High Yield Nutriton and Metabolism V2

What happens to insulin during early starvation?

Insulin decreases as blood glucose falls; pancreatic β-cells reduce secretion → decreased glucose uptake into muscle and fat, increased lipolysis in adipose tissue, increased glycogenolysis and gluconeogenesis in the liver, and signals a fasting state to the hypothalamus

What happens to glucagon during early starvation and why?

Glucagon increases; secreted by pancreatic α-cells in response to low blood glucose → increases glycogen breakdown, gluconeogenesis, and fat breakdown to maintain blood glucose for the brain and RBCs

What is ghrelin, where is it produced, and what triggers its release during starvation?

Ghrelin is the hunger hormone produced by the stomach fundus; released when the stomach is empty and energy stores are low; rises during starvation to stimulate appetite

How does ghrelin stimulate appetite at the hypothalamic level?

Ghrelin acts on the arcuate nucleus of the hypothalamus → stimulates NPY/AgRP neurons (orexigenic neurons) → increases hunger and food-seeking behaviour

What happens to leptin during starvation and what are the consequences?

Fat stores decrease → leptin levels fall → removes inhibition of NPY/AgRP neurons, decreases stimulation of POMC/CART neurons → appetite increases dramatically and energy expenditure decreases

What are NPY/AgRP neurons and what stimulates them?

NPY/AgRP neurons are orexigenic (appetite-increasing) neurons in the arcuate nucleus; stimulated by increased ghrelin and low leptin and insulin; strongly increase hunger and reduce energy expenditure

What are POMC/CART neurons and what happens to them during starvation?

POMC/CART neurons are anorexigenic (appetite-suppressing) neurons; normally stimulated by leptin and insulin; during starvation, decreased leptin and insulin reduce their activity → reduced satiety signalling and increased appetite

What is the role of cortisol during prolonged starvation?

Cortisol is released from the adrenal cortex via HPA axis activation → increases protein breakdown, provides amino acids for gluconeogenesis, maintains blood glucose, and can increase appetite

What is the role of growth hormone during prolonged starvation?

Growth hormone is stimulated partly by ghrelin → preserves muscle mass, increases lipolysis, reduces glucose uptake by tissues, and conserves glucose for the brain

What happens to GLP-1 during starvation and why does it matter?

GLP-1 decreases during starvation (normally released after meals to promote satiety) → less satiety signalling → increased appetite

What happens to CCK during starvation?

CCK decreases (normally released when fats and proteins enter the duodenum to produce fullness) → less satiety signalling during starvation

What happens to Peptide YY (PYY) during starvation?

PYY decreases (normally released after eating to reduce appetite) → appetite increases during starvation

What is the primary cellular change in adipose tissue during obesity?

Excess caloric intake → increased storage of glucose, fatty acids, and triglycerides → adipocyte hypertrophy (enlargement) and hyperplasia (increased number) → increased adipose tissue mass

How does adipose tissue become dysfunctional in obesity?

Adipocytes enlarge excessively → blood supply becomes inadequate → local hypoxia develops → inflammation, macrophage infiltration, and increased cytokine production (TNF-α, IL-6) → chronic inflammation

What is leptin resistance in obesity?

As fat mass increases, leptin levels rise but the brain becomes resistant to leptin → satiety signals are ignored → appetite remains elevated and energy expenditure decreases

What is the normal function of adiponectin?

Adiponectin increases insulin sensitivity, promotes fatty acid oxidation, and reduces inflammation

What happens to adiponectin in obesity and what are the consequences?

Adiponectin decreases in obesity → increased insulin resistance, increased inflammation, and increased cardiovascular risk

How does normal insulin action work at the cellular level?

Insulin binds receptors on muscle, liver, and adipose tissue → promotes glucose uptake via GLUT4, glycogen synthesis, and reduced hepatic glucose production

How do excess free fatty acids and cytokines from large adipocytes cause insulin resistance?

