Download Unravelling Insulin Resistance

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• Perhaps the single point that deserves the most emphasis
is that insulin resistance is not a disease, but the
description of a physiologic state that greatly increases the
chances of an individual developing several closely related
abnormalities and associated clinical syndromes.
•
Reaven, G.The metabolic syndrome or the insulin resistance syndrome? Different names,
different concepts, and different goals. Endocrinol Metab Clin N Am, 2004, Vol. 33, pp. 283-303.
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• Should there be any disturbances to the binding of
insulin to the receptors, or of the receptor response to
insulin, there will be reduced insulin activity, or insulin
resistance.
•
Cosford, R. Insulin resistance, obesity and diabetes: the connection. J Aust Coll Nutr Env Med, 1999,
Vol. 18, No. 1, pp. 3-10.
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• Thus, by definition, insulin resistance is a defect in signal
transduction.
•
Pessin, JE. and Saltiel, AR. Signaling pathways in insulin action: molecular targets of insulin
resistance. J Clin Invest, 2000, Vol. 106, No. 2, pp. 165-169.
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INSULIN
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• First discovered in 1921 by
Sir Fredrick Banting and
Charles Herbert Best.
• One of the smallest proteins
in the body that is built from
51 amino acids.
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INSULIN PROTEIN
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Beta Cells
• Insulin is secreted
in the pancreas by
Beta-cells (-cells)
found in the Islets
of Langerhans.
Pancreas
Insulin
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• Islets of Langerhans are irregular clusters of endocrine
cells that are scattered throughout the tissue of the
pancreas that secrete insulin and glucagon.
•
Editors of the American Heritage® dictionaries, 2000 The American Heritage Dictionary of the English
Language, Fourth Ed., Houghton Mifflin Company, Boston.
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• Insulin functions in the regulation of the metabolism of
carbohydrates and fats, especially the conversion of
glucose to glycogen, which lowers the blood glucose level.
•
Editors of the American Heritage® dictionaries, 2000 The American Heritage Dictionary of the English
Language, Fourth Ed., Houghton Mifflin Company, Boston.
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Insulin
Glucose
• Insulin Receptor
Insulin
Receptor
Glucose
Transporters
Insulin Receptor
Substrates
Phosphatidylinositol-3 Kinase
Protein Kinase B
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KinaseIn biochemistry, a kinase is a type of enzyme that transfers
phosphate groups from high-energy donor molecules, such
as ATP, to specific target molecules (substrates); the
process is termed phosphorylation. An enzyme that
removes phosphate groups from targets is known as a
phosphatase.
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Insulin
• Insulin signalling is triggered
by binding of insulin to its
receptor in the plasma
membrane of the cell.
•
Biddinger, SB. and Kahn, CR. From mice to men:
insights into the insulin resistance syndromes.
Annu Rev Physiol, 2006, Vol. 68, pp. 123-158.
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Alpha
Units
Beta Sub Units
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Insulin
• The receptor phosphorylates
several proximal substrates
– including members of the
insulin receptor substrate
(IRS) family.
•
Bryant, NJ. et al. Regulated transport of the glucose
transporter GLUT4. Nature Rev Mol Cell Biol, 2002,
Vol. 3, pp. 267-77.
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Insulin Receptor Substrate
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IRS Proteins
• The IRS proteins act as important mediators of insulin
action. Their regulation serves to augment the specificity of
the insulin signalling cascade.
•
Johnston, AM. et al. Molecular mechanisms of insulin receptor substrate protein-mediated
modulation of insulin signalling. FEBS Letters, 2003, Vol. 546, pp. 32-36.
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• Tyrosine phosphorylated IRS
proteins recruit more effector
molecules, such as
Phosphatidylinositol-3 Kinase
(PI3k).
Insulin Receptor Substrate
Phosphatidylinositol-3 Kinase
•
Bryant, NJ. et al. Regulated transport of the
glucose transporter GLUT4. Nature Rev Mol Cell
Biol, 2002, Vol. 3, pp. 267-77.
