Metabolism: Concept Checklist

Concepts covered across the module lectures, grouped by lecture. Tick each once you can explain it from memory.

L1 Metabolic Overview (24 Apr) L1 Metabolism Metabolic Overview

• Three routes linking metabolism to disease: inherited enzyme defects, dysregulation, ischaemia
• Prevalence and cost of obesity and diabetes in NZ, and obesity as a cause of liver disease
• Energy balance equation and why obesity is not simple
• Competing hypotheses for obesity: genetic (FTO), endocrine, dietary, metabolic adaptation
• Hypothalamic arcuate nucleus circuit: NPY/AgRP vs melanocortin neurons, and the roles of leptin, insulin, ghrelin and PYY
• Metabolic adaptation after weight loss: persistently lowered basal metabolic rate
• Core metabolic map: interconversions of protein, glycogen, glucose, fatty acids and acetyl-CoA; citric acid cycle; ketone bodies; urea
• Anabolic vs catabolic pathways with their substrates and products
• Fuel stores in a 70 kg adult and the aims of energy homeostasis
• Resting energy expenditure by organ: rate per kg vs share of total
• Preferred fuels and exported fuels of brain, muscle, heart, adipose tissue and liver; interorgan fuel exchange
• Fed, between-meal and starved states, and the brain’s fuel requirement as the constraint on the fasting response

L2 Regulation of fuel metabolism (24 Apr) L2 Metabolism Regulation of fuel metabolism

• Glucose homeostasis: normal range, glycogen as a buffer, hypoglycaemic vs hyperglycaemic hormones, 24-hour insulin and glucagon pattern
• Glucose-stimulated insulin secretion in the beta cell (GLUT2, glucokinase, ATP/ADP, KATP closure, Ca2+ influx), and stimulators and inhibitors of secretion
• Insulin structure and processing from preproinsulin to insulin and C-peptide; hexamer storage with zinc
• The incretin effect; GLP-1 short half-life, DPP-4 breakdown, long-acting analogues and GLP-1 receptor signalling
• Overall metabolic effects of insulin on liver, muscle and adipose tissue
• Reversible phosphorylation as a regulatory mechanism
• Insulin receptor signalling: Ras/MAPK growth branch vs PI3K/Akt metabolic branch; GLUT4 translocation
• Regulation of glycogen synthase and glycogen phosphorylase by insulin (PP1, GSK3)
• Tissue differences in glucose sensing: GLUT2 vs GLUT4, glucokinase vs hexokinase kinetics
• Adiponectin: source and protective actions on liver, muscle and heart
• Glucagon: control of secretion, target tissues, metabolic effects, and the cAMP/PKA/phosphorylase kinase cascade
• Adrenaline: stimuli, actions including on muscle glycogen, and stress hyperglycaemia
• Glycogen storage diseases: enzyme defects, organs affected and key manifestations (von Gierke, Pompe, McArdle, others)

L3 Dysregulation of fuel metabolism in diabetes (29 Apr) L3 Metabolism Dysregulation of fuel metabolism in diabetes

• Hypoglycaemia: thresholds, early autonomic (sweating, trembling, tachycardia) vs neuroglycopenic symptoms, causes, and treatment (oral glucose, IM glucagon, IV glucose)
• Diabetes mellitus vs diabetes insipidus; symptoms of hyperglycaemia
• Diagnostic criteria for diabetes (fasting, random, HbA1c, GTT) and when a single test suffices
• Type 1 vs type 2 diabetes: cause, onset, genetics, obesity, ketoacidosis risk, treatment response, complications
• MODY: frequency, genes involved and why the diagnosis matters
• Metabolic derangements of the diabetic state in liver, muscle and adipose tissue
• Insulin resistance: failure to suppress hepatic glucose output and lipolysis, and to promote peripheral glucose uptake
• Treatment of type 1 and type 2 diabetes, and long-term follow-up
• Acute complications of diabetes, including DKA pathogenesis (hyperglycaemia and ketogenesis pathways) and management principles
• Chronic microvascular and macrovascular complications; HbA1c as a time-averaged measure
• Biochemical basis of complications: polyol pathway, non-enzymatic glycation, AGEs and RAGE signalling
• Molecular mechanisms of insulin resistance: inhibitory serine phosphorylation of IRS, SOCS, PTPases, PI3K, Akt/AS160
• AMPK: its normal metabolic roles and its inhibition in obesity-related insulin resistance; activation by exercise, adiponectin, metformin

