty acids in the signaling between the insulin receptor
and glucose transporter-4 [9].
The toll-like receptor-4 may be implicated in some, but
not all, routes to insulin resistance
Saturated fatty acids are thought to induce insulin resistance
partially through activation of the toll-like receptor-4, which
in turn transcriptionally activates hepatic ceramide synthesis
leading to inhibition of insulin signaling. However, toll-like
receptor-4 signaling is not directly required for impairment of
insulin-stimulated insulin receptor substrate signaling. Saturated
fat-induced insulin resistance may sometimes be independent of
TLR-4 activation and ceramides [10]. Toll-like receptor-4 may not
Figure 1: Removal of glucose from the bloodstream without excess
saturated fatty acids.
Figure 2: Impaired removal of glucose from the bloodstream with excess
saturated fatty acids.
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Int J Transl Sci. 2021;1(1):4
always be involved in saturated fat-induced insulin resistance [11].
Saturated fatty acids stimulated adipose tissue inammation by
a process that involved toll-like receptor-4. Toll-like receptor-4
binds bacterial lipopolysaccharides, also known as endotoxins.
Lipopolysaccharides come from cooked bacteria and may be found
in meat, dairy products, and sh. It has been seen that toll-like
receptor-4 deciency protected against insulin resistance in obesity
induced by a diet high in saturated fatty acids. This suggests that
toll-like receptor-4 is one link between excess dietary saturated
fatty acids and insulin resistance. Less diet-induced insulin
resistance and adipose tissue inammation have been observed in
mice with low function of their toll-like receptor-4 [12].
Excess dietary saturated fatty acids decreased the amount of
insulin-st
imulated glucose uptake. Inammation may play a role,
since saturated fats activated the nuclear transcription factor-κB
pathway and induced interleukin-6, tumor necrosis factor-α , and
monocyte chemoattractant protein-1 mRNA expressions. The
insulin-activated glucose uptake was reduced even though the mice
were decient in Toll-like re
ceptor-4, indicating another mechanism
may be involved [11]. However, in another study, saturated fatty
acids served as a naturally occurring ligand for toll-like receptor-4,
thereby inducing inammatory changes in both adipocytes and
macrophages through nuclear transcription factor-κB activation
[13].
Saturated fatty acids can suppress insulin production
By the time diabetes is diagnosed, half of the insulin-producing
cells may have suered apoptosis [14]. The remaining beta cells
can be inhibited by excess free saturated fatty acids. This can lower
their production of insulin. During rapid weight loss (or bariatric
surgery), over 8 weeks, these beta cells can start responding again
and producing insulin in response to need—relieving high blood
sugar [14].
Animal fats can increase circulating levels of free saturated fatty
acids. The beta cells that produce insulin in the pancreas can die
o from these free fatty acids from animal fats (30-60% decrease)
[15]. The beta cells die o principally as a result of damage to
the endoplasmic reticulum. There are then less beta cells to make
insulin. Oleic acid has been found to be protective, reducing beta
cell apoptosis from glucolipotoxicity induced by free saturated
fatty acids, diacylglycerols, and ceramides.
Saturated fatty acids released from adipose tissue can also reduce
insulin secretion by beta cells in the pancreas. Circulating levels
of free saturated fatty acids in the portal system can be increased
when there is increased abdominal fat. This abdominal fat can
create more free saturated fatty acids in the bloodstream, killing
o beta cells that produce insulin [16].
Blood sugar is burned for energy or stored as glycogen in muscle
cells. If there is an excess of glucose, liver cells can convert this
excess glucose into palmitic acid, a 16-carbon saturated fatty acid.
A constant excess of calories can lead to non-alcoholic fatty liver
disease. This excess fat in liver cells can later be turned into blood
sugar—thus raising fasting blood sugar levels [14].
Saturated fatty acids may impair energy production in
the mitochondria
In muscle cells, saturated free fatty acids induced mitochondrial
dysfunction. This mitochondrial dysfunction may be associated
with impaired glucose metabolism. These saturated fatty acids
reduced glucose oxidation and lactate production. Palmitic and
stearic acids impaired mitochondrial function as demonstrated by
a decrease in ATP generation [3].
Another way that excess free fatty acids may reduce energy
production is through a reduction in the number of mitochondria
in muscle cells. Exercise can ameliorate this eect of excess free
fatty acids in muscle cells by stimulating mitochondrial biogenesis
[17]—and burning free fatty acids. Another way to increase the
biogenesis of mitochondria is to reduce the amount of excess fatty
acids in muscle cells. Reduced excess fatty acids increase the
amount of peroxisome proliferator activated receptor-gamma co-
activator 1-alpha (PGC-1α). Higher amounts of PGC-1α stimulate
more mitochondrial biogenesis. Modest over-expression of PGC-
1α in muscle increases the glucose transporter GLUT4 expression
and increases insulin-stimulated glucose uptake [18].