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Phosphatidylinositol-3 kinase (PI3k)
• PI3k has a pivotal role in the metabolic and mitogenic
actions of insulin and Insulin Growth Factor 1 (IGF-1).
Inhibitors of class 1a PI3k block most metabolic actions of
insulin, including stimulation of glucose transport,
glycogen and lipid synthesis.
•
Saltiel, AR. and Kahn, CR. Insulin signalling and the regulation of glucose and lipid metabolism.
Nature, 2001, Vol. 414, No. 6865, pp. 799-806.
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• PI3k activates the serinethreonine kinase Akt/Protein
Kinase B (PKB).
Phosphatidylinositol-3
Kinase
•
Pessin, JE. et al. Signalling pathways in insulin
action: molecular targets of insulin resistance, J
Clin Invest, 2000, Vol. 106, pp. 165-69.
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Akt/PKB
• The membrane bound form of Akt in 3T3-L1 adipocytes
results in increased glucose transport and persistent
localisation of Glucose Transport-4 (GLUT4) to the plasma
membrane.
•
Biddinger, SB. and Kahn, CR. From mice to men: insights into the insulin resistance syndromes.
Annu Rev Physiol, 2006, Vol. 68, pp. 123-58.
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• Insulin stimulates
increased glucose
transport by causing the
redistribution of GLUT4
from an intracellular pool
to the cell surface where it
acts as a facilitative
transporter to enhance
entry of glucose into the
cell.
•
Glucose
Glucose
Transporters
Nystrom, FH. and Quon, MJ. Insulin signalling:
metabolic pathways and mechanisms for
specificity. Cell Signal, 1999, Vol. 11, No. 8, pp.
563-574.
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GLUTS (Glucose Transport Proteins)
• GLUT1- is widely distributed in foetal tissues. In the adult,
it is expressed at highest levels in erythrocytes and also in
the endothelial cells of barrier tissues such as the bloodbrain barrier.
• GLUT2- is expressed by liver and pancreatic β cells.
• GLUT3- is an isoform expressed mostly in neurons where
it is believed to be the main glucose transporter isoform.
• GLUT4- is the insulin-regulated glucose transporter found
in adipose and muscle tissue that is responsible for insulinregulated glucose disposal.
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• In the absence of stimulation, GLUT4 is almost completely
excluded from the plasma membrane. The addition of
insulin, or exercise in the case of muscle cells, causes
GLUT4 to shift from its intracellular location to the plasma
membrane.
•
Bryant, NJ. et al. Regulated transport of the glucose transporter GLUT4. Nature Rev Mol Cell Biol,
2002, Vol. 3, pp. 267-77.
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• Once the glucose pathway is opened by GLUT4, glucose is
polymerised (many sugars linked together) within the cell.
Under normal conditions it is then broken down as required
to meet the body’s energy needs.
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Receptor Defects
Post Receptor Defects
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• Over Nutrition
• Obesity
−Adipose Tissue
−Free Fatty Acids
• Inflammation
−Tumour Necrosis Factor (TNF-)
−Interleukin-6 (IL-6)
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• High carbohydrate diets decrease insulin receptor
numbers, probably as a result of increased cellular contact
with insulin and resultant insulin receptor down regulation.
•
Cosford, R. Insulin resistance, obesity and diabetes: the connection. J Aust Coll Nutr Env Med, 1999,
Vol. 18, No. 1, pp. 3-10.
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• Diets high in saturated fats and trans fatty acids have been
shown to decrease membrane fluidity and decrease insulin
receptor binding, thus promoting insulin resistance.
•
Cosford, R. Insulin resistance, obesity and diabetes: the connection. J Aust Coll Nutr Env Med, 1999,
Vol. 18, No. 1, pp. 3-10.
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• An acquired loss of PI3k activation in muscle is also seen
as a result of a high fat diet.
