Download Metabolic pathology, alterations of S/F in

Pathophysiology
• JP Advis DVM, Ph.D.
Bartlett Hall, Animal Sciences, Cook,
932 - 9240, [email protected]
23
• Course website: rci.rutgers.edu/~advis
• Lectures, tests, grades, office hours, textbook,
Lectures 1-2: Introduction to Pathophysiology (2)
Lectures 3-4: Mechanisms of Self-Defense and Stress (2)
Lectures 5-8: Endocrine and Nervous System Dysfunctions (4)
Lecture
9: Alterations of Skeletal Muscle Function (1)
REVIEW AND TEST #1
Lectures 12-18: Cardiovascular, Respiratory and Renal Dysfunctions (7)
REVIEW AND TEST #2
Lectures 21-24: Alterations of Digestive Function and Intermediary Metabolism (4)
Lectures 25-26: Alterations of the Reproductive System (2)
REVIEW AND TEST #3
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Introduction
Structure / Function
pancreatic insulin and
glucagon, adrenal cortisol,
GH axis and GH abuse
Metabolic syndrome
insulin resistance, compensatory hyperinsulinemia, DM
and vascular diseases
Diabetes and Obesity
risk factor & consequences,
hormonesrelated to their
complications
Link to other diseases
metabolic syndrome,
coronary heart disease,
diabetes mellitus type 2,
polycystic ovarian syndrome
Page 1
Introduction
Structure / Function
pancreatic insulin and
glucagon, adrenal cortisol,
GH axis and GH abuse
Metabolic syndrome
insulin resistance, compensatory hyperinsulinemia, DM
and vascular diseases
Diabetes and Obesity
risk factor & consequences,
hormonesrelated to their
complications
Link to other diseases
metabolic syndrome,
coronary heart disease,
diabetes mellitus type 2,
polycystic ovarian syndrome
Page 2
Introduction
Structure / Function
pancreatic insulin and
glucagon, adrenal cortisol,
GH axis and GH abuse
Metabolic syndrome
insulin resistance, compensatory hyperinsulinemia, DM
and vascular diseases
Diabetes and Obesity
risk factor & consequences,
hormonesrelated to their
complications
Link to other diseases
metabolic syndrome,
coronary heart disease,
diabetes mellitus type 2,
polycystic ovarian syndrome
Page 3
Introduction
Structure / Function
pancreatic insulin and
glucagon, adrenal cortisol,
GH axis and GH abuse
glycogen phosphorilase
insulin resistance, compensatory hyperinsulinemia, DM
and vascular diseases
glucose
G-6-P
F - 1,6 -diP
F-1,6-diPase
triose
glucose
PFK
insulin
glucagon
epinephrin
cortisol
pyruvate
transaminases
acetyl CoA
amino acids
Link to other diseases
metabolic syndrome,
coronary heart disease,
diabetes mellitus type 2,
polycystic ovarian syndrome
hexokinase
F-6-P
Diabetes and Obesity
risk factor & consequences,
hormonesrelated to their
complications
glycogen synthetase
G-1-P
G-6-Pase
Metabolic syndrome
glycogen
proteins
Page 4
Krebs
cycle
fats
Glycogen
glycogen phosphorilase
glycogen synthetase
G-1-P
G-6-Pase
hexokinase
G-6–P
glucose
glucose
F-6-P
F - 1,6 -diP
F-1,6-diPase
PFK
triose
insulin
glucagon
epinephrine
cortisol
pyruvate
transaminases
acetyl CoA
amino acids
proteins
Krebs
cycle
Introduction
Structure / Function
pancreatic insulin and
glucagon, adrenal cortisol,
GH axis and GH abuse
Metabolic syndrome
insulin resistance, compensatory hyperinsulinemia, DM
and vascular diseases
Diabetes and Obesity
risk factor & consequences,
hormonesrelated to their
complications
Link to other diseases
metabolic syndrome,
coronary heart disease,
diabetes mellitus type 2,
polycystic ovarian syndrome
Page 5
fats
Introduction
Structure / Function
pancreatic insulin and
glucagon, adrenal cortisol,
GH axis and GH abuse
Metabolic syndrome
insulin resistance, compensatory hyperinsulinemia, DM
and vascular diseases
Diabetes and Obesity
risk factor & consequences,
hormonesrelated to their
complications
Link to other diseases
metabolic syndrome,
coronary heart disease,
diabetes mellitus type 2,
polycystic ovarian syndrome
Page 6
Metabolic syndrome
Structure / Function
pancreatic insulin and
glucagon, adrenal cortisol,
GH axis and GH abuse
Metabolic syndrome
insulin resistance, compensatory hyperinsulinemia, DM
and vascular diseases
Diabetes and Obesity
risk factor & consequences,
hormonesrelated to their
complications
Link to other diseases
metabolic syndrome,
coronary heart disease,
diabetes mellitus type 2,
polycystic ovarian syndrome
A state of metabolic dysregulation characterized by insulin
resistance, hyperinsulinemia and a predisposition to type 2
diabetes, atherosclerosis, vascular disease, hypertension and
many other disorders, including Alzheimer’s disease and
certain cancers.