L4 Overview of the role of diet in health and disease (29 Apr) L4 Metabolism Overview of the role of diet in health and disease

• Diet as the single largest risk factor for health loss in NZ, and its component dietary risks
• Obesity and overweight trends in NZ and international comparison
• Genetic susceptibility vs environment in obesity, and rare monogenic causes (MC4R, leptin, leptin receptor, POMC)
• Type 2 diabetes and prediabetes prevalence in NZ by age and ethnicity, and projected trends
• Finnish Diabetes Prevention Study: lifestyle targets and dose-response with diabetes incidence
• DiRECT trial: weight loss and remission of type 2 diabetes, dose-response with weight lost; benefits of moderate vs substantial weight loss
• Ischaemic heart disease mortality trends in NZ and the role of diet
• Body fatness and cancer risk by site (convincing vs probable), and dietary fibre dose-response
• The obesogenic food environment, industry tactics, and the failure of policy to reverse obesity
• Food labelling and shared responsibility for preventing diet-related disease

L7 Gluconeogenesis and response to trauma (4 May) L7 Metabolism Gluconeogenesis and response to trauma

• Gluconeogenesis: sites, timing relative to glycogenolysis after a meal, and precursors (lactate, glycerol, alanine)
• Why acetyl-CoA and fatty acids cannot be converted to glucose (irreversible PDH)
• The gluconeogenic pathway and the bypasses of pyruvate kinase and PFK-1; key regulatory enzymes
• Bypass of pyruvate kinase: pyruvate carboxylase and PEPCK; allosteric regulation by acetyl-CoA; hormonal control of PK and PEPCK
• Transcriptional regulation of PEPCK and G6Pase by insulin (Akt/FOXO), glucagon, cortisol and others
• Fructose-2,6-bisphosphate as the allosteric switch between glycolysis and gluconeogenesis, and its control by insulin and glucagon via PFK2
• Conditions of impaired gluconeogenesis (prematurity, alcohol via NADH excess, enzyme deficiencies) and overactive gluconeogenesis (insulin resistance, diabetes, trauma)
• Phases of the metabolic response to injury and the endocrine changes in each
• Effects of injury and sepsis on glucose, insulin, glucagon and substrate oxidation
• Catabolic phase: features, contributing factors, stress-induced glucose intolerance
• Inter-organ coordination during stress: lipolysis and proteolysis supplying hepatic gluconeogenesis
• Altered glucose metabolism in cancer cells

L8 Antioxidants, oxidants and oxidative stress _ Oxidative stress in metabolism _ disease (4 May) L8 Metabolism Antioxidants, oxidants and oxidative stress _ Oxidative stress in metabolism _ disease

• Redox basics (OIL RIG) and oxygen as a free radical with two unpaired electrons
• Stepwise reduction of O2 to superoxide, hydrogen peroxide, hydroxyl radical and water; enzyme-controlled vs pathological (Fenton, lipid peroxidation) routes
• Biologically important radical and non-radical ROS, including peroxynitrite and HOCl
• Endogenous ROS sources: mitochondrial electron leak, NADPH oxidases, xanthine oxidoreductase, ER; exogenous sources
• Physiological roles of ROS, including redox cell signalling
• Definition of an antioxidant and mechanisms of antioxidant defence
• Enzymatic antioxidant network (SODs, catalase, glutathione peroxidase/reductase, peroxiredoxins/thioredoxin) and subcellular compartmentalisation
• Endogenous and dietary antioxidant molecules; vitamin E as a lipid peroxyl scavenger; vitamin C roles, saturable absorption, higher requirement in type 2 diabetes
• Definitions of oxidative stress and oxidative damage; difficulty measuring ROS and features of a good biomarker
• The antioxidant paradox: failure of supplementation trials, possible harms, blunting of exercise benefits
• Mechanisms linking oxidative stress to obesity, type 2 diabetes and metabolic syndrome
• Hyperglycaemia-driven oxidative stress: AGE formation, AGE-RAGE signalling via NF-kB, PKC activation
• Crosstalk between oxidative stress and insulin signalling in insulin resistance
• Keap1-Nrf2-ARE pathway: basal degradation, cysteine oxidation, nuclear translocation and target genes; dietary Nrf2 activators
• Nrf2 in diabetes and approved Nrf2-activating drugs (dimethyl fumarate, omaveloxolone)