•
Kahn, BB. and Flier, JS. Obesity and insulin resistance. J Clin Invest, 2000, Vol. 106, No. 4, pp. 473-481.
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• Picture of centrally obese man
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• Obesity is the most common cause of insulin resistance
and type 2 diabetes.
•
Petersen, KF. and Shulman, GI. Eitiology of insulin resistance. Am J Med, 2006, Vol. 119, No. 5a, pp.
10s-16s.
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• Central (intra abdominal) deposits of fat are more strongly
linked to insulin resistance, type 2 diabetes and
cardiovascular disease than are peripheral
(gluteal/subcutaneous) fat deposits.
•
Kahn, BB. and Flier JS. Obesity and insulin resistance. J Clin Invest, 2000, Vol.106, No. 4, pp. 473-481.
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• Hotamisligil suggested that obesity appears to be a state of
chronic inflammation with increased production of
cytokines and other acute-phase reactants that play a
crucial role in regulation of systemic insulin action.
•
Bloomgarden, ZT. Inflammation and Insulin Resistance, Diab Care, 2004, Vol 26(5), pp. 1619-23.
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• Adipocytes have recently been shown to be dynamic
endocrine cells that produce and secrete various bioactive
molecules (known as adipokines or adipocytokines), some
of which affect the insulin sensitivity of other tissues.
•
Kanda, H. et al. MCP-1 contributes to macrophage infiltration into adipose tissue, insulin
resistance, and hepatic steatosis in obesity. J Clin Invest, 2006, Vol. 116, No. 6, pp. 1494-1505.
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• Insulin resistance that accompanies obesity is attributable,
at least in part, to changes in adipokine secretions.
•
Kanda, H. et al. MCP-1 contributes to macrophage infiltration into adipose tissue, insulin
resistance, and hepatic steatosis in obesity. J Clin Invest, 2006, Vol. 116, No. 6, pp. 1494-1505.
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• The release of a wide variety of molecules including
hormones such as leptin, cytokines such as TNF- and
substrates such as free fatty acids (FFA’s) allow the
adipose organ to play a major regulatory role in energy
balance and glucose homoeostasis.
•
Kahn, BB. and Flier, JS. Obesity and insulin resistance. J Clin Invest, 2000, Vol. 106, No. 4, pp. 473-481.
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• Elevated FFA’s impair insulin’s ability to suppress hepatic
glucose output, stimulate glucose uptake into skeletal
muscle and inhibit insulin secretion from pancreatic -cells.
•
Kahn, BB. and Flier, JS. Obesity and insulin resistance. J Clin Invest, 2000, Vol. 106, No. 4, pp. 473-481.
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• In humans, the triglyceride content of muscle correlates
directly with the degree of insulin resistance.
•
Kahn, BB. and Flier, JS. Obesity and insulin resistance. J Clin Invest, 2000, Vol. 106, No. 4, pp. 473-481.
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• Increasing evidence from human population studies and
animal research has established correlative as well as
causative links between chronic inflammation and insulin
resistance.
•
Xu, H. et al. Chronic inflammation in fat plays a crucial role in the development of obesity-related
insulin resistance. J Clin Invest, 2003, Vol. 112, No. 12, pp. 1821-1830.
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• TNF-, IL-6 and undoubtedly other pro- or antiinflammatory cytokines appear to participate in the
induction and maintenance of the subacute inflammatory
state associated with obesity.
•
Shoelson, SE. et al. Inflammation and insulin resistance. J Clin Invest, 2006, Vol. 116, No. 7, pp. 1793801.
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TNF-
• Adipose tissue expression of TNF- is increased in humans
and is positively correlated with adiposity and insulin
resistance.
•
Kershaw, EE. and Flier, JS. Adipose tissue as an endocrine organ. J Clin Endocrinol Metab, 2004, Vol. 89,
No. 6, pp. 2548-2556.