Affected individuals are obese or show subtle manifestation of
increase adiposity (abdominal fat, fat cell size), decrease capacity of exercise and evidence of low grade inflammation and
pro-coagulant state. Type 2 diabetes develops when they are
no longer able to sustain the high insulin levels required for
normal glucose homeostasis.
Clinically, it is diagnosed on the basis of abnormalities in
plasma glucose and lipids, and increases in blood pressure
and waist circumference, which independently might not be
sufficient to lead to therapeutic intervention. Its importance is
that: 1) antedates the multiple disorders with which it is
associated; 2) it might be a target for therapeutic intervention,
and 3) it is extremely common (50 millions in the USA alone).
Page 7
Metabolic dysfunctions
Structure / Function
obesity, overnutrition, diet
genetics
inactivity
pancreatic insulin and
glucagon, adrenal cortisol,
GH axis and GH abuse
metabolic dysregulation
(peripheral, CNS)
Metabolic syndrome
insulin resistance, compensatory hyperinsulinemia, DM
and vascular diseases
Diabetes and Obesity
risk factor & consequences,
hormonesrelated to their
complications
diabetes
hypertension
insulin resistance
hyperinsulinemia
ectopic lipid
certain
cancers
Alzheimer
Link to other diseases
proinflammatory
and procoagulant
states
metabolic syndrome,
coronary heart disease,
diabetes mellitus type 2,
polycystic ovarian syndrome
atherosclerosis
dyspipidemia
non-alcoholic
fatty liver disease,
non-alcoholic
steatohepatitis,
polycyctic ovarian
syndrome
Metabolic dysfunctions
Structure / Function
pancreatic insulin and
glucagon, adrenal cortisol,
GH axis and GH abuse
Metabolic syndrome
insulin resistance, compensatory hyperinsulinemia, DM
and vascular diseases
Diabetes and Obesity
risk factor & consequences,
hormonesrelated to their
complications
Link to other diseases
metabolic syndrome,
coronary heart disease,
diabetes mellitus type 2,
polycystic ovarian syndrome
The presence of insulin resistance in otherwise normal offspring
of people with type 2 diabetes, hypertriglyceridemias, and hypertension has led to the notion that is a causal factor for metabolic
syndrome or an early pathogenic event.
According to this idea, insulin resistance affects a number of
organs (muscle, liver, adipose), and hyperinsulinemia due to
increase pancreatic secretion and decrease insulin degradation
by the liver, is a compensatory phenomenon.
This idea is in agreement with observations that treatments
increasing insulin sensitivity and lowering plasma insulin, such
as life-style modification (diet and exercise) and treatment with
metformin ot thiazolidinediones, prevent or delay the onset of
diabetes in individuals with glucose intolerance, as well as the
efficacy of these therapies in individuals with non-alcoholic fatty
liver disease (NAFLD) and polycystic ovarian syndrome (PCOS).
Insulin resistance and hyperinsulinemia in humans and animals
have been linked to obesity and dysregulation of cellular lipid
metabolism. FFA cause insulin resistance in muscle, but newly
discovered hormones and intracellular regulators also do it.
