Microvascular Dysfunction and the Development of Whole-body Insulin Resistance
Condition: Insulin Resistance; Type 2 Diabetes; Obesity
MeSH terms: Diabetes Mellitus, Type 2; Insulin Resistance
Study type: Interventional

Summary: 
      This study aims to elucidate the role of the microcirculation in the development of whole
      body insulin resistance. The investigators hypothesize that impaired insulin signaling in the
      vasculature is an early phenomenon in the development of whole body insulin resistance.
      Furthermore, the investigators aim to identify improvement of microvascular function as a
      potential target in diabetes prevention and treatment.
    

Detailed description: 
      In today's society, food availability grossly exceeds our body's caloric demands. Excessive
      caloric intake causes weight gain and induces insulin resistance, a common characteristic of
      obesity and major risk factor for type 2 diabetes (T2DM) and cardiovascular disease.

      The primary targets of insulin action are skeletal muscle, adipose tissue and the liver, but
      recent data point to the vascular endothelium as an important target. Insulin directly
      targets the endothelial cell where it activates phosphoinositide 3-kinase, resulting in
      Akt-mediated phosphorylation of endothelial nitric oxide synthase (eNOS). This leads to NO
      production - a potent vasodilator in the human body. Simultaneously insulin also activates
      the mitogen-activated protein kinase pathway in endothelial cells, which enhances the
      generation of the vasoconstrictor endothelin-1 via extracellular signal-regulated kinases 1/2
      signaling. Via these two pathways insulin can regulate vascular tone.

      In healthy individuals, insulin signaling in the endothelial cell leads to capillary
      recruitment in skeletal muscle tissue via vasodilatation of terminal arterioles. It has been
      proposed that insulin in this matter regulates the delivery of insulin and glucose to
      skeletal muscle by increasing endothelial surface area. In obese individuals and patients
      with T2DM, insulin-mediated capillary recruitment in skeletal muscle tissue is impaired and
      insulin-dependent glucose uptake is diminished. Whether these two processes are linked or
      occur in parallel remains unknown.

      Interestingly, studies in rodents demonstrated that during obesity induced by high fat
      feeding, insulin resistance develops in the vasculature before these responses are detected
      in muscle, liver, or adipose tissue. Therefore, insulin signaling in endothelium might change
      in response to a positive energy balance to prevent nutrient overload in muscle and optimize
      nutrient storage in adipose tissue. Conversely, it has been hypothesized that early reversal
      of endothelial insulin resistance could prevent peripheral insulin resistance, assuming a
      cause-and-effect relationship between these processes. The most compelling evidence for this
      hypothesis came from studies in endothelial cell specific insulin receptor substrate-2
      (IRS-2) knock-out mice. Kubota et al. demonstrated that impaired insulin signaling in
      endothelial cells, due to reduced IRS-2 expression and insulin-induced eNOS phosphorylation,
      caused attenuation of insulin-induced capillary recruitment and insulin delivery, which
      reduced glucose uptake by skeletal muscle. Moreover, restoration of insulin-induced eNOS
      phosphorylation in endothelial cells by infusion of beraprost sodium - a stable prostaglandin
      analogue - completely reversed the reduction in capillary recruitment and insulin delivery in
      tissue-specific knockout mice lacking IRS-2 in endothelial cells and fed a high-fat diet. As
      a result, glucose uptake by skeletal muscle was restored in these mice.

      These data suggest that pharmacological stimulation of tissue perfusion may hold promise as a
      therapeutic strategy to increase whole body glucose disposal and thus prevent or reduce
      hyperglycaemia. In humans however, data linking improvement of capillary recruitment by
      pharmacological agents to restoration of whole-body glucose uptake are lacking. Low dose
      iloprost infusion - another stable prostaglandin analogue - has been shown to improve
      insulin-stimulated whole-body glucose uptake, but the mechanistic role of microvascular
      response was not assessed. Overall, it remains to be demonstrated whether improving capillary
      recruitment by endothelial insulin signaling or direct stimulation of smooth muscle tissue
      may serve as an attractive preventive or therapeutic approach to bypass cellular resistance
      to glucose disposal.

      In conclusion, vascular insulin resistance leads to blunted capillary recruitment in the
      skeletal muscle and may lead to diminished glucose uptake due to a decreased capillary
      surface area for nutrient exchange. Up till now however it remains unclear if these processes
      are interrelated or occur in parallel. Evidence from animal studies suggest that vascular
      insulin resistance precedes diminished whole-body glucose uptake and myocellular impairments.
      This indicates a potential cause-effect relationship. In humans, however, this was never
      demonstrated. On the other hand, decreased capillary recruitment of skeletal muscle tissue
      could also protect muscle tissue from nutrient overload and shunt excess calories towards
      adipose tissue. Presently, it is unknown whether insulin redistributes blood flow from
      skeletal muscle to adipose tissue during hypercaloric conditions. Finally, it is unknown if
      stimulation of tissue perfusion with a pharmacological agent can restore whole-body glucose
      uptake is therefore an effective strategy in prevention or treatment of insulin resistance.
    

Intervention name(s): Hypercaloric diet; Normocaloric diet
Intervention type(s): Dietary Supplement; Other
Intervention description(s): Hypercaloric diet consisting of 60% excess calories based on resting energy expenditure (REE). Calories will be provided in the form of snacks in between the ad libitum meals. A subsequent hypocaloric diet will consist of 1.0x resting energy expenditure.; Normocaloric diet
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Basic Science
Keywords: Obesity; Type 2 Diabetes Mellitus; Hypercaloric diet; Microcirculation; Microvascular dysfunction; Insulin Resistance; Insulin Sensitivity; Insulin signaling