New Method Simulated to Estimate Insulin Sensitivity

Written by Kathleen Doheny

By Francesca Piccinini, with commentary by J. Michael Gonzalez-Campoy, MD, PhD

Evaluating patients for insulin resistance is a routine, crucial task among endocrinologists and primary care clinicians caring for patients with diabetes as much as for researchers involved in clinical trials involving people with diabetes. However, there is general, even uncontested, agreement that no optimal method for assessing insulin resistance exists to date.1

Now, scientists at Cedars Sinai Medical Center in Los Angeles have proposed a new model to accurately measure insulin sensitivity, essentially revising the oral glucose minimal model.1 A new mathematical model was introduced by Francesca Piccinini, PhD, a research scientist at the Cedars Sinai Medical Center's Diabetes and Obesity Research Institute in Los Angeles, California, in an oral abstract presentation at the World Congress on Insulin Resistance, Diabetes, and Cardiovascular Disease 2017 in Universal City, California.

"We used a lower oral glucose dose: 25 grams instead of 75 grams, and also we added an insulin injection at 60 minutes,'' said Dr. Piccinini, in presenting the research, which was conducted with Richard Bergman, PhD, director of the Diabetes and Obesity Research Institute at Cedars-Sinai.

Protocol for the Proposed Insulin Sensitivity Measure

According to Dr. Piccinini, the first minimal model relies on the intravenous glucose tolerance test (IVGTT) to estimate critical parameters in determining glucose tolerance:

In the past, “researchers have tried to extend this methodology to the OGTT. However, glucose and insulin patterns are similar to each other during the OGTT, so changes in unrelated processes often produce a misinterpreted calculated value of SI,” she said. Among the unrelated processes involved in insulin regulation are:  glucose absorption rate, renal glucose clearance, and glucose effectiveness.1

The Cedars-Sinai researchers designed a new OGTT protocol, employing three changes to correct for false values for insulin sensitivity, including a lower glucose dose (25 grams), administration of exogenous insulin during the test (0.03 units/kg at 60 minutes), and a reliance on simplified assumptions regarding the absorption of glucose.

Assessing the Validity of the Updated Protocol

In simulations, we tested this new method on subjects with normal, moderately reduced, and very reduced insulin sensitivity, said Dr. Piccinini. The subjects were divided into cohorts as follows: healthy (no diabetes), impaired glucose tolerance, and very reduced insulin sensitivity with a diagnosis of type 2 diabetes (T2D).1

Results of the revised OGTT were assessed for plausibility, precision (standard deviation [SD]), predictive accuracy, parsimony, and randomness of weighted residuals.

"Parimsomy is a compromise between the complexity of the model—that is the number of parameters to be estimated—and ability to predict data. and in this case, plausibility is a model of the actual physiology," said Dr. Piccinini.

“In refining the methodology by employing a reduced oral glucose dose and insulin injection, the estimates accounting for SI and SG—independent of changes in processes beyond insulin resistance—were more accurate,” Dr. Piccinini said. See Table 1 (Reprinted with the author's permission).

                              Table 1. Subject Values for Healthy and T2D Participants

The refined method provided more accurate estimates of both insulin sensitivity and glucose effectiveness,1 according to the researchers. The values are as follows for normal and type 2 diabetes subjects.

Perspective on the Proposed GTT Approach 

The concept of insulin resistance is important for all healthcare professionals to understand as it affects how we approach and manage individual patients," said J. Michael Gonzalez-Campoy, MD, PhD, medical director of the Minnesota Center for Obesity, Metabolism & Endocrinology in Eagan, Minnesota, in reviewing the findings for EndocrineWeb.

It's important to note, ''increasing insulin resistance is the same as declining insulin sensitivity; for patients, this means having progressively higher insulin needs," said Dr. Gonzalez-Campoy.

This research illustrates yet another of many methods currently available to measure or estimate insulin sensitivity or resistance, he said. However, because the exogenous insulin administration is intravenous, ''it still remains a research center protocol that is likely to have little impact in clinical practice," he told EndocrineWeb, ''If the exogenous insulin administration were delivered subcutaneously, it would open the field by allowing the calculation of insulin sensitivity in a broader number of clinical settings," and this might allow the endocrinology to move toward a more consistent methodology for assessing patients for glucose tolerance.

Is an Evolution in Diabetes Assessment Ahead?

We believe that there is a need for a better approach than currently is used as the oral glucose tolerance test, as done now, is not accurate, said Dr. Piccinini. Clinical trials employing the new protocol are expected to begin within one to two years, and animal studies even sooner, she said.  She was not sure if the research team would develop a subcutaneous method. 

Dr. Picinnini and Dr. Gonzalez-Campoy have no financial conflicts.

Sources

  1. Piccinini F, Bergman RN. New methods for the estimation of insulin sensitivity from the oral glucose tolerance test. Presented at: World Congress on Insulin Resistance, Diabetes, and Cardiovascular Disease, November 30—December 2, 2017, Universal City, California.
  2. Staten, MA, and Kelley, DE. Using Oral Challenge Testing to Assess Insulin Action and Secretion with Mathematical Modeling. Diabetes.. 2014:63(4) 1188-1190.