Page 8
Metabolic dysfunctions
Structure / Function
pancreatic insulin and
glucagon, adrenal cortisol,
GH axis and GH abuse
Metabolic syndrome
insulin resistance, compensatory hyperinsulinemia, DM
and vascular diseases
Diabetes and Obesity
risk factor & consequences,
hormonesrelated to their
complications
Link to other diseases
metabolic syndrome,
coronary heart disease,
diabetes mellitus type 2,
polycystic ovarian syndrome
Page 9
Metabolic dysfunctions
Structure / Function
pancreatic insulin and
glucagon, adrenal cortisol,
GH axis and GH abuse
obese
adypocyte
oxidation in
mitochondria
(1)
FFA
Metabolic syndrome
insulin resistance, compensatory hyperinsulinemia, DM
and vascular diseases
FACoA
dystrophic
adypocyte
risk factor & consequences,
hormonesrelated to their
complications
(2)
Link to other diseases
metabolic syndrome,
coronary heart disease,
diabetes mellitus type 2,
polycystic ovarian syndrome
Malonyl-CoA
(4)
proinflammatory
molecules
Diabetes and Obesity
(3)
TG, ceramide
DAG, PKC
IKKB – NFkß
JNK1
ROS
ER stress
cellular
dysfunction
Insulin
resistance
Pathogenesis of the metabolic syndrome-the lipid hypothesis: (1) Increased FFA and
inflammatory cytokines (2) secondary to impaired tryglyceride storage an enhanced
lipolysis in fat cell, (3) increased FACoA and inappropriately normal or decreased
mitochondrial fatty acid oxidation in liver, muscle and other tissues due to increase
malonyl CoA and other factors, and (4) increased estearification of FACoA to form
triglicerides (TG), DAG and in some tissues ceramide.
obese
adipocyte
oxidation in
mitochondria
(1)
FFA
(3)
Malonyl-CoA
FACoA
dystrophic
adipocyte
(4)
proinflammatory
molecules
(2)
TG, ceramide
DAG, PKC
IKKB – NFkß
JNK1
ROS
ER stress
cellular
dysfunction
Insulin
resistance
Pathogenesis of the metabolic syndrome-the lipid hypothesis: (1) Increased FFA and
inflammatory cytokines (2) secondary to impaired tryglyceride storage an enhanced
lipolysis in fat cell, (3) increased FACoA and inappropriately normal or decreased
mitochondrial fatty acid oxidation in liver, muscle and other tissues due to increase
malonyl CoA and other factors, and (4) increased estearification of FACoA to form
triglicerides (TG), DAG and in some tissues ceramide. By mechanisms only partially
understood, these abnormalities can in turn lead to activation of various PKC
isoforms, ROS and endoplasmic reticulum stress, and the IJJB-NFkß system.
Page 10
Metabolic dysfunctions
Structure / Function
pancreatic insulin and
glucagon, adrenal cortisol,
GH axis and GH abuse
Metabolic syndrome
insulin resistance, compensatory hyperinsulinemia, DM
and vascular diseases
Diabetes and Obesity
risk factor & consequences,
hormonesrelated to their
complications
CRITERIA FOR THE DIAGNOSIS OF
METABOLIC SYNDROME
(3 of the next 5 traits)
1.- increased waist circumference
(>35 - 40 in, females-males).
2.- plasma triglycerides > 150 mg/dl.
3.- plasma HDL cholesterol
(> 40 – 50 mg/dl, males – females).
Link to other diseases
metabolic syndrome,
coronary heart disease,
diabetes mellitus type 2,
polycystic ovarian syndrome
4.- blood pressure > 130 / 85 mmHg.
5.- fasting plasma glucose > 100 mg/dl.
Metabolic dysfunctions
Structure / Function
pancreatic insulin and
glucagon, adrenal cortisol,
GH axis and GH abuse
Metabolic syndrome
insulin resistance, compensatory hyperinsulinemia, DM
and vascular diseases
Diabetes and Obesity
risk factor & consequences,
hormonesrelated to their
complications
Link to other diseases
metabolic syndrome,
coronary heart disease,
diabetes mellitus type 2,
polycystic ovarian syndrome
Pathophysiology of Diabetes Mellitus
Page 11
Metabolic dysfunctions
Structure / Function
pancreatic insulin and
glucagon, adrenal cortisol,
GH axis and GH abuse
Metabolic syndrome
insulin resistance, compensatory hyperinsulinemia, DM
and vascular diseases
Diabetes and Obesity
risk factor & consequences,
hormonesrelated to their
complications
Link to other diseases
metabolic syndrome,
coronary heart disease,
diabetes mellitus type 2,
polycystic ovarian syndrome
Some links among insulin resistance, diabetes, and obesity
Page 12
Metabolic dysfunctions
Structure / Function
pancreatic insulin and
glucagon, adrenal cortisol,
GH axis and GH abuse
Metabolic syndrome
insulin resistance, compensatory hyperinsulinemia, DM
and vascular diseases
Diabetes and Obesity
risk factor & consequences,
hormonesrelated to their
complications
Link to other diseases
metabolic syndrome,
coronary heart disease,
diabetes mellitus type 2,
polycystic ovarian syndrome
Amylin, also known as Islet Amyloid PolyPeptide (IAPP), is cosecreted with insulin in a 100:1 ratio by beta cells. It prevents
post-prandial spikes in blood glucose levels.
Amylin contributes to glycemic control by slowing the rate of
appearance of glucose from a meal by slowing down gastric
emptying, inhibiting digestive secretions (gastric acid, pancreatic enzymes, bile ejection) and food intake. Appearance of new
glucose is slow down by inhibiting the gluconeogenic hormone
glucagon.
Amylin actions collectively reduce total insulin demand and are
mostly carried out via a glucose-sensitive part of the brain (the
area postrema). Amylin effects might be overridden by hypoglycemia. Rodent amylin knock-out experiments show that
knock-out animals failed to show the normal anorexia following
food consumption, suggesting that amylin might be involved in
the anorectic effect.
Some links among insulin resistance, diabetes, and obesity
Page 13
Metabolic dysfunctions
Structure / Function
pancreatic insulin and
glucagon, adrenal cortisol,
GH axis and GH abuse
Metabolic syndrome
insulin resistance, compensatory hyperinsulinemia, DM
and vascular diseases
Diabetes and Obesity
risk factor & consequences,
hormonesrelated to their
complications
Link to other diseases
metabolic syndrome,
coronary heart disease,
diabetes mellitus type 2,
polycystic ovarian syndrome
Amylin or IAPP is co-secreted with insulin.
Insulin resistance in type II DM produces a
greater demand for insulin production which
results in the secretion of proinsulin. ProIAPP is secreted simultaneously, but the
enzyme that converts these precursors
molecules into insulin and IAPP, are not able
to keep up with high secretion levels
ultimately leading to accumulation of proIAPP. This is the key factor in accumulation
of amyloid in beta-cells and the apoptotic
process in islet beta-cells. The pro-IAPP
acts as a seed, collecting IAPP from
neighboring cells and forming an intracellular amyloid. As the amyloid grows, it
spreads outside the cell. The extracellular
amyloid began to excrete IAPP to other
cells, inducing similar amyloid formation in
other beta-cells (possible link to Alzheimer).
Some links among insulin resistance, diabetes, and obesity
Metabolic dysfunctions
Structure / Function
pancreatic insulin and
glucagon, adrenal cortisol,
GH axis and GH abuse
Metabolic syndrome
insulin resistance, compensatory hyperinsulinemia, DM
and vascular diseases
Diabetes and Obesity
risk factor & consequences,
hormonesrelated to their
complications
Link to other diseases
metabolic syndrome,
coronary heart disease,
diabetes mellitus type 2,
polycystic ovarian syndrome
Diabetic ketoacidosis (DKA) and hyperosmotic
hyperglycemic and non-ketotic syndrome (HHNKS)
Page 14
Metabolic dysfunctions
Structure / Function
pancreatic insulin and
glucagon, adrenal cortisol,
GH axis and GH abuse
Metabolic syndrome
insulin resistance, compensatory hyperinsulinemia, DM
and vascular diseases
Diabetes and Obesity
risk factor & consequences,
hormonesrelated to their
complications
Link to other diseases
metabolic syndrome,
coronary heart disease,
diabetes mellitus type 2,
polycystic ovarian syndrome
Diabetes mellitus, insulin resistance and atherosclerosis
Page 15
Metabolic dysfunctions
Structure / Function
pancreatic insulin and
glucagon, adrenal cortisol,
GH axis and GH abuse
Metabolic syndrome
insulin resistance, compensatory hyperinsulinemia, DM
and vascular diseases
Diabetes and Obesity
risk factor & consequences,
hormonesrelated to their
complications
Link to other diseases
metabolic syndrome,
coronary heart disease,
diabetes mellitus type 2,
polycystic ovarian syndrome
Pathophysiology and common complications of obesity
Page 16
Metabolic dysfunctions
Structure / Function
pancreatic insulin and
glucagon, adrenal cortisol,
GH axis and GH abuse
Metabolic syndrome
insulin resistance, compensatory hyperinsulinemia, DM
and vascular diseases
Adiponectin, is a protein hormone that modulates a number
of metabolic processes, including glucose regulation and
fatty acid catabolism.
Adiponectin is exclusively secreted from adipose tissue (and
also from the placenta in pregnancy). Its blood levels are
inversely correlated with body fat percentage in adults.
Transgenic mice with increased adiponectin show impaired
adipocyte differentiation and increased energy expenditure
associated with protein uncoupling.
Diabetes and Obesity
risk factor & consequences,
hormonesrelated to their
complications
Adiponectin plays a role in the metabolic derangement that
may result in type 2 DM, obesity, atherosclerosis, nonalcoholic fatty acid disease, and an independent risk factor
for the metabolic syndrome.
Link to other diseases
metabolic syndrome,
coronary heart disease,
diabetes mellitus type 2,
polycystic ovarian syndrome
Adiponectin in combination with leptin has been shown to
completely reverse insulin resistance in mice.
Pathophysiology and common complications of obesity
Page 17
Metabolic dysfunctions
Structure / Function
pancreatic insulin and
glucagon, adrenal cortisol,
GH axis and GH abuse
Metabolic syndrome
insulin resistance, compensatory hyperinsulinemia, DM
and vascular diseases
Diabetes and Obesity
risk factor & consequences,
hormonesrelated to their
complications
Link to other diseases
metabolic syndrome,
coronary heart disease,
diabetes mellitus type 2,
polycystic ovarian syndrome
SAME EFFECTS OF ADIPONECTIN
Adiponectin metabolic effects:
Improved glucose flux by lowering gluconeogenesis and rising
glucose uptake
Improved lipid catabolism by affecting beta-oxidation and
triglyceride clearance
Provide protection from endothelial atherosclerotic dysfunction
Improved insulin sensitivity
Improved weight loss
Participate in the control of energy metabolism
Up-regulate uncoupling proteins
Hypoadiponectinemia is an independent risk factor for the
metabolic syndrome and for diabetes mellitus
Pathophysiology and common complications of obesity
Metabolic dysfunctions
Structure / Function
pancreatic insulin and
glucagon, adrenal cortisol,
GH axis and GH abuse
Metabolic syndrome
insulin resistance, compensatory hyperinsulinemia, DM
and vascular diseases
Diabetes and Obesity
risk factor & consequences,
hormonesrelated to their
complications
Link to other diseases
metabolic syndrome,
coronary heart disease,
diabetes mellitus type 2,
polycystic ovarian syndrome
BRAIN STRESS AND INFLAMMATION IN THE
DEVELOPMENT OF METABOLIC SYNDROME.
Overnutrition in the forms of high circulating levels of glucose,
free fatty acid (FFA), and amino acids (AA) is the predominant
pathogenic inducer of central metabolic inflammation.
Excessive nutrients transported into cells can pose severe
stresses on cellular metabolic machinery, affecting organelles
such as mitochondria and endoplasmic reticulum (ER) which
are responsible for nutrient oxidation and protein synthesis,
respectively. As a result, intracellular reactive oxygen species
(ROS) increase due to heightened mitochondrial activities,
leading to intracellular oxidative stress. In parallel, high levels
of cellular metabolic activities demand increased protein
synthesis and folding by ER, leading to ER stress. Additionally,
high levels of intracellular ROS from oxidative stress can
escalate ER stress. Prolonged oxidative stress and ER stress
can cause intracellular accumulation of dysfunctional
mitochondria, ER, and other cytosolic proteins, leading to
increased autophagy stress and autophagic defect.
Page 18
Metabolic dysfunctions
Structure / Function
pancreatic insulin and
glucagon, adrenal cortisol,
GH axis and GH abuse
Metabolic syndrome
insulin resistance, compensatory hyperinsulinemia, DM
and vascular diseases
Diabetes and Obesity
risk factor & consequences,
hormonesrelated to their
complications
Link to other diseases
metabolic syndrome,
coronary heart disease,
diabetes mellitus type 2,
polycystic ovarian syndrome
BRAIN STRESS AND INFLAMMATION IN THE
DEVELOPMENT OF METABOLIC SYNDROME.
All these intracellular stresses are activators of cellular proinflammatory kinases, among which INFk-B kinase (IKK) and cJun N-terminal kinase (JNK) have been implicated. Activation
of these pro-inflammatory pathways leads to transcription of
inflammatory response genes via nuclear transcription factors
NFk-B and AP-1. Endoplasmic Reticulum (ER) stress can also
directly induce transcription of inflammatory genes via
activating transcription factor X-box binding protein-1 (XBP1).
