Insulin resistance

Insulin resistance is fundamentally a stress reaction, not a simple consequence of carbohydrate consumption. 2 Peat argued that the condition is not a generalized failure of cells to respond to insulin, but a differential sensitivity: under stress, the liver becomes resistant to insulin, impairing glucose disposal, while fat cells become highly sensitive to insulin, actively converting sugar into fat. 2 This explains why hyperglycemia and obesity can coexist, as the stress-induced hormonal environment directs energy toward storage rather than oxidation. 1 The diagnostic failure to measure blood insulin routinely means that stress-induced hyperglycemia is often mislabeled as classical insulin-deficiency diabetes, leading to inappropriate insulin prescriptions. 3

The primary driver of this metabolic block is the Randall cycle, the competition between free fatty acids and glucose for mitochondrial oxidation. 2 Dinkov has emphasized that insulin resistance is driven by an excess of fatty acids in the bloodstream, which prevents cells from properly oxidizing glucose. 2 This is not an intrinsic cellular defect but a state imposed by the metabolic environment; cells forced to oxidize fats cannot simultaneously metabolize carbohydrates, causing glucose to be diverted into lactic acid or converted into fat via fatty acid synthase. 10 The accumulation of unstable polyunsaturated fats is particularly problematic, as they not only block glucose oxidation but also spontaneously form toxic aldehydes that further impair metabolic function. 7

The hormonal context of insulin resistance is dominated by the catabolic stress hormones cortisol and estrogen. 2 Dinkov views the entire metabolic syndrome spectrum as an endocrine disorder on the continuum of Cushing's syndrome, where cortisol drives gluconeogenesis, producing the majority of elevated blood glucose seen in diabetics, and redistributes fat centrally to create visceral adiposity. 8 These stress hormones directly suppress thyroid function and metabolic rate, creating a vicious cycle where a low metabolic rate both causes and is worsened by insulin resistance. 9 The condition is therefore a sign of systemic energy failure, where the ratio of catabolic to anti-catabolic hormones has shifted unfavorably. 2

This framework explains why insulin resistance is not exclusive to obesity. Dinkov has noted that lean individuals can develop the condition, and that some extremely obese populations never develop diabetes because they lack the continuous endogenous supply of fatty acids from stress-driven lipolysis. 2 The crucial factor is the combination of accumulated fat and elevated baseline lipolysis, which floods the bloodstream with free fatty acids. 4 Simply adding more sugar to an already insulin-resistant state can worsen the problem by triggering an insulin response that provokes a compensatory cortisol release, further increasing fatty acid mobilization. 10 The therapeutic implication is that lowering the supply of fat to the bloodstream—whether by reducing stress, blocking cortisol, or eliminating polyunsaturated fats—should restore the cell's ability to oxidize glucose, as there is no inherent damage to the cellular machinery. 10