L9 Lipogenesis, lipolysis and ketogenesis (6 May) L9 Metabolism Lipogenesis, lipolysis and ketogenesis

• Define lipogenesis, de novo lipogenesis, lipolysis, beta-oxidation and ketogenesis
• Hepatic and adipose handling of glucose and fat in the fed state; when de novo lipogenesis actually runs
• De novo lipogenesis pathway: glucokinase, PDH, citrate export, citrate lyase, ACC, fatty acid synthase, TAG assembly and VLDL export
• Transcriptional regulation of lipogenesis by insulin (SREBP-1c) and glucose (ChREBP)
• Allosteric and covalent regulation of acetyl-CoA carboxylase
• Malonyl-CoA inhibition of CPT1 as the switch preventing simultaneous lipogenesis and beta-oxidation
• AMPK as a cellular fuel gauge and its effects on glucose uptake, lipogenesis, cholesterol synthesis and fat oxidation
• Non-alcoholic fatty liver disease: significance, case features and progression to NASH, fibrosis and cirrhosis
• How insulin resistance loads the liver with fat: increased FFA flux, impaired LPL, increased de novo lipogenesis
• Regulation of lipolysis, hormone-sensitive lipase and the glucagon-cAMP-PKA cascade in adipocytes
• Fatty acid oxidation between meals, the carnitine shuttle, and carnitine deficiency
• Ketogenesis in the liver and ketone body use in peripheral tissues; plasma ketone levels in different states
• Why ketogenesis is high in type 1 diabetes but limited in type 2 diabetes

L10 Metabolic syndrome (8 May) L10 Metabolism Metabolic syndrome

• Definition of metabolic syndrome and comparison of IDF, WHO and harmonized diagnostic criteria, including ethnicity-specific waist thresholds
• History of the concept from Joslin and Vague to Reaven’s Syndrome X and the CKM model
• Prevalence of metabolic syndrome and its components, and increase with age
• Why metabolic syndrome matters: increased risk of diabetes, cardiovascular disease and mortality
• Problems with the definition: common components, circularity, visceral vs subcutaneous fat, limits of BMI and waist circumference
• Pathophysiology: insulin resistance and hyperinsulinaemia preceding diabetes
• Obesity as chronic low-grade inflammation: adipocyte enlargement, macrophage crown-like structures, pro-inflammatory cytokines, reduced adiponectin
• Cross-organ effects of expanded adipose tissue on liver, muscle, pancreas and vasculature; prothrombotic state
• Integrated mechanism leading to MASLD, type 2 diabetes, and cardiorenal disease via lipotoxicity and glucotoxicity
• Associated conditions: renal disease, MASLD/MASH, PCOS, obstructive sleep apnoea; CKM syndrome
• Management: weight loss, diet, physical activity, STENO-2 multifactorial evidence, pharmacotherapy classes and their effects, bariatric surgery

L11 Nutritional management and guidelines for type 1 _ 2 diabetes (8 May) L11 Metabolism Nutritional management and guidelines for type 1 _ 2 diabetes