Certain extracellular nutrient species can bind to toll-like
receptors to activate intracellular pro-inflammatory signaling.
Furthermore, local or systemic inflammatory cytokines can
reinforce metabolic inflammation via cytokine receptor signals.
Such collective onset of cellular inflammation impairs normal
cellular functions, leading to central dysregulation of various
physiological processes across energy balance, glucose
tolerance, and cardiovascular homeostasis, which underlies
the development of metabolic syndrome and related diseases.
Metabolic dysfunctions
Structure / Function
pancreatic insulin and
glucagon, adrenal cortisol,
GH axis and GH abuse
Metabolic syndrome
insulin resistance, compensatory hyperinsulinemia, DM
and vascular diseases
Diabetes and Obesity
risk factor & consequences,
hormonesrelated to their
complications
Link to other diseases
metabolic syndrome,
coronary heart disease,
diabetes mellitus type 2,
polycystic ovarian syndrome
Brain stress and inflammation in the development of the
metabolic stress
Page 19
Metabolic dysfunctions
Structure / Function
pancreatic insulin and
glucagon, adrenal cortisol,
GH axis and GH abuse
Metabolic syndrome
insulin resistance, compensatory hyperinsulinemia, DM
and vascular diseases
Diabetes and Obesity
risk factor & consequences,
hormonesrelated to their
complications
Link to other diseases
metabolic syndrome,
coronary heart disease,
diabetes mellitus type 2,
polycystic ovarian syndrome
High fructose consumption combined with low dietary
magnesium intake may increase the incidence of the
metabolic syndrome by inducing inflammation*
Magnesium Research. Volume 19, Number 4, 237-43, 2006,
Y Rayssiguier, E Gueux, W Nowacki, E Rock, A Mazur
The metabolic syndrome is a cluster of common pathologies:
abdominal obesity linked to excess of visceral fat, insulin resistance,
dyslipidemia and hypertension. This syndrome is occurring at epidemic
rates, with dramatic consequences for human health worldwide, and
appears to have emerged largely from changes in our diet and reduced
physical activity. An important but not well-appreciated dietary change
has been the substantial increase in fructose intake, which appears to
be an important causative factor in the metabolic syndrome. There is
also experimental and clinical evidence that the amount of magnesium
in the western diet is insufficient to meet individual needs and that
magnesium deficiency may contribute to insulin resistance. In recent
years, several studies have been published that implicate subclinical
chronic inflammation as an important pathogenic factor in development
of metabolic syndrome. Pro-inflammatory molecules produced by
adipose tissue have been implicated in the development of insulin
resistance
Page 20
High fructose consumption combined with low dietary
magnesium intake may increase the incidence of the
metabolic syndrome by inducing inflammation*
Magnesium Research. Volume 19, Number 4, 237-43, 2006,
Y Rayssiguier, E Gueux, W Nowacki, E Rock, A Mazur
The metabolic syndrome, high fructose intake and low magnesium (Mg) diet may all be linked to
the inflammatory response. In many ways, fructose-fed rats display changes observed in the
metabolic syndrome and high-fructose feeding is associated with NADPH oxidase and reninangiotensin activation. The production of reactive oxygen species results in the initiation and
development of insulin resistance, hyperlipemia and high blood pressure.
In a fructose-fed rat model, a few days of experimental magnesium deficiency produces a clinical
inflammatory syndrome characterized by leukocyte and macrophage activation, release of
inflammatory cytokines, appearance of the acute phase proteins and excessive production of free
radicals. Because magnesium acts as a natural calcium antagonist, the molecular basis for the
inflammatory response is probably the result of a modulation of the intracellular calcium
concentration.
Potential mechanisms include the priming of phagocytic cells, the opening of calcium channels,
activation of N-methyl-D-aspartate (NMDA) receptors, the activation of nuclear factor-kappaB
(NFkB) and activation of the renin-angiotensin system. Since magnesium deficiency has a proinflammatory effect, the expected consequence would be an increased risk of developing insulin
resistance when magnesium deficiency is combined with a high-fructose diet.
Accordingly, magnesium deficiency combined with a high-fructose diet induces insulin
resistance, hypertension, dyslipidemia, endothelial activation and prothrombic changes in
combination with the up-regulation of markers of inflammation and oxidative stress.
Page 21