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•
TNF- is raised in adipocytes in obesity and has been
shown to:
− Inhibit insulin stimulated tyrosine phosphorylation of
the IRS
− Stimulate down regulation of the IRS
− Stimulate down regulation of insulin-sensitive glucose
transporters.
•
Cosford, R. Insulin resistance, obesity and diabetes: the connection. J Aust Coll Nutr Env Med,
1999, Vol. 18, No. 1, pp. 3-10.
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IL-6
• Adipose tissue IL-6 expression and circulating
concentrations are positively correlated with obesity,
impaired glucose tolerance and insulin resistance.
•
Kahn, BB. and Flier, JS. Obesity and insulin resistance. J Clin Invest, 2000, Vol. 106, No. 4, pp. 473-481.
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• IL-6 decreases insulin signalling in peripheral tissues by:
– Reducing expression of insulin receptor signalling
components
– Inducing suppressor of cytokine signalling 3 (SCS3), a
negative regulator of insulin signalling.
•
Kershaw, EE. and Flier, JS. Obesity and insulin resistance. J Clin Endocrinol Metab, 2004, Vol. 89, No. 6,
pp. 2458-56.
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Over Nutrition
IL-6
TNF-
Obesity
FFA’s &
High Fat Diets
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HERBS
• Botanical products can improve glucose metabolism and
the overall condition of individuals with diabetes not only
by hypoglycaemic effect but also by improving lipid
metabolism, antioxidant status and capillary function.
•
Khan, A. et al. Cinnamon improves glucose and lipids of people with type 2 diabetes. Diab Care,
2003, vol. 26, No. 12, pp. 3215-3218.
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• Cinnamon, also known as Sweet Wood and Gui Zhi is
traditionally harvested in Asian countries. It is, perhaps,
one of the oldest herbal medicines, having been mentioned
in Chinese texts as long as 4000 years ago.
•
Qin, B. et al. Cinnamon extract potentiates in vivo insulin-regulated glucose utilisation via
enhancing insulin signalling in rats. Diab Res Clin Pract, 2003, Vol. 62, pp. 139-48.
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• Significant reduction of plasma glucose after four months
of treatment was observed in the Cinnamon group but not
in the placebo.
•
Mang, B. et al. Effects of a cinnamon extract on blood glucose in db/db mice. J Ethnopharm, 2006,
Vol. 104, pp. 119-123.
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• Cinnamon activates insulin receptor kinase and inhibits
dephosphorylation of the insulin receptor, leading to
maximal phosphorylation of the insulin receptor.
•
Khan, A. et al. Cinnamon improves glucose and lipids of people with type 2 diabetes. Diab Care,
2003, Vol. 26, No.12, pp. 3215-3218.
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• Results reveal that Cinnamon administration increases the
IRS-1/ PI3k association; therefore, this change results in
PI3k activation.
•
Qin, B. et al. Cinnamon extract prevents the insulin resistance induced by a high-fructose diet.
Horm Metab Res, 2004, Vol. 36, pp. 119-125.
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• Sushruta (6th Century B.C.)
and practitioners of Ayurveda
have recommended the use of
the ‘sala saadi’ group for
maturity onset diabetes in
addition to dietary restrictions.
•
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Baskaran, K. et al. Antidiabetic effect of a leaf
extract of gymnema sylvestra in NIDDM patients.
J Ethnopharm, 1990, Vol. 30, pp. 295-305.
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• Gymnemic acid inhibits glucose absorption from the small
intestine and suppresses the increase in plasma glucose
levels.
•
Porchezhian, E. and Dobriyal, RM. An overview on the advances of gymnema sylvestre: chemistry,
pharmacology and patents. Pharmazie, 2003, Vol. 58, No. 1, pp. 5-12.
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• Gymnema’s major mode of action is via permeabilisation of
-cell plasma membranes, leading to up-regulated loss of
insulin from the cells.
•
Persaud, SJ. et al. Gymnema sylvestra stimulates insulin release in vitro by increased membrane
permeability. J Endocrinol, 1999, Vol. 163, pp. 207-212.