Large adipocytes release excess FFAs, TNF-α, and IL-6 → these interfere with insulin signalling pathways → reduced GLUT4 translocation → reduced glucose uptake → insulin resistance

How does the pancreas compensate for insulin resistance and what is the eventual outcome?

Pancreatic β-cells produce more insulin (hyperinsulinaemia); initially blood glucose remains normal; eventually β-cell dysfunction develops → insulin production becomes inadequate → hyperglycaemia → prediabetes and T2DM

What is the central event in metabolic syndrome and what does visceral fat release?

The central event is visceral obesity; visceral fat releases FFAs, TNF-α, IL-6, and resistin → drive insulin resistance

How does insulin resistance cause hyperglycaemia in metabolic syndrome?

Insulin resistance → reduced glucose uptake by muscle + increased hepatic glucose production → elevated blood glucose

How does visceral obesity cause dyslipidaemia?

Excess FFAs enter the liver → liver produces increased VLDL and triglycerides → increased triglycerides and low HDL cholesterol

How does obesity cause hypertension?

Hyperinsulinaemia → increased sympathetic nervous system activity and sodium retention by kidneys; adipose tissue activates RAAS → vasoconstriction, fluid retention, and increased BP

What causes the pro-inflammatory state in metabolic syndrome?

Visceral fat continuously releases TNF-α, IL-6, and stimulates CRP production via the liver → chronic low-grade inflammation → accelerated atherosclerosis

What causes the pro-thrombotic state in obesity?

Obesity increases PAI-1 (plasminogen activator inhibitor-1) and fibrinogen → increased risk of clot formation → increased risk of MI and stroke

What are the genetic risk factors for T1DM?

Strongly associated with HLA class II genes (HLA-DR3, HLA-DR4, DQ2, DQ8); family history increases risk but inheritance is not deterministic

What autoantibodies are characteristic of T1DM?

Anti-GAD (glutamic acid decarboxylase), anti-IA2 (tyrosine phosphatase), and insulin autoantibodies; T-cell mediated cytotoxicity is the main destructive mechanism

What are the environmental triggers for T1DM?

Viral infections, early life environmental exposures, and possible role of microbiome changes

Describe the 5-step pathogenesis of T1DM

Step 1: Environmental trigger in genetically susceptible person activates immune response; Step 2: CD4+ and CD8+ T-cells infiltrate pancreatic islets (insulitis); Step 3: Progressive β-cell destruction over months-years; Step 4: Loss of insulin secretion → decreased glucose uptake, increased gluconeogenesis/glycogenolysis; Step 5: Hyperglycaemia, lipolysis, ketone production, risk of DKA

What are the types and examples of basal insulin used in T1DM?

Long-acting basal insulin: glargine, detemir, degludec; controls fasting glucose

What are the types and examples of bolus insulin used in T1DM?

Rapid-acting bolus insulin: aspart, lispro, glulisine; covers meals

What are the two delivery methods for insulin in T1DM?

Multiple Daily Injections (MDI) and insulin pump (continuous subcutaneous insulin infusion, CSII)

What is the principle of basal-bolus insulin therapy?

It mimics physiological insulin secretion: basal insulin controls fasting glucose; bolus insulin covers meals

How is mild hypoglycaemia managed in T1DM?

Fast-acting carbohydrates such as glucose tablets or juice

How is severe hypoglycaemia managed in T1DM?

Glucagon injection or IV dextrose; education on recognising symptoms (sweating, tremor, confusion)

What are the four components of DKA emergency management?

IV fluids, IV insulin infusion, electrolyte replacement (especially potassium), and treating the underlying trigger (e.g., infection or missed insulin)

What long-term complications should T1DM patients be screened for?

Regular screening for retinopathy, nephropathy, and neuropathy; cardiovascular risk management including blood pressure and lipid management

What is the primary defect in DKA and why does it matter?

Absolute insulin deficiency due to β-cell destruction → insulin cannot promote glucose uptake, inhibit ketogenesis/lipolysis, or suppress hepatic glucose output

What happens to counter-regulatory hormones in DKA?

