Hormones, Signalling & Integrated Metabolism HB

Insulin is secreted from pancreatic beta cells when nutrient-related signals indicate abundance. Its receptor is a receptor tyrosine kinase. Activation initiates phosphorylation cascades that alter glucose transport, enzyme activity, gene expression and anabolic metabolism.

In skeletal muscle and adipose tissue, insulin promotes recruitment of GLUT4-containing vesicles to the plasma membrane, increasing glucose uptake. In liver, glucose transport itself uses different transport logic, but insulin strongly changes enzyme activity and gene expression to favour glycogen synthesis, glycolysis and lipogenesis while suppressing excessive gluconeogenesis.

Insulin also suppresses adipose lipolysis and supports protein synthesis. The fed state is therefore an integrated anabolic program, not merely a fall in blood glucose.

Glucagon is secreted from pancreatic alpha cells when glucose availability is low and acts prominently on liver through G-protein-coupled signalling and cyclic AMP-dependent pathways. It favours hepatic glycogenolysis and gluconeogenesis while opposing selected insulin-driven storage pathways.

As fasting continues, liver glycogen declines and gluconeogenesis assumes greater importance. Adipose lipolysis supplies fatty acids that provide energy to many tissues and glycerol that can contribute to glucose synthesis.

High hepatic fatty-acid oxidation generates acetyl-CoA and supports ketogenesis. This coordinated adaptation preserves limited glucose for tissues with substantial obligatory glucose needs.

The liver acts as a metabolic hub: it stores glycogen, produces glucose during fasting, oxidizes and synthesizes fatty acids, forms ketones and packages lipid into lipoproteins. Skeletal muscle uses glucose, fatty acids and sometimes ketones according to activity and hormonal state, but its glycogen is reserved locally because muscle lacks glucose-6-phosphatase.

Adipose tissue stores triacylglycerol after feeding and releases fatty acids during fasting. The brain normally relies heavily on glucose but increases ketone use during prolonged fasting. Mature red blood cells lack mitochondria and therefore depend on glycolysis, producing lactate.

These differences are why metabolic questions must specify both tissue and state. The same metabolite can have different fates in different organs.

Exercise increases ATP turnover in muscle. Early energy comes from existing ATP/phosphocreatine and rapidly activated glycolysis, while sustained activity increasingly depends on oxidative metabolism according to intensity and oxygen delivery. Muscle glycogen and circulating fuels contribute in proportions that change with duration and training.

Catecholamines and other stress signals mobilize fuel by supporting glycogen breakdown and lipolysis. Liver helps maintain circulating glucose, while increased blood flow delivers oxygen and substrates to working muscle.

Severe illness or trauma can produce a catabolic stress state with insulin resistance, increased proteolysis, lipolysis and hepatic glucose production. This is metabolically different from uncomplicated starvation even though both can involve mobilization of stored fuel.

In type 1 diabetes, severe insulin deficiency removes a major anabolic signal and permits unopposed counter-regulatory effects. Hepatic glucose output rises, peripheral glucose handling is impaired, adipose lipolysis increases and hepatic ketogenesis can become excessive. Hyperglycaemia produces osmotic diuresis, worsening dehydration and electrolyte loss.

Type 2 diabetes is characterized by insulin resistance with progressive beta-cell dysfunction to varying degrees. Metabolic abnormalities extend beyond glucose and commonly involve hepatic, adipose and lipid physiology.

The biochemical lesson is that diabetes is not simply 'too much sugar.' It is a disorder of inter-organ fuel signalling and partitioning whose manifestations follow from altered pathway regulation.

Metabolism is coordinated across organs rather than occurring as isolated pathways. Hormones communicate nutritional and physiological state so liver, adipose tissue, skeletal muscle, brain and other organs can use, store or release fuels appropriately.

In the fed state, insulin promotes glucose utilization, glycogen synthesis, lipid storage and protein anabolism. During an overnight fast, lower insulin and relatively greater glucagon action favour hepatic glycogen breakdown, gluconeogenesis and adipose lipolysis. With prolonged fasting, glycogen becomes depleted, gluconeogenesis continues and ketone-body availability rises, reducing but not eliminating glucose requirements in selected tissues.

Hormone signalling begins with receptor binding and proceeds through intracellular transduction. Membrane receptors commonly use second messengers or kinase cascades; intracellular receptors can directly influence gene transcription. Signal amplification permits small hormonal concentrations to produce substantial metabolic effects.

Organ specialization matters. Liver can export glucose under appropriate conditions; skeletal muscle stores glycogen mainly for its own use; adipose tissue stores triacylglycerol and releases fatty acids; red blood cells depend on glycolysis because they lack mitochondria. The brain usually depends heavily on glucose but can increase ketone use during prolonged fasting.

Mechanism map: identify nutritional state → dominant hormonal signals → tissue-specific enzyme regulation → direction of pathway flux → exported/imported fuels. Never interpret a pathway without specifying organ and physiological state.

Clinical integration includes diabetes, starvation, obesity, endocrine disorders and metabolic response to stress. Metabolic disease often represents failed coordination rather than failure of a single reaction.

Common confusion: a pathway being biochemically possible does not mean it is simultaneously active at high flux in every tissue. Reciprocal regulation prevents wasteful substrate cycling.