Gluconeogenesis

Gluconeogenesis is the creation of new glucose from non-carbohydrate precursors, a process that Ray Peat’s framework views as a stress-driven adaptation rather than a benign, demand-driven feature of metabolism. 2 Peat argued that under stress, when efficient glucose oxidation fails, the body shifts to burning fat and breaking down tissue protein to produce sugar, a process mediated by the rise of cortisol and ACTH. 2 He emphasized that this shift is a restrained, catabolic reaction because the body has no protein storage; thus, when cortisol rises to drive gluconeogenesis, it means some part of the body is undergoing a loss of function and structural integrity. 2

The hormonal cascade governing this process is hierarchical and reveals why proponents of low-carbohydrate diets misinterpret its activation. Danny Roddy, drawing on Peat’s work, has detailed that glucagon and catecholamines are the immediate "emergency hormones" released when blood sugar falls, acting to mobilize stored glycogen. 2 Cortisol is a slower, more sustained late-stage stress hormone that becomes necessary when glycogen is depleted, breaking down tissue to supply amino acids for glucose production. 2 Roddy notes that the claim that gluconeogenesis is harmless because it is driven by glucagon rather than cortisol is a false comfort, as glucagon itself is a stress hormone rapidly released in response to various stressors, and its elevation is part of a complex biochemical web that includes adrenaline and ultimately requires cortisol to sustain the process. 2

The context of dietary carbohydrate restriction fundamentally alters the nature of gluconeogenesis. Kyle Mamounis, in discussion with Roddy, distinguished between a normal, demand-driven state—where intense exercise might transiently upregulate the process—and the supply-driven state of a low-carb diet, where excess dietary protein beyond what can be used for synthesis is inevitably converted to glucose. 1 This chronic reliance on gluconeogenesis for baseline blood sugar maintenance is seen as inherently stressful, chronically activating the hypothalamic-pituitary-adrenal (HPA) axis. 2 Roddy has pointed out that elevated fasting blood glucose in a low-carb context, often misattributed to dietary carbohydrate, is frequently a direct result of this hormonally-driven glucose production, a phenomenon observed in meticulous self-experimentation by individuals attempting to lower their glucose by manipulating protein intake. 2

The inefficiency and systemic cost of this pathway are central to its negative characterization. Peat explained that forcing physiology to rely on fat and protein for energy produces less carbon dioxide, a protective molecule that prevents glycation and delivers oxygen to tissues, and generates more inflammatory breakdown products. 10 Roddy and Mamounis further note that the process is linked to increased ammonia production and is fundamentally inefficient compared to direct glucose oxidation. 2 The broader bioenergetic view holds that a healthy metabolism should have a robust appetite for carbohydrate, and the absence of this appetite signals a reliance on the life-subtracting adaptive substances like glucagon and cortisol that drive gluconeogenesis. 5