Palmitic acid may inhibit the biosynthesis of glycogen
Saturated palmitic and stearic acids decreased insulin-induced
glycogen synthesis, thus reducing substrates for energy production
[3]. Glycogen is produced in the cell by the enzyme glycogen
synthase. Palmitate was found to impart a dose-dependent
inhibition of glycogen synthase activity in cultured muscle cells.
Inactivation of glycogen synthase could be the mechanism for
saturated long-chain fatty acid inhibition of insulin-mediated
carbohydrate storage. The presence of palmitate resulted in a
glycogen synthase activity that was 73% of the normal glycogen
synthase activity [19].
Chromium assists transport of glucose into the cell
Chromium improves insulin sensitivity in a variety of cellular and
animal models of insulin resistance. When sucient chromium is
present, there were enhanced levels of tyrosine phosphorylation
of insulin receptor substrate-1. Phosphorylation of protein
kinase-B was also increased. Presence of chromium also improved
phosphatidlinositol-3-kinase activity. Higher chromium levels
also increased levels of the glucose transporter-4 in the plasma
membrane [4].
Chromium has been observed to increase the uidity of the cell
membrane by decreasing membrane cholesterol. Chromium has
also been shown to cause an up-regulation of sterol regulatory
element-binding protein, a membrane-bound transcription factor
responsible for controlling cellular cholesterol balance [4].
Summary
Dietary saturated fatty acids play a central role in the development
and progression of type 2 diabetes. Reducing excessive dietary
saturated fats provides a safe and eective treatment strategy for
patients and clinicians wanting to target the root cause of insulin
resistance and type 2 diabetes. Without addressing this, it is
unlikely that disease reversal is possible. Diet and exercise remain
rst-line treatment options for type 2 diabetes, and are among the
most eective approaches to combatting this disease. The data
contained herein underscore the importance of dietary saturated fat
intake in the development of insulin resistance, and set the stage
for future dietary human interventional studies analyzing the direct
eects of saturated fat intake on the development, progression, and
potential reversal of type 2 diabetes.
Conict of interest and funding
The authors declare that there is no conict of interest and no
funding was used.
References
1. Neumann KF, Rojo L, Navarrete LP, Farías G, Reyes P, et al. Insulin
Resistance and Alzheimer´s Disease: Molecular Links & Clinical
Page 4 of 4
Int J Transl Sci. 2021;1(1):4
Implications. Curr Alzheimer Res. 2008; 5: 438-447.
2. Dey D, Mukherjee M, Basu D, Datta M, Roy SS, et al. Inhibition
of Insulin Receptor Gene Expression and Insulin Signaling by Fatty
Acid: Interplay of PKC Isoforms Therein. Cell Physiol Biochem.
2005; 16: 217-228.
3. Hirabara SM, Curi R, Maechler P. Saturated Fatty Acid-Induced
Insulin Resistance Is Associated With Mitochondrial Dysfunction in
Skeletal Muscle Cells. J Cell Physiol. 2010; 222: 187-194.
4. Hua Y, Clark S, Ren J, Sreejayan N. Molecular Mechanisms of
Chromium in Alleviating Insulin Resistance. J Nutr Biochem. 2012;
23: 313-319.
5. Blennow K, de Leon MJ, Zetterberg H. Alzheimer’s disease. The
Lancet. 2006; 368: 387-403.
6. Ebbesson SO, Tejero ME, López-Alvarenga JC, Harris WS, Ebbesson
LO, et al. Individual saturated fatty acids are associated with
dierent components of insulin resistance and glucose metabolism:
the GOCADAN study. Int J Circumpolar Health. 2010; 69: 344-351.
7. Vessby B, Uusitupa M, Hermansen K, Riccardi G, Rivellese
AA, et al. Substituting dietary saturated for monounsaturated
fat impairs insulin sensitivity in healthy men and women: The
KANWU study. Diabetologia. 2001; 44: 312-319.
8. Bhattacharya S, Kundu R, Dasgupta S, Bhattacharya S.
Mechanism of Lipid Induced Insulin Resistance: An Overview.
Endocrinol Metab. 2012; 27: 12-19.
9. Martins AR, Nachbar RT, Gorjao R, Vinolo MA, Festuccia WT,
et al. Mechanisms underlying skeletal muscle insulin resistance
induced by fatty acids: importance of the mitochondrial function.
Lipids Health Dis. 2012; 11: 30.
10. Galbo T, Perry RJ, Jurczak MJ, Camporez JP, Alves TC, et al.
Saturated and unsaturated fat induce hepatic insulin resistance
independently of TLR-4 signaling and ceramide synthesis in vivo.
