Understanding Insulin Resistance   (Part 2)

This is the second part of our series on insulin resistance. If you are uncertain about the basics and the molecular pathways involved, then you should read the first part first. If you want to discuss with our experts and want to see how insulin resistance is measured in mice and humans, then our upcoming free online seminar may be the right thing for you. 

Recall the physiological as well as pathological pathways and then enjoy the second part of this blog series on insulin resistance.

Assessment of insulin resistance

Numerous surrogate measures have been used to quantify insulin resistance, but the accurate assessment of insulin resistance is still a challenge due to the dynamics of glucose homeostasis and the presence of several confounding variables. In addition to insulin and glucose, other biomarkers like adiponectin have been suggested as simple measures to quantify insulin resistance from a single fasting blood sample [51-53].  As already addressed, adiponectin released from the visceral adipose tissue is a linker between visceral adiposity and the development of insulin resistance. The measurement of adiponectin levels is a helpful tool for the assessment of insulin resistance, and monitoring of dynamic changes in adiponectin levels due to therapeutic interventions.

The homeostasis model assessment of insulin resistance (HOMA-IR) is a widely used surrogate to characterise insulin resistance based on a simple measurement of fasting insulin and glucose levels [(fasting insulin concentration x fasting glucose concentration)/22.5] [54]. The quick insulin sensitivity check index (QUICKI) is a log transformation of HOMA to yield directly an insulin sensitivity index [55]. As both indices (HOMA; QUICKI) rely on a fasting blood sampling, and the liver is playing the fundamental role in glucose haemostasis in fasting conditions, they can be assumed to be markers of hepatic insulin sensitivity rather than peripheral insulin sensitivity.  

While assessment of insulin resistance under fasting conditions mainly reflects hepatic insulin sensitivity, several technologies have been implemented to address peripheral insulin resistance. The oral glucose tolerance test (OGTT) can be used to calculate the whole body insulin sensitivity index, or to appraise the ratio of glucose and insulin areas under the curve as a simplified measure for insulin resistance in the postprandial stage [56,57]. The frequently sampled intravenous glucose tolerance test (fsIVGTT) establishes insulin resistance by mathematical modelling of insulin and blood glucose levels after intravenous glucose application [58].
A major limitation of the aforementioned HOMA-IR, OGGT-derived indices, and the fsIVGTT is that they rely on intact beta cell physiology, and their reliability become worse in case of declining beta cell function and increasing proinsulin levels [59,60].

The euglycaemic-hyperinsulinaemic clamp is considered to be the gold standard for the assessment of insulin resistance [61-63]. The glucose infusion rate during the steady state phase of a euglycaemic-hyperinsulinaemic clamp is usually achieved after 2-3 hours and after that time, insulin sensitivity is expressed by the average glucose infusion rate over a defined time period (M-value), or the M/I ratio defined as the average glucose infusion to the average plasma insulin concentration during the same period [64]. Since it is assumed that during hyperinsulinaemic conditions hepatic glucose output is widely suppressed, the glucose infusion rate within the hyperinsulinaemic- euglycaemic clamp will mostly reflect peripheral glucose uptake. The additional use of isotope tracers in the clamp investigation enables further quantification of hepatic (endogenous) glucose production and peripheral glucose disposal rates [65]. While the euglycaemic-hyperinsulinaemic clamp arguably is the most standardised and reproducible way to measure insulin resistance, it is expensive, time consuming, and requires experienced investigators. Due to both, its sophisticated methodology and its high expense, conduct of high-quality clamp assessments remains reserved to specialised centres.

Therapeutic Interventions in Insulin Resistance

Whilst lifestyle and weight loss remains the cornerstone of managing IR and T2DM, metformin and thiazolidinediones are the currently available pharmacological options to counter IR. Even they affect hepatic and peripheral IR, their impact is not sustained and they might have significant adverse event profiles. Hence, there is a need to establish new treatments for the intervention in subjects with IR. Certain pharmacological candidates to improve insulin signalling are under preclinical or clinical development.

Insulin receptor activators or insulin mimetics are small molecules that address the insulin receptor or the downstream IRS-proteins. Activating insulin receptor signalling by non-peptide ligands might have the advantage of activating the insulin receptor by a non-peptide ligand, overcoming IR without need for injections [66]. In contrast, insulin receptor potentiators work by prolonging the phosphorylation of the insulin receptor ß-subunit or by antagonising the pathways that inhibit tyrosine kinase activity, or the inhibition of tyrosine phosphatases [67,68]. Protein Tyrosine Phosphatase Inhibitors dephosphorylate the insulin receptor ß-subunit, and inhibition of this process is thought to improve insulin signalling [66,68,69]. Protein kinase C (PKC) inhibitors, Phosphatase and Tensin Homolog (PTEN) inhibitors, Inosol derivates, Inosol Phosohatases Inhibitors, Resveratol, and other molecules have been identified to interfere with intracellular insulin signalling at several trigger points, and are under investigation as potential insulin sensitizing agents [66]. In addition, on-going research on adipokines (e.g. adiponectin; leptin), or adipokine like molecules, should clarify their role as a potential treatments for IR and/or T2DM. A number of drugs in clinical development address obesity and should support weight reduction in obese subjects, which also should evolve pronounced effects on IR.

In conclusion, numerous new approaches are in development to improve insulin sensitivity or insulin signalling in pre-diabetic or diabetic subjects. For a better evaluation of potential risks and benefits of new approaches to address IR, careful pre-clinical and clinical studies should characterize their effects with regard to their metabolic and cardiovascular capabilities.   

What comes next?

Having understood the basics of insulin resistance and the underlying molecular pathways as well as the relevance for clinical development and methods to measure insulin resistance is a wonderful foundation to join our online seminar on studying insulin resistance in preclinical and clinical trials. Here you can learn more about how to plan the right experiments and how to optimize study design for a smooth transition from preclinical to clinical trials of a compound. In this online seminar we bring together experts from the preclinical side and clinical trial experts who will discuss this topic in a 45 minute presentation. Register for this free online seminar now, as seats are limited.  

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