Insulin resistance as a physiological defense against metabolic stress: implications for the management of subsets of type 2 diabetes

Abstract

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.

Figure 1

Hypothetical model illustrating the molecular basis of insulin-induced metabolic stress in patients with poorly controlled T2D in which both blood glucose and FFA levels are persistently elevated. Depicted here is a cell in which (A) IR protects from nutrient overload and metabolic stress by limiting glucose flux into the cell and (B) the IR protection is overridden by a high dose of exogenous insulin therapy, which promotes excess glucose uptake and glucolipotoxicity. Excess glucose supply to the mitochondria results in reducing equivalent overload of the electron transfer chain and enhanced production of ATP and ROS, resulting in oxidative damage. The resulting increased ATP/AMP ratio inhibits AMPK, which has the effect of decreasing FFA oxidation (limiting nutrient detoxification) favoring fat deposition. Enhanced glucose uptake can also result in excessive glycogen deposition and increased activities of the toxic polyol, hexosamine, and AGE formation pathways. Glucose that is metabolized via the anaplerosis pathway can also increase cytosolic acetyl-CoA (AcCoA) and malonyl-CoA (MalCoA). AcCoA and MalCoA are then available for cholesterol and fatty acid synthesis, increasing the lipid load on the cell. MalCoA also inhibits fatty acyl-CoA (FACoA) entry into the mitochondria such that FACoA is more available for synthesis of complex lipids, including glycerolipids (phospholipids, diacylglycerols, and triglycerides) and ceramides. This can result in endoplasmic reticulum stress and the accumulation of lipid droplets (steatosis). Increased ROS production, toxic lipid accumulation, and reduced AMPK activity are factors that also activate the inflammasome contributing to cardiac injury. The overall effect is nutrient overload and metabolic stress causing cell dysfunction or death and cardiac inflammation. CD36, free fatty acid transporter; DAG, diacylglycerols; ER, endoplasmic reticulum; ETC, electron transport chain; GLUT4, facilitative glucose transporter 4; IRc, insulin receptor; MITO DYSF, mitochondrial dysfunction; OXID STRESS, oxidative stress; Pyr, pyruvate; PL, phospholipids; TG, triglycerides; Tx, treatment.

Figure 2

Differential beneficial or adverse effects of insulin therapy on vascular endothelial cells depending on the level of metabolic control achieved. Insulin signaling in endothelial cells can be via the PI3K (causes vasodilation and is anti-thrombotic) and the MAPK pathway (causes vasoconstriction and is prothrombotic) such that there is a balance of beneficial and harmful effects. In response to an excess nutrient supply, as occurs in metabolically uncontrolled T2D, selective IR in the PI3K pathway will occur such that signaling through the MAPK pathway will be unopposed, increasing the risk of vascular events. Insulin treatment will either improve or worsen vascular health depending on whether it is effective or not at bringing blood nutrient levels under control. If high exogenous insulin therapy is successful at improving blood nutrient levels, then insulin signaling through the PI3K pathway will increase such that insulin therapy will be beneficial to blood vessel health. However, if high dose exogenous insulin therapy fails to control blood nutrients (i.e., in refractory patients), then the IR in the PI3K pathway will not be relieved and insulin signaling will predominate via the harmful MAPK pathway and increase the risk of vascular events.

Figure 3

The potential benefit of nutrient off-loading approaches compared with the overriding of IR to lower blood glucose in subjects with poorly controlled T2D. Insulin-responsive tissues, such as the heart, skeletal muscle, adipose tissue, and the liver, are able to protect themselves from nutrient-induced damage by developing IR. Other tissues, such as nerves, eye, kidney, and the vasculature, are less protected by IR. The clinician has the choice to 1) treat the hyperglycemia with enough insulin to override IR and reduce nutrient toxicity in tissues at longer-term risk of microvascular complications but with the risk of increasing insulin-induced metabolic stress in the insulin-responsive tissues or to 2) use alternative nutrient off-loading approaches to glucose lowering to benefit all tissues. Insulin-induced metabolic stress is more likely to occur with high-dose insulin therapy in patients who are refractory to improved glycemic regulation. Sulfonylureas could potentially have similar effects to high-dose insulin as they increase insulin levels without effect to nutrient off-load. Bariatric surgery, GLP-1 receptor (GLP-1R) agonists, α-glucosidase inhibitors, and SGLT2 inhibitors have well-known mechanisms by which they nutrient off-load. Metformin likely detoxifies nutrients because it is a mild inhibitor of mitochondrial function that is thought to activate AMPK in liver and other tissues. TZDs, via promoting nutrient partitioning to adipose tissue, may nutrient off-load other more critical tissues. DPP-4 inhibitors do not appear to have nutrient off-loading effects.

Figure 4

The appropriateness of insulin therapy in patients with T2D. The need for insulin therapy depends on whether it is being used as replacement in insulin-deficient patients (less likely to cause harm) or to override IR (more likely to cause harm). Insulin-deficient patients are more likely to be lean and in neutral or negative energy balance, with low C-peptide levels and poor glycemic control. Insulin-induced harm is more likely to occur in overweight and obese subjects with IR and high C-peptide levels and an inability to achieve negative energy balance through lifestyle change. In these patients, lifestyle and pharmacological therapies aimed at reversing the excess nutrient imbalance are more advisable than insulin therapy.