Proc Natl Acad Sci U S A. 2013; 110: 12780-12785.
11. Zhou YJ, Tang YS, Song YL, Li A, Zhou H, et al. Saturated Fatty Acid
Induces Insulin Resistance Partially Through Nucleotide-binding
Oligomerization Domain 1 Signaling Pathway in Adipocytes. Chin
Med Sci J. 2013; 28: 211-217.
12. Chait A, Kim F. Saturated Fatty Acids and Inammation: Who Pays
the Toll?. Arterioscler Thromb Vasc Biol. 2010; 30: 692-693.
13. Suganami T, Tanimoto-Koyama K, Nishida J, Itoh M, Yuan X, et al.
Role of the Toll-like Receptor 4/NF-kB Pathway in Saturated Fatty
Acid–Induced Inammatory Changes in the Interaction Between
Adipocytes and Macrophages. Arterioscler Thromb Vasc Biol. 2007;
27: 84-91.
14. Taylor R. Reversing the twin cycles of Type 2 diabetes. Diabet
Med. 2013; 30: 267-275.
15. Cnop M. Fatty acids and glucolipotoxicity in the pathogenesis of
Type 2 diabetes. Biochem Soc Trans. 2008; 36: 348-352.
16. Estadella D, da Penha Oller do Nascimento CM, Oyama LM, Ribeiro
EB, Dâmaso AR, et al. Lipotoxicity: Eects of Dietary Saturated and
Transfatty Acids. Mediators Inamm. 2013; 2013: 137579.
17. Jornayvaz FR, Shulman GI. Regulation of mitochondrial
biogenesis. Essays Biochem. 2010; 47: 69-84.
18. Eckardt K, Taube A, Eckel J. Obesity-associated Insulin Resistance
in Skeletal Muscle: Role of Lipid Accumulation and Physical
Activity. Rev Endocr Metab Disord. 2011; 12: 163-172.
19. Mott DM, Stone K, Gessel MC, Bunt JC, Bogardus C. Palmitate
action to inhibit glycogen synthase and stimulate protein phosphatase
2A increases with risk factors for type 2 diabetes. Am J Physiol
Endocrinol Metab. 2008; 294: E444-E450.
*Correspondence: Steve Blake, ScD, Director of Nutritional
Neuroscience, Maui Memory Clinic, P O Box 81426, Haiku, HI, USA,
Tel: (808) 280-6894, E-mail: steve@drsteveblake.com
Rec: 11 Sep 2021; Acc: 18 Oct 2021; Pub: 22 Oct 2021
Int J Transl Sci. 2021;1(1):104
DOI: 10.36879/IJTS.21.000104
Copyright © 2021 e Author(s). is is an open-access article
distributed under the terms of the Creative Commons Attribution 4.0
International License (CCBY).
... Furthermore, inappropriate consumption of saturated fat in animal-based food products may associate with negative human health effects, such as the risk of cardiovascular diseases and other physiological disorders (Blake & Rudolph, 2021;Hooper et al., 2020;Shingfield et al., 2013), although the negative impact of saturated fat is becoming increasly challenged, particularly for dairy foods (Givens, 2022). Moreover, Vasilopoulou et al. (2020) showed that compared to conventional dairy products, a human diet containing dairy products (milk, hard cheese, and butter) with a proportion of the saturated fatty acids replaced with monounsaturated fatty acids showed potentially beneficial effects on fasting low-density lipoprotein (LDL) cholesterol, and endothelial function although it is not known whether this was due to all three dairy products. ...
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Increased plasma levels of free fatty acids (FFA) occur in states of insulin resistance such as obesity and type 2 diabetes mellitus. These high levels of plasma FFA are proposed to play an important role for the development of insulin resistance but the mechanisms involved are still unclear. This study investigated the effects of saturated and unsaturated FFA on insulin sensitivity in parallel with mitochondrial function. C2C12 myotubes were treated for 24 h with 0.1 mM of saturated (palmitic and stearic) and unsaturated (oleic, linoleic, eicosapentaenoic, and docosahexaenoic) FFA. After this period, basal and insulin-stimulated glucose metabolism and mitochondrial function were evaluated. Saturated palmitic and stearic acids decreased insulin-induced glycogen synthesis, glucose oxidation, and lactate production. Basal glucose oxidation was also reduced. Palmitic and stearic acids impaired mitochondrial function as demonstrated by decrease of both mitochondrial hyperpolarization and ATP generation. These FFA also decreased Akt activation by insulin. As opposed to saturated FFA, unsaturated FFA did not impair glucose metabolism and mitochondrial function. Primary cultures of rat skeletal muscle cells exhibited similar responses to saturated FFA as compared to C2C12 cells. These results show that in muscle cells saturated FFA-induced mitochondrial dysfunction associated with impaired insulin-induced glucose metabolism.