• Distinguish a dietitian from a nutritionist
• Goals of nutrition therapy in diabetes
• NZSSD initial management algorithm for type 2 diabetes: HbA1c target, weight loss thresholds for improvement vs remission, choice of add-on agents, when to start insulin
• DiRECT trial evidence for weight-loss-driven remission and pancreatic recovery; diet as a driver of global T2DM burden
• Shift from nutrient-focused to food-based nutrition guidance; NZ food groups, key nutrients and serving sizes; hand-portion guide
• Structure of a wholegrain and nutrient loss on refining
• Glycaemic targets in T2DM and glycaemic responses to refined carbohydrate, sugars and resistant starch
• Dietary strategies for glycaemic control, the healthy plate model, and limits of traffic-light food classification
• Fukushima prison cohort: effect of structured diet and routine on glycaemic control
• NZSSD dietary guidance and adjustments for hypertension, dyslipidaemia and renal disease
• Glycaemic index: definition, calculation, categories, examples and limitations including individual variability
• Type 1 diabetes: glucose targets, CGM and pumps, carbohydrate counting, insulin-to-carbohydrate ratios and correction doses
• Recognition and treatment of hypoglycaemia in conscious vs unconscious patients; sources of 15 g fast carbohydrate
• Mechanism of alcohol-induced hypoglycaemia via NADH excess impairing gluconeogenesis, and prevention advice

L12 Neuroendocrine control of appetite (8 May) L12 Metabolism Neuroendocrine control of appetite

• Evidence that body weight is tightly regulated physiologically rather than by free will; difficulty sustaining weight loss
• Heritability of obesity, single-gene animal models, and the thrifty genotype hypothesis
• The gut-brain-adipose signalling loop, and falling leptin as a signal defending against weight loss
• Parabiosis experiments and what they revealed about leptin (ob/ob) vs leptin receptor (db/db) defects
• Leptin actions on appetite, body weight and fertility; response to leptin replacement in deficiency
• Peripheral signals regulating intake and BMR: leptin, insulin, adiponectin, ghrelin, PYY, CCK, GLP-1; the ileal brake
• Arcuate nucleus circuit: AgRP/NPY vs POMC neurons, their inputs and outputs, and the NTS satiety centre
• Leptin resistance in human obesity and its proposed mechanisms
• Leptin signalling via JAK2/STAT3 and SOCS-3 negative feedback
• Pharmacotherapy for obesity: mechanisms, efficacy and adverse effects of approved drugs
• Newer agents: setmelanotide, semaglutide, tirzepatide, retatrutide; mechanism of GLP-1/GIP agonists including central action; personalised and maintenance-dependent response
• Bariatric surgery types, long-term weight outcomes, and increased GLP-1 and PYY after Roux-en-Y bypass
• Matching treatment intensity to obesity severity, and reframing obesity away from blaming the patient

L13 Nitrogen balance and shuttling (11 May) L13 Metabolism Nitrogen balance and shuttling

• The amino acid pool: inputs, fates, and whole-body protein turnover by organ
• Essential vs non-essential amino acids, origins of non-essential amino acids, conditionally essential cysteine and tyrosine
• Amino acids as precursors: catecholamines, thyroid hormones, melanin, serotonin, melatonin, histamine, NO, creatine, carnitine, glutathione
• Nitrogen balance: why it matters, determinants, positive vs negative balance, role of energy intake
• Negative nitrogen balance in injury and trauma, and phases of the metabolic response to injury
• Glucogenic vs ketogenic carbon skeletons and their entry points
• Urea: site of synthesis and role; gut production of ammonia; hepatic encephalopathy
• Key nitrogen-handling enzymes: glutamine synthetase, glutaminase, aminotransferases, glutamate dehydrogenase
• Inter-organ nitrogen shuttling via alanine and glutamine between muscle, liver and kidney
• Hepatic zonation: periportal urea cycle vs perivenous glutamine synthetase
• Urea cycle: steps, compartments, sources of the two nitrogens, link to the TCA cycle, energy cost
• Regulation of the urea cycle: enzyme induction and N-acetylglutamate activation of CPS
• Urinary nitrogen compounds; renal ammoniagenesis and bicarbonate generation; purine degradation to uric acid
• Inborn errors of metabolism: general features and NZ newborn screening
• Phenylketonuria: genetics, biochemistry, clinical features, pathophysiology, treatment, and challenges of lifelong dietary management
• Clinical application: negative nitrogen balance and hyperglycaemia risk in Crohn’s disease, and effect of TPN