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• In humans there are no descriptions of alpha Lipoic acid
(ALA) deficiency; however, lower concentrations have been
found in patients with acne vulgaris, neurodermatitis, liver
cirrhosis, advanced arteriosclerosis, psoriasis, different
types of polyneuropathy, and diabetes.
•
Konrad, T. et al. Alpha Lipoic acid treatment decreases serum lactate and pyruvate concentrations
and improves glucose effectiveness in lean and obese patients with type 2 diabetes. Diab Care,
1999, Vol. 22, pp. 280-287.
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• Findings now demonstrate that oxidants produced by ALA
are involved in:
– Activation of insulin receptor
(Cho, KJ. et al. Alpha Lipoic acid decreases
thiol reactivity of the insulin receptor and protein tyrosine phosphatase 1B in 3T3-L1
adipocytes. Biochem Pharmacol, 2003, Vol. 66, pp. 849-858.)
– Increased tyrosine phosphorylation of IRS-1
– Activation of PI3k and serine-threonine kinase Akt1
– Translocation of glucose transporters GLUT 1 & 4 (Konrad, D.
et al. The antihyperglycemic drug alpha Lipoic acid, stimulates glucose uptake via both
GLUT-4 translocation and GLUT-4 activation. Diabetes, 2001, Vol. 50, pp. 1464-1471.)
Leading to elevated glucose uptake into 3T3-L1 adipocytes.
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alpha Lipoic acid
PI3k
p38 MAPK
Akt
GLUT4
Translocation
GLUT4
Activation
Stimulation of glucose uptake
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• In both muscle and adipocyte cells ALA mimics insulin
action in stimulating glucose uptake via a pathway
requiring PI3k activity.
•
Estrada, D. et al. Stimulation of glucose uptake by the natural coenzyme alpha Lipoic acid /
thioctic acid. Diabetes, 1996, Vol. 45, pp. 1798-1804.
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3.5
Troglitazone
Insulin
2
Lipoic Acid
1.5
1
Metformin
0.5
0
Control
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Co
Gly
MET
La
Ins
Glyburide
TRO
mmol/l
3
2.5
69
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• Microscopic analysis showed that Chromium (Cr) treatment
for 16hrs increased the basal-state level of GLUT4 in the
plasma membrane and insulin’s effect was enhanced in the
presence of Cr.
•
Chen, G. et al. Chromium activates glucose transporter 4 trafficking and enhances insulin
stimulated glucose transport in 3T3-L1 adipocytes via a cholesterol dependant mechanism. Mol
Endocrinol, 2006, Vol. 20, pp. 857-70.
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• Microscopic and biochemical data show clearly that
chromium elicits an insulin like accumulation of GLUT4 at
the plasma membrane in 3T3-L1 adipocytes.
•
Chen, G. et al. Chromium activates glucose transporter 4 trafficking and enhances insulin
stimulated glucose transport in 3T3-L1 adipocytes via a cholesterol dependant mechanism. Mol
Endocrinol, 2006, Vol. 20, pp. 857-70.
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• Alterations of Magnesium (Mg) metabolism induce and/or
exacerbate insulin resistance which is confirmed by data in
humans, showing that dietary induced Mg deficiency is
correlated with insulin resistance.
•
Barbagallo, M. and Dominguez, LJ. Magnesium metabolism in type 2 diabetes, metabolic syndrome
and insulin resistance. Arch Biochem Biophys, 2006, Epub ahead of print.
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• Mg depletion induces a severe insulin resistance that is
shown to be dependent, at least in part, upon a defective
tyrosine kinase activity of the insulin receptors.
•
Barbagallo, M. et al. Role of magnesium in insulin action, diabetes and cardio-metabolic syndrome
X. Mol Aspect Med, 2003, Vol. 24, pp. 39-52.
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• Zinc ions have an insulin-like (insulinomimetic) effect. A
particularly sensitive target of zinc ions is protein tyrosine
phosphatase 1B (PTP 1B), a key regulator of the
phosphorylation state of the insulin receptor.
