PREDIABETIC INSULIN RESISTANCE PDIR

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PREDIABETIC INSULIN RESISTANCE (PDIR) LEADS TO
OBESITY AND DIABETES PDIR is preventable PDIR is
treatable W. Wayne Lautt Professor of
Pharmacology Therapeutics University of
Manitoba Winnipeg, Manitoba Canada Email
wlautt_at_cc.umanitoba.ca Phone [phone]
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Type 1 Diabetes (5-10) caused by lack of
insulin Type 2 Diabetes (90-95) caused by lack
of HISS HISS Hepatic Insulin Sensitizing
Substance
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In the fed state insulin causes the release of
Hepatic Insulin Sensitizing Substance that acts
selectively on skeletal muscle and accounts for
approximately 55 of whole body insulin action.
Absence of HISS action leads to postprandial
hyperglycemia, hyperinsulinemia, hyperlipidemia,
and increased oxidative stress.
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Rapid Insulin Sensitivity Test RIST TIMELINE A
Transient Hyperinsulinemic Euglycemic Clamp
RIST INDEX mg glucose/kg bw
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Dynamic Insulin Action in Fasted and Re-Fed Humans
(Patarrao et al Can J Physiol Pharmacol 86
880-888, 2008)
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HISS Action Results in Meal-Induced Insulin
Sensitization (MIS)

• MIS can be quantified
• Fasted ? Fed
• Fed ? Atropine

(Sadri et al Br J Nutr 95 288-295, 2006)
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SUCROSE-INDUCED AMIS
(Ribeiro et al., Diabetologia 48 976-983, 2005)
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• In order for insulin to cause HISS release, the
  liver must receive two feeding signals
• Hepatic parasympathetic nerve signal
• Elevation in hepatic glutathione (GSH)

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(Bethanechol)
Insulin
NERVE SIGNAL
HISS
GSH SIGNAL
(N-acetylcysteine)
Licensed to DiaMedica Inc.
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Effect of Bethanechol (BE) and N-Acetyl-L-Cysteine
(NAC) On Meal-Induced Insulin Sensitization
(MIS) In the 9 week 35 liquid sucrose diet
rodent model
Control
9 Week Sucrose
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SAMEC Antioxidant Cocktail
S-Adenosylmethionine elevates hepatic
GSH Vitamin E protects lipid phase of
cells Vitamin C protects aqueous phase of cells
Synergistic effect shown Ming et al., Free Rad
Biol Med 40 617-624, 2006
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HYPOTHESIS The cumulative consequences of having
AMIS at every meal an AMIS syndrome
Postprandial
glycemia
insulin
HISS
Insulin
Test Chronic manipulation of MIS Age 9,
26, 52 weeks SAMEC 26, 52 weeks 5 Sucrose
26, 52 weeks Sucrose SAMEC 26, 52 weeks
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Normal Aging (9,26,52 wk) results in HDIR HDIR is
accelerated by a sucrose supplement and
attenuated by antioxidants
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As HISS action decreases, adiposity increases.
Age, sucrose and antioxidants impact adiposity
through effects on HISS action.
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SAMEC Protection in Aged (12 month) Rats on a
Sucrose (5) Supplement Compared with Young (9
week) Rats
Parameter Protection Arterial Pressure
41 Fasting Glucose
55 Postprandial Glucose 75 Fasting
Insulin 50 Postprandial Insulin
66 Whole Body Fat 28 Visceral
Fat 27 Fasting Triglycerides
50 LDL/HDL Cholesterol 48 HISS
Action 75
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Absence of Meal-Induced Insulin Sensitization
Syndrome (AMISS)
Death
Alzheimers
Asthma
Neuropathy
Fatty Liver
Kidney
Hypertension
Eye (Retina Glaucoma)
Pancreatic Exhaustion
Bladder
Fasting Glucose ?
AMISS Progression
Adiposity
Fasting Insulin ? and Triglycerides ?
Cardiac Dysfunction
Endothelial ?
ROS, PP hyperinsulinemia, PP glucose, PP
triglycerides ?
AMIS
HDIR
Diabetes
Organ Dysfunction
Death
AMIS
ROS
Sugar Diet
TIME
Age
Pregnancy
Fat Diet
Fetal Alcohol
Obesity
Inactivity
Inflammation
Toxicity
Contributing Factors
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ACKNOWLEDGEMENTS Data shown were from studies
carried out by the following
CANADA Dallas Legare Zhi
Ming Joshua Schafer PORTUGAL M. Paula Macedo
Rita Patarrao Ricardo Afonso
Rogerio Ribeiro FUNDED BY DiaMedica
Inc. Canadian Institutes of Health
Research Manitoba Health Research Council
Regional Partnership Program Canadian Diabetes
Association