L15 Childhood obesity (13 May) L15 Metabolism Childhood obesity

• Prevalence of childhood overweight and obesity in NZ by age, sex, ethnicity and deprivation, and time trends
• Complications of childhood obesity and tracking into adulthood
• The obesogenic environment: food marketing, cost, and density of fast food and convenience outlets by deprivation
• Four-stage weight management pathway: monitor, assess, manage, maintain
• Monitoring: BMI centiles on NZ-WHO charts, overweight (>91st) and obesity (>98th) cut-offs, action by centile band, value of trends over single measurements
• Accuracy of BMI as a screening tool in children, and why waist circumference is not recommended
• Talking about weight: permission, person-first language, avoiding blame; health literacy and cultural competence
• Assessment: history, BEARS sleep screen, examination findings and their significance, secondary causes (endocrine, genetic syndromes), laboratory tests
• Management goal of slowing weight gain; FAB approach: food changes, physical activity recommendations by age, reducing sedentary and screen time
• Five behavioural tools: self-monitoring, stimulus control, problem solving, contingency management, cognitive restructuring
• Orlistat and criteria for bariatric surgery in adolescents
• Sleep and obesity: epidemiological risk by age, proposed mechanisms, DREAM trial evidence, recommended sleep durations and sleep hygiene
• Long-term maintenance and the doctor’s role, including advocacy for dietitians and healthy environments

L16 Intro to bariatric surgery (14 May) L16 Metabolism Intro to bariatric surgery

• Distribution of NZ adults by BMI class, and medical problems associated with obesity by system
• Evolutionary mismatch and why weight loss is hard to sustain: compensatory hunger and reduced metabolic rate; energy deficit arithmetic
• Bariatric procedures: Roux-en-Y gastric bypass, one-anastomosis gastric bypass, sleeve gastrectomy
• Mechanisms of improved glycaemia after bariatric surgery: anatomical effects, mediators (bile acids, microbiome, gut hormones), effects on glucose homeostasis
• GLP-1 physiology: production, degradation by DPP-4, and effects on multiple organs
• Comparison of the three procedures: weight loss, diabetes and reflux effects, deficiencies, long-term consequences, NSAID restrictions, perioperative risk
• Indications for bariatric surgery by BMI and comorbidity
• GLP-1 receptor agonists available in NZ: indications, cost, common and serious adverse effects
• Trial evidence for semaglutide (STEP) and tirzepatide (SURMOUNT), including weight regain after withdrawal
• Real-world incretin outcomes limited by discontinuation; surgery vs incretin therapy comparison
• Edmonton Obesity Staging System stages and prediction of mortality

L20 Alcohol (15 May) L20 Metabolism Alcohol

• Alcohol as an energy source but not a nutrient (29 kJ/g), and fermentation chemistry
• Absorption and distribution of alcohol in total body water; calculating blood alcohol from standard drinks
• Three pathways of alcohol metabolism (ADH, MEOS, catalase), the ADH-ALDH sequence, and diversion of acetyl-CoA to fatty acid synthesis when NADH is high
• Factors affecting alcohol metabolism: rate limit of ADH, sex, body size, genetic variants causing flushing
• Standard drinks and alcohol content of common beverages
• Mechanisms of harm: acetaldehyde toxicity, raised NADH:NAD+ ratio, MEOS induction and tolerance
• Dose-response effects of blood alcohol on the brain; hidden energy in alcoholic drinks
• NZ drinking patterns and current NZ, Canadian and proposed drinking guidelines; no safe level in pregnancy and warning labels
• The French paradox and confounding in the J-shaped curve; resveratrol dose implausibility
• GBD 2016 evidence that the safest level of drinking is none
• China Kadoorie Biobank: conventional vs genetic (Mendelian randomisation) evidence on alcohol and cardiovascular disease
• Alcohol-attributable cancer burden
• Positions of WHO and the NZ Heart Foundation; why alcohol is more harmful for young people; industry influence on policy

