THE METABOLIC SYNDROME A Reversible Life-Threatening Condition

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THE METABOLICSYNDROMEA Reversible
Life-Threatening Condition

• Metabolic Syndrome and Insulin Resistance

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Insulin Resistance (IR)
IS Insulin Sensitive Haffner SM et al. Diabetes
Care, 1999 22 562-568.
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IR as a CVD risk factor
Bonora E. et al., Diabetes Care 2002 25(7)
1135-1141.
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Risk of CVD rises as IR inceases
Hanley A.J. et al. Diabetes Care 2002 25
1177-1184. (San Antonio Heart Study)
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Glucometabolic effects of insulin
NEFA Non Esterified Fatty Acids
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Common insulin resistance (IR)

• underlies most cases of T2DM, central obesity and
  metabolic syndrome
• driven by overweight/obesity, as a result of
  adipokines/FFA imbalance and lipotoxicity
• represents a ? in insulin-mediated glucose uptake
  (IMGU) and glycogen synthesis, mostly in skeletal
  muscle (responsible for the bulk of IMGU)
• Liver IR usually present, resulting from portal
  adipokines/FFA imbalance and lipotoxicity
  associated with fatty tissue expansion
• IR is a continuous variable often considered
  present when IMGU lt lower quartile of a normal
  control cohort

Beck-Nielsen et al. in Insulin Resistance, Kumar
ORahilly eds. 2005 John Wiley Sons, Ltd
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Measuring Insulin Sensitivity ( Secretion )

• reciprocal of fasting plasma insulin (FPI -1)
• oral glucose tolerance test (OGTT)
• Intravenous glucose tolerance test (IVGTT)
• Homeostatic Model Assessment Continuous
  Infusion of Glucose with Model Assessment
  (HOMA-CIGMA)
• Quantitative Insulin sensitivity ChecK Index
  (QUICKI)
• frequently sampled IVGTT with MinMod
• euglycemic hyperinsulinemic clamp (hyperglycemic
  clamp)
• glucose-insulin infusion
• Bonoras insulin tolerance test
• insulin suppression test

Various methods are currently used to assess
insulin sensitivity. The  gold standard 
euglycemic hyperinsulinemic clamp is used for
research purposes and pharmacological studies,
and is not applicable to large numbers. At the
opposite end, the reciprocal of fasting insulin
can be used in large scale epidemiological
studies in normal glucose tolerance subjects. In
subjects with impaired glucose tolerance or type
2 diabetes, methods that provide both beta cell
function estimates and insulin sensitivity (such
as HOMA) are often preferred and increasingly
used for routine testing.
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The next two slides illustrate two scenarios
linking obesity, insulin resistance and
components of the MetS

• the most common scenario starts from acquired
  adipose tissue expansion in overweight-obese
  individuals, with secondary muscle IR
• another scenario starts from muscle IR and
  intramyocellular fat accumulation, often
  associated with mitochondrial dysfunction,
  resulting in fat overflow in various organs,
  including ectopic fat deposition
• in predisposed individuals, the common scenario
  sequence can coexist alongside genetic or
  acquired defects in myocellular metabolism or
  mitochondrial function, amplifying each other.

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Insulin Resistance (IR) and T2DM

• precedes hyperglycemia based in muscle/liver and
  modulated by adipo-cytokines and NEFAs
  originating from adipose tissue expansion
• ? NEFAs availability induces ? in
  intramyocellular long chain fatty acyl-CoA
  (LCFAcyl-CoA), resulting in
• ? insulin PIP3 PKB/Akt signaling
• ? glucose transport (GLUT4) / phosphorylation
• ? insulin-stimulated glycogen synthesis and
  oxidative phosphorylation (ATP synthesis)
• ? ectopic triglycerides (intramyocellular lipids
  and intrahepatocytic lipids)
• downregulation of PPARg coactivator-1 (PGC-1) and
  PGC-1-controlled genes (mitochondrial biogenesis
  and oxidative phosphorylation)

