Mechanotransduction and the Myogenic Response in Diabetes - The Mechanobiology of Obesity and Related Diseases - page 244

4.1 Experimental Animal Studies: Insulin Resistance; Type 1
and 2 Diabetes Models
4.1.1 Insulin Resistance
Considering the literature, it is currently not clear whether insulin resistant states are
specifically associated with impaired myogenic tone. For example, varying results
have been reported amongst studies using western diet models for induction of
insulin resistance. Simandle et al. showed in male Sprague Dawley (SD) rats that a 4-
week fructose-rich diet did not change the spontaneous tone of isolated, pressurized,
middle cerebral arteries at 80 mmHg [ 103 ]. Similarly, Howitt et al. demonstrated
that a longer duration of high-fat feeding (16-20 weeks) in the same animal model
also did not alter myogenic responses of middle cerebral arteries across a pressure
range of 30-120 mmHg [ 104 ]. In contrast, these authors reported that myogenic tone
was increased at a low pressure (30 mmHg) in isolated cremaster muscle arterioles
[ 104 ]. While this may suggest that the cremaster arterioles are more sensitive to
insulin resistant states than cerebral arteries the significance of a difference at low
(non-physiological) pressures is uncertain [ 104 ]. In apparent contrast to these
studies, impaired myogenic responses were demonstrated in mesenteric resistance
(5th order) arteries of SD rats fed either a high-fat or high sucrose diet [ 105 ].
In addition to diet-induced insulin resistant states a number of studies have been
performed in genetic models of the metabolic disorder. For example, the Obese
Zucker Rat (OZR) is characterized by leptin receptor dysfunction leading to a
hyperphagia-induced weight gain that is associated with insulin resistance, dysli-
pidemia and moderate hypertension [ 106 - 108 ]. In this model, Frisbee and col-
leagues have demonstrated increased myogenic responsiveness of resistance
arteries from both cerebral and skeletal muscle circulations [ 109 , 110 ]. The
increased myogenic responsiveness was attributed to increased oxidant stress in
arterioles from skeletal muscle and an impaired dilator component in vessels from
the cerebral circulation.
4.1.2 Type 1 Diabetes Models
All studies of type1 diabetes in animal models have involved injection with
streptozotocin (STZ), a diabetogenic agent acting via a direct toxicity to pancreatic
b-cells. Similar to insulin resistance, it is also unclear how type 1 diabetes impacts
myogenic responsiveness. Hill et al. demonstrated that STZ-induced diabetes in
the SD rats is associated with an impaired cremaster arteriolar myogenic response
to increased intravascular pressure both in vitro and in vivo [ 111 , 112 ]. In addition,
Hayashi et al. reported that myogenic responses in kidney afferent arterioles were
impaired in STZ-induced diabetic SD rats. In contrast to these results, cerebral
arteries have been shown to demonstrate increased myogenic tone and vasocon-
striction to agonists. Thus, Zimmermann et al. showed that pressure-induced