Glucagon, adrenaline, cortisol, and growth hormone all rise → body enters a starvation-like state despite high blood glucose

How does DKA lead to osmotic diuresis and dehydration?

Hyperglycaemia → glucose spills into urine (glycosuria) → water follows → osmotic diuresis → loss of water, sodium, and potassium → dehydration, hypotension, tachycardia

How does ketogenesis occur in DKA?

Cells enter a starvation-like state → lipolysis increases → FFAs released into bloodstream → FFAs enter liver mitochondria → converted into ketone bodies: acetoacetate, β-hydroxybutyrate, and acetone; driven by increased glucagon and low insulin

How does DKA cause metabolic acidosis?

Ketone bodies are acidic → accumulate faster than they can be excreted → high anion gap metabolic acidosis → decreased blood pH

What is Kussmaul breathing and why does it occur in DKA?

Deep, rapid breathing triggered by the acidotic state stimulating the respiratory centre; tries to blow off CO₂ to compensate for metabolic acidosis

Why may serum potassium be normal or high in DKA despite total body potassium depletion?

Insulin deficiency shifts K⁺ out of cells; acidosis also drives K⁺ out of cells → serum K⁺ appears normal/high even though total body K⁺ is low (lost in urine)

What gene is strongly associated with T2DM genetic predisposition and what does it affect?

TCF7L2; affects insulin secretion, insulin signalling pathways, and β-cell function

What lifestyle and environmental factors increase T2DM risk?

Obesity, sedentary lifestyle, high calorie/fat diet, aging, sleep disturbance, and ethnicity-related risk

What are the two core pathophysiological defects in T2DM?

Insulin resistance and progressive β-cell dysfunction (failure)

How does insulin resistance manifest in muscle in T2DM?

Decreased GLUT4 translocation and glucose uptake → hyperglycaemia after meals

How does insulin resistance manifest in the liver in T2DM?

Insulin fails to suppress gluconeogenesis and glycogenolysis → increased fasting glucose

How does insulin resistance manifest in adipose tissue in T2DM?

Increased lipolysis → increased free fatty acids → worsens insulin resistance

What three processes cause progressive β-cell failure in T2DM?

Glucotoxicity (high glucose damages β-cells), lipotoxicity (high fatty acids damage β-cells), and amyloid deposition (islet amyloid polypeptide)

What is the net metabolic result of T2DM?

Increased fasting and post-prandial blood glucose; persistent hyperinsulinaemia early then decline; no ketosis initially because insulin is still partially present

What are the key mechanisms by which chronic hyperglycaemia causes tissue damage in T2DM?

Advanced glycation end products (AGEs), oxidative stress, endothelial dysfunction, basement membrane thickening, and microvascular ischaemia

What are the early and late structural changes in diabetic nephropathy?

Early: glomerular hyperfiltration; then AGEs → thickening of glomerular basement membrane, mesangial expansion and sclerosis, podocyte injury → Kimmelstiel-Wilson nodules

What is the clinical progression of diabetic nephropathy?

Microalbuminuria → proteinuria → declining GFR → end-stage renal disease

What are the pathophysiological changes in early diabetic retinopathy?

Capillary basement membrane thickening, pericyte loss (weakens capillary walls), microaneurysm formation, and retinal ischaemia → VEGF release

What distinguishes non-proliferative from proliferative diabetic retinopathy?

Non-proliferative: microaneurysms, dot-blot haemorrhages, cotton wool spots; Proliferative: neovascularisation (fragile new vessels), risk of vitreous haemorrhage and retinal detachment

What are the two major mechanisms of diabetic neuropathy?

Metabolic injury (sorbitol accumulation via polyol pathway, oxidative stress, mitochondrial dysfunction) and microvascular ischaemia (reduced blood flow → nerve hypoxia)

What is the pattern of peripheral neuropathy in diabetes?

"Stocking-glove" distribution; symptoms include numbness, tingling, and pain

What are four manifestations of autonomic neuropathy in diabetes?

Gastroparesis, postural hypotension, erectile dysfunction, and bladder dysfunction