01 / Core mental model
Diabetes is broken fuel-state signaling, not just high glucose.

Without effective insulin action, the body behaves as if it is fasting even when glucose is abundant in the blood.

The fed-state command
STORE
Insulin directs tissues to build and retain fuel stores.
The fasting-state command
MOBILIZE
Glucagon protects circulating fuel availability.
02
Fuel-state switch
The insulin-to-glucagon ratio sets the metabolic direction.
High insulin / low glucagon
Fed state
Glycogen synthesis, fat synthesis and protein synthesis.
↔
Low insulin / high glucagon
Fasting state
Glycogenolysis, gluconeogenesis, lipolysis and ketogenesis.
03
Pancreatic islet map
Four endocrine cell types, four signals.
Beta
Insulin
Alpha
Glucagon
Delta
Somatostatin
PP
Pancreatic polypeptide
04
Hormonal contrast
Insulin vs glucagon: the ratio matters more than either alone.
Fed-state hormone
Insulin
Released from beta cells after nutrient abundance.
Promotes: GLUT4 glucose uptake, glycogen synthesis, glycolysis, lipogenesis, protein synthesis and K+ uptake into cells.
Inhibits: gluconeogenesis, glycogenolysis, lipolysis, ketogenesis and proteolysis.
Fasting-state hormone
Glucagon
Released from alpha cells when blood glucose is low or fuel must be mobilized.
Promotes mainly in liver: glycogenolysis, gluconeogenesis, fatty acid oxidation and ketogenesis.
Inhibits in liver: glycogen synthesis, glycolysis and lipogenesis.
05
Sensing and transport
How glucose becomes an insulin signal.
Beta-cell glucose sensing
Glucose → ATP → KATP closure → depolarization → Ca2+ influx → insulin release
Glucose enters
ATP rises
KATP closes
Membrane depolarizes
Ca2+ enters
Granules release
A
High glucose increases ATP production in beta cells.
B
ATP-sensitive K+ channels close, reducing K+ efflux and depolarizing the membrane.
C
Voltage-gated Ca2+ channels open, and Ca2+ triggers insulin granule exocytosis.
D
Sulfonylureas close KATP channels and can cause hypoglycemia.
GLUT4
Insulin-sensitive glucose uptake in skeletal muscle and adipose tissue.
GLUT2
Low-affinity, high-capacity transporter in liver, beta cells, kidney and intestine.
GLUT1
Basal uptake; important in RBCs and the blood-brain barrier.
GLUT3 / 5
GLUT3: neurons. GLUT5: fructose in intestine and sperm.
06
Fed vs fasting metabolism
The fuel program changes with time and tissue.
Fed state / liver
Build and export
Glycogen synthesis, glycolysis, fatty acid synthesis, triglyceride synthesis and VLDL production.
Fed state / muscle
Take up and build
GLUT4 glucose uptake, glycogen synthesis, amino acid uptake, protein synthesis and K+ uptake.
Fed state / adipose
Store triglyceride
GLUT4 glucose uptake, LPL activity, fatty acid uptake and triglyceride storage; HSL inhibited.
Early fasting
Use glycogen
Liver glycogