Insulin Resistance: The Inconvenient Truth

What is the origin of the term ‘insulin resistance’?

Is insulin resistance the cause or the consequence?

Does insulin resistance routinely require long-term medications?

The term Insulin Resistance (IR) was first introduced by Professor Wilhelmina Faltu in 1931 and this was reiterated by Sir Harold Percival Himsworth in 1936.¹ Interestingly, insulin therapy was introduced before this in 1922.² Most of the early patients required increasingly large doses of insulin to control hyperglycemia. As early forms of insulin were impure and derived from nonhuman species, people often developed antibodies to therapeutic insulin leading to resistance.³ In the present era of recombinant human insulin, anti-insulin antibodies do not raise to levels sufficient to impair insulin action.

The modern-day understanding and clinical spectrum of IR has changed markedly. IR may be defined as a subnormal glucose response to endogenous and/or exogenous insulin. Physiological stress like pregnancy (placental lactogen) may lead to IR. Pathological stress with excess counter-regulatory hormones like cortisol, growth hormone, catecholamines, and glucagon may also cause IR. Also, medications (glucocorticoids, antiretrovirals, oral contraceptives), or medical conditions such as lipodystrophy, genetic defects in insulin-signaling pathways (Type A insulin resistance) and blocking autoantibodies against the insulin receptor (Type B insulin resistance) may lead to IR. Rare inherited conditions like Leprechaunism, Rabson-Mendenhall syndrome and lipodystrophy disorders may warrant genetic testing and appropriate management to limit IR-related mortality.⁴

IR has been implicated in the causation of many conditions like polycystic ovarian syndrome (PCOS), Type 2 Diabetes mellitus, the metabolic syndrome, fatty liver and coronary artery disease. The precise basis for the link between IR and these clinical conditions is not yet identified. In all these conditions it is widely believed that the cells are resistant to the action of insulin. Insulin levels are variable in patients with Type 2 diabetes mellitus, PCOS, and in the metabolic syndrome. Failure of beta cells to produce insulin may be the issue in some. There is no consistent relationship between insulin levels and occurrence or severity of the condition in patients with PCOS. Estimation of insulin levels are no longer recommended for the diagnosis of PCOS.⁵ Relative calorie excess and sedentary lifestyle in all these conditions may contribute to the elevation in serum insulin levels.

IR can be diagnosed by IV glucose/insulin tolerance testing or from individual blood tests like HOMA-IR ASSAY or Quicki assay.⁶ While these tests can also be performed in a medical practice, we often encounter them in research settings. Insulin level is not routinely measured in Type 2 diabetes mellitus and metabolic syndrome. Insulin levels when estimated do not show a consistent pattern in patients with Type 2 diabetes mellitus. In some portion of IR patients, beta cell failure with low serum insulin levels coexists. More often, insulin level is positively correlated to glucose levels. As the blood glucose level goes up, insulin level goes up too. When patients can still produce enough insulin, elevated serum insulin is the consequence of raised glucose level and not the cause of it.

With the worldwide obesity epidemic, some physicians find it increasingly impolite to confront their patients with the real problems of sedentary habits, over-eating, sugar-added food/beverage consumption and resultant obesity. Intellectualizing and reframing ‘insulin resistance’ as an independent medical entity allows for lifelong palliation with numerous diabetic medications, downstream expensive cardiovascular and peripheral revascularization procedures as well as excess morbidity and mortality.

IR as originally described has taken a back seat with the bulk of the current patient population being comprised of obesity-related derangements and complications (Figure 1). Deregulation of fatty acid metabolism and mitochondrial dysfunction may genetically predispose some to IR. Thin patients with PCOS may have IR as an independent medical condition and require medications. Improved lifestyle, emphasizing diet, exercise, stress control, and optimal sleep can specifically improve IR, reduce medication requirement and enhance long term outcomes in all these conditions.

Figure 1.

Label of Insulin resistance – changing etiology over last 100 years

The term ‘Insulin Resistance’ (IR) originally described antibodies to animal forms of insulin in 1930s, while genetic etiology for IR remains a small fraction. The dramatic increase in IR over the last 2–3 decades corresponds to the obesity epidemic. IR is not formally quantified but presumed to be the basis for several metabolic derangements. This distracts from the real issue of over nutrition, sedentary habits and obesity.

Much of the modern IR epidemic is due to inflammation, sugar-added diet, stress-related neurohumoral activation, and visceral adiposity. Type 2 diabetics typically respond to increasing serum insulin-either exogenous formulations or sulphonylurea mediated endogenous stimulation-indicating that IR is not the primary issue. Over time, the term ‘IR’ has assumed new meaning and is thought of as the very basis for PCOS, Type 2 Diabetes Mellitus and Metabolic Syndrome. All these conditions have significant over-nutrition and weight gain as the underlying pathophysiological basis. A recent UK diet study resulted in 86% remission and withdrawal of antidiabetic medications with 15kg weight loss.⁷ Calorie restriction increased longevity across the animal kingdom mediated by dramatic cardiometabolic risk reduction seen in primates.^8,9 Even amongst healthy normal weight humans, 25% calorie restriction reduces IR significantly and future risk of diabetes with tremendous public health potential.¹⁰

In conclusion, insulin resistance is widely misunderstood among clinicians and patients alike. The originally described condition in diabetics developing antibodies to impure early insulin formulations, and thus requiring dose escalations, has become exceedingly rare now. Genetic forms account for a small minority of real IR in non-obese healthy individuals. In most Type 2 diabetics, elevated insulin level is the consequence of raised glucose load and not the cause of it. IR is often not an independent medical condition requiring long term medications. Obesity needs to be addressed as such, directly and specifically. Targeting diet, exercise, and weight reduction offers a window of opportunity to resolve ‘insulin resistance’ and oftentimes cure metabolic syndrome minimizing chronic disease management with medications.