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Etiology of LCFAcyl-CoA pool expansion
upstreamof the mitochondria

• adipose tissue expansion and adipokine/FFA
  imbalance
• ? mitochondria number, size, function, or
  combination
• mutations (acquired or genetic) Mt DNA / or
  Nucl DNA
• ageing, drugs, oxidative stress
• fat overload (excess VLDL-C, dietary)
• decreased AMPK activity
• CPT-1 inhibition
• Young offspring of T2DM ? fibers IIb

Hereditary IR
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Insulin Resistance (IR) and T2DM

• any ? in intramyocellular lipids (IMCL) and
  intrahepatocytic lipids (IHL) can cause IR
• acquired and/or genetic mitochondrial dysfunction
  (MD) and oxidation associated with IMCL and IHL
  in subjects at risk for T2DM and in T2DM
• abnormalities can combine MD ? ?
  Intramyocellular Lipids Intrahepatic Lipids
  (IMCL-IHL) ? ? lipid oxidation and IR, amplifying
  each other (vicious cycle)
• IR may start primarily as MD in genetic IR, or,
  more commonly, from increased IMCL in
  environmental-nutritional IR associated with
  overweight-obesity
• quantitative or qualitative sarcopenia secondary
  to reduced anabolic-anticatabolic effects of
  insulin in IR subjects

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Insulin Sensitivity (IS) x b-Cell Function (bCF)
definesa functional area that determines glucose
homeostasis
Adapted from Kahn SE, Prigeon RL, McCulloch DK,
Boyko EJ, Bergman RN, Schwartz MW, Neifing JL,
Ward WK, Beard JC, Palmer JP, et al.
Quantification of the relationship between
insulin sensitivity and beta-cell function in
human subjects. Evidence for a hyperbolic
function. Diabetes. 1993, 421663-72. Bergman RN,
Ader M, Huecking K, Van Citters G. Accurate
assessment of beta-cell function the hyperbolic
correction. Diabetes.2002, 51 Suppl 1S212-20.
Bergman RN. Pathogenesis and prediction of
diabetes mellitus lessons from integrative
physiology. Mt Sinai J Med. 2002, 69280-90.
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IS x bCF defines a functional area that
determinesglucose homeostasis
Adapted from Kahn SE, Prigeon RL, McCulloch DK,
Boyko EJ, Bergman RN, Schwartz MW, Neifing JL,
Ward WK, Beard JC, Palmer JP, et al.
Quantification of the relationship between
insulin sensitivity and beta-cell function in
human subjects. Evidence for a hyperbolic
function. Diabetes. 1993, 421663-72. Bergman RN,
Ader M, Huecking K, Van Citters G. Accurate
assessment of beta-cell function the hyperbolic
correction. Diabetes.2002, 51 Suppl 1S212-20.
Bergman RN. Pathogenesis and prediction of
diabetes mellitus lessons from integrative
physiology. Mt Sinai J Med. 2002, 69280-90.
16
IS x bCF defines a functional area that
determinesglucose homeostasis
Adapted from Kahn SE, Prigeon RL, McCulloch DK,
Boyko EJ, Bergman RN, Schwartz MW, Neifing JL,
Ward WK, Beard JC, Palmer JP, et al.
Quantification of the relationship between
insulin sensitivity and beta-cell function in
human subjects. Evidence for a hyperbolic
function. Diabetes. 1993, 421663-72. Bergman RN,
Ader M, Huecking K, Van Citters G. Accurate
assessment of beta-cell function the hyperbolic
correction. Diabetes.2002, 51 Suppl 1S212-20.
Bergman RN. Pathogenesis and prediction of
diabetes mellitus lessons from integrative
physiology. Mt Sinai J Med. 2002, 69280-90.
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Hyperbolic relation between IS x bCF

Bonora E. et al. Diabetes Care, 2002 26 (7)
1153-1141.
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90 of T2DM IR and MS
Adapted from International Diabetes Center (IDC),
Minneapolis, Minnesota.