Table 1.

Overactivation of the survival switch may drive metabolic diseases.

survival feature	disease	initial reversible mechanism	chronic less-reversible mechanism	references
weight gain and fat accumulation	visceral obesity	leptin resistance, ↑intestinal absorptive area, mitochondrial oxidative stress, lipogenesis, impaired fat oxidation	adipocyte senescence and mitochondria loss may lead to persistent obese state	[38,41,47,72,78,175]
systemic insulin resistance and islet dysfunction	type 2 diabetes	systemic insulin resistance and impaired insulin secretion	loss of islets from oxidative injury and scarring leads to persistent diabetic state	[132]
elevation of blood pressure	primary hypertension	uric acid-induced hypertension due to endothelial dysfunction, oxidative stress and angiotensin II	kidney-dependent hypertension associated with inflammation and salt-sensitivity	[176,177]
fat deposition in liver	nonalcoholic fatty liver disease	fat deposition with mild inflammation	cirrhosis	[25,178]
increase in lipids in blood	dyslipidaemia	increased risk for fat deposition in blood vessels	atherosclerosis	[179]
preservation of kidney excretion	chronic kidney disease	uric acid-dependent hyperfiltration and elevated glomerular filtration pressure	progressive nephron loss from arteriolopathy, inflammation and hyperfiltration	[91,92,180]
elevations in uric acid (part of general survival response)	gout, CKD and heart disease	gout and urate crystal deposition in blood vessels and kidney, systemic inflammation	crystal deposition leads to local injury and scarring, atherosclerotic plaques, vascular calcification	[181,182]
protect from hypoxia (mitochondrial suppression with stimulation of glycolysis)	obesity-associated cancers	stimulate cancer growth by allowing cells to better survive in hypoxic environments before blood supply is established	cancer metastases (especially breast, colon, pancreatic)	[111]
	activated at sites of tissue ischaemia (kidney, heart)	local oxidative stress and inflammation exacerbate local tissue injury	cardiac remodelling, kidney tissue scarring	[16,183]
foraging behaviour	behavioural disorders (ADHD, bipolar disease, gambling), Alzheimer's disease	decreased cerebral glucose metabolism in insulin-dependent areas associated with self-control, deliberation and recent memory	mitochondrial loss, neuronal loss	[74,75,88]
recurrent activation of the switch	accelerated ageing	low grade inflammation, mitochondrial suppression, decreased Nrf2, sirtuins	mitochondria loss, capillary loss, low grade scarring	[145]
pregnancy	preeclampsia	ischaemia drives continued fructose generation in placenta and fetus	increased long-term risk for hypertension and kidney disease	[18]
chronic stimulation of ACTH via V1b receptor	aldosteronism	aldosterone breakthrough, aldosterone effects in resistant hypertension	development of primary aldosteronoma	[184]