Insulin resistance as a physiological defense against metabolic stress: implications for the management of subsets of type 2 diabetes
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Insulin resistance as a physiological defense against metabolic stress : implications for the management of subsets of type 2 diabetes. / Nolan, Christopher J; Ruderman, Neil B; Kahn, Steven E; Pedersen, Oluf; Prentki, Marc.
In: Diabetes, Vol. 64, No. 3, 03.2015, p. 673-86.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Insulin resistance as a physiological defense against metabolic stress
T2 - implications for the management of subsets of type 2 diabetes
AU - Nolan, Christopher J
AU - Ruderman, Neil B
AU - Kahn, Steven E
AU - Pedersen, Oluf
AU - Prentki, Marc
N1 - © 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.
PY - 2015/3
Y1 - 2015/3
N2 - Stratifying the management of type 2 diabetes (T2D) has to take into account marked variability in patient phenotype due to heterogeneity in its pathophysiology, different stages of the disease process, and multiple other patient factors including comorbidities. The focus here is on the very challenging subgroup of patients with T2D who are overweight or obese with insulin resistance (IR) and the most refractory hyperglycemia due to an inability to change lifestyle to reverse positive energy balance. For this subgroup of patients with T2D, we question the dogma that IR is primarily harmful to the body and should be counteracted at any cost. Instead we propose that IR, particularly in this high-risk subgroup, is a defense mechanism that protects critical tissues of the cardiovascular system from nutrient-induced injury. Overriding IR in an effort to lower plasma glucose levels, particularly with intensive insulin therapy, could therefore be harmful. Treatments that nutrient off-load to lower glucose are more likely to be beneficial. The concepts of "IR as an adaptive defense mechanism" and "insulin-induced metabolic stress" may provide explanation for some of the unexpected outcomes of recent major clinical trials in T2D. Potential molecular mechanisms underlying these concepts; their clinical implications for stratification of T2D management, particularly in overweight and obese patients with difficult glycemic control; and future research requirements are discussed.
AB - Stratifying the management of type 2 diabetes (T2D) has to take into account marked variability in patient phenotype due to heterogeneity in its pathophysiology, different stages of the disease process, and multiple other patient factors including comorbidities. The focus here is on the very challenging subgroup of patients with T2D who are overweight or obese with insulin resistance (IR) and the most refractory hyperglycemia due to an inability to change lifestyle to reverse positive energy balance. For this subgroup of patients with T2D, we question the dogma that IR is primarily harmful to the body and should be counteracted at any cost. Instead we propose that IR, particularly in this high-risk subgroup, is a defense mechanism that protects critical tissues of the cardiovascular system from nutrient-induced injury. Overriding IR in an effort to lower plasma glucose levels, particularly with intensive insulin therapy, could therefore be harmful. Treatments that nutrient off-load to lower glucose are more likely to be beneficial. The concepts of "IR as an adaptive defense mechanism" and "insulin-induced metabolic stress" may provide explanation for some of the unexpected outcomes of recent major clinical trials in T2D. Potential molecular mechanisms underlying these concepts; their clinical implications for stratification of T2D management, particularly in overweight and obese patients with difficult glycemic control; and future research requirements are discussed.
KW - Diabetes Mellitus, Type 2
KW - Humans
KW - Hypoglycemic Agents
KW - Insulin
KW - Insulin Resistance
KW - Stress, Physiological
U2 - 10.2337/db14-0694
DO - 10.2337/db14-0694
M3 - Journal article
C2 - 25713189
VL - 64
SP - 673
EP - 686
JO - Diabetes
JF - Diabetes
SN - 0012-1797
IS - 3
ER -
ID: 150711633