•
Haase, H. and Maret, W. Protein tyrosine phosphatases as targets of the combined insulinomimetic
effects of zinc and oxidants. Biometals, 2005, Vol. 18, No. 4, pp. 333-338.
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• Vitamin D3 not only facilitates the biosynthetic capacity of
-cells but also accelerates the conversion of pro-insulin to
insulin.
•
Chiu, KC. et al. Hypovitaminosis D is associated with insulin resistance and beta cell dysfunction.
AJCN, 2004, Vol. 79, pp. 820-825.
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• Observations in the current study suggests that increasing
Vitamin D from 10 to 30ng/mL can improve insulin
sensitivity by 60%.
•
Chiu, KC. et al. Hypovitaminosis D is associated with insulin resistance and beta cell dysfunction.
AJCN, 2004, Vol. 79, pp. 820-825.
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• Furthermore, the 60% improvement in insulin sensitivity
that results from Vitamin D treatment indicates that it is
more potent than either Troglitazone or Metformin
treatment.
•
Chiu, KC. et al. Hypovitaminosis D is associated with insulin resistance and beta cell dysfunction.
AJCN, 2004, Vol. 79, pp. 820-825.
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• Results show that Biotin increases insulin secretion in
normoglycaemic and hyperglycaemic conditions.
•
Romero-Navarro, G. et al. Biotin regulation of pancreatic glucokinase and insulin in primary
cultured rat islets and in biotin-deficient rats. Endocrinol, 1999, Vol. 140, pp. 4595-45600.
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• Biotin enhances glucose induced insulin secretion by
elevating ATP synthesis in pancreatic Islets of Langerhans.
•
Sone, H. et al. Biotin enhances ATP synthesis in pancreatic cell islets of the rat, resulting in
reinforcement of glucose-induced insulin secretion. Biochem Biophys Res Comm, 2004, Vol. 314, pp.
824-829.
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FISH OIL
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• Polyunsaturated fatty acids (PUFA’s), especially total n-3 fatty acids,
were independently associated with lower levels of pro-inflammatory
markers (IL-6, TNF-) and higher levels of anti-inflammatory markers,
independent of confounders. Findings support the notion that n-3 fatty
acids may be beneficial in patients affected by diseases characterised
by active inflammation.
•
Ferruci, L. et al. Relationship of plasma polyunsaturated fatty acids to circulating inflammatory markers. J Clin
Endocrinol Metab, 2006, Vol. 91, pp. 439-446.
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• Exercise training reverses insulin resistance by enhancing
the recruitment of GLUT4 to the cell surface.
•
Cosford, R. Insulin resistance, obesity and diabetes: the connection. J Aust Coll Nutr Env Med, 1999,
Vol. 18, No. 1, pp. 3-10.
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Cinnamon
•
•
•
Activates insulin receptor kinase
Maximises phosphorylation of insulin receptor
PI3k activation
Chromium
•
Increases GLUT4 translocation
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alpha Lipoic acid
•
•
•
•
Activates insulin receptor
Increased tyrosine phosphorylation of IRS-1
Activation of PI3k and serine-threonine kinase Akt
Translocation of glucose transporters GLUT 1 & 4
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Magnesium
• Depletion causes reduced tyrosine kinase activity at the
insulin receptor
Zinc
• Affects phosphorylation at the insulin receptor
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Zinc
Magnesium
alpha Lipoic acid
Cinnamon
Chromium
Exercise
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Gymnema
•
•
•
Increases insulin release from -cells
Inhibition of glucose absorption from small intestine
Increases permeabilisation of -cell plasma membranes
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Vitamin D
•
•
Facilitates the biosynthetic capacity of -cells
Helps with the conversion of insulin to pro-insulin
Biotin
•
Increases insulin secretion
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Gymnema
Pancreas
Biotin
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Vitamin D
96
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