L21 Exercise and metabolism (18 May) L21 Metabolism Exercise and metabolism

• Three energy systems: power vs capacity trade-off, and their contribution by exercise duration and intensity
• VO2 and VO2max: definition, measurement, typical values, and inverse association with cardiovascular disease and mortality
• Acute cardiorespiratory responses to exercise and chronic training adaptations
• Oxygen deficit at exercise onset, faster steady state in trained individuals, and excess post-exercise oxygen consumption
• Indirect calorimetry: respiratory exchange ratio and interpreting fat vs carbohydrate oxidation
• Fuel selection by exercise intensity (shift from plasma FFA to muscle glycogen from 25% to 85% VO2max) and by duration (shift to fat via lipolysis)
• Training effects on fat metabolism and fatty acid trafficking from adipocytes and capillaries to muscle
• Contributions of muscle glycogen, blood glucose, intramuscular and plasma fat, and protein to exercise energy
• GLUT4 regulation by exercise: acute insulin-independent translocation (AMPK, Ca2+) and chronic increased synthesis; how exercise improves glucose regulation
• Lactate myths: not caused by lack of oxygen, not the source of acidosis (ATP hydrolysis releases H+), not the cause of fatigue or soreness
• Metabolic health benefits of exercise: postprandial triglycerides, glucose control, exercise snacking and breaking up sitting
• Structural, biochemical and systemic adaptations to endurance training

L22 The metabolism and genetics of gout (18 May) L22 Metabolism The metabolism and genetics of gout

• Epidemiology of gout in NZ, including high prevalence in Māori and Pacific peoples
• Stages of gout progression from hyperuricaemia to chronic tophaceous gout
• Clinical features of a gout flare (podagra), tophi and characteristic bone erosions
• Diagnosis: synovial MSU crystals as gold standard, serum urate threshold, imaging, excluding septic arthritis
• Treatment of acute flares and flare prophylaxis at ULT initiation
• Urate-lowering therapy: indications, treat-to-target urate, allopurinol dose titration; limited lifestyle evidence; patient education
• Purine catabolism to uric acid via xanthine oxidase, and evolutionary loss of uricase in humans
• Urate balance: under-excretion vs over-production, renal vs intestinal excretion, sites of action of urate-lowering drugs
• Urate levels across the lifespan by sex and across populations
• Gout flare mechanism: priming via TLR/NF-kB, NLRP3 inflammasome assembly by MSU crystals, IL-1 beta amplification, resolution via NETs
• Dietary and other flare triggers
• Genetics of urate (SLC2A9/GLUT9, GWAS loci) and of gout, including IL-37 variants in Polynesian populations
• Pharmacogenetics: ABCG2 Q141K and allopurinol response; allopurinol-induced SCAR (SJS/TEN) and HLA-B*5801 testing
• Gaps in NZ gout management: underdosing, lack of urate monitoring, ethnic inequities in regular ULT and hospitalisation

L24 Sports _ exercise nutrition (22 May) L24 Metabolism Sports _ exercise nutrition

• Aims of sports nutrition, and recreational exercisers as athletes who present to GPs
• Common nutritional issues in athletes: inadequate intake, iron deficiency, fatigue, disordered eating, amenorrhoea, stress-related problems
• The sports nutrition pyramid: basic diet, sports nutrition, supplements; the athlete’s plate by training load
• Carbohydrate metabolism in exercise and daily carbohydrate targets by activity level (g/kg/day), with worked calculation
• Protein, fat and fluid recommendations for athletes, including when to use sports drinks
• Weight-loss diets in athletes and Relative Energy Deficiency in Sport: low energy availability and its health and performance consequences
• Supplements: Maughan’s rules, what counts as a supplement, Food First but Not Always Food Only decision framework, third-party batch testing
• Drug testing in sport: checking medication status (e.g. hydrocortisone by route and competition status) and the Therapeutic Use Exemption process
• Case approach to an adolescent endurance athlete with low iron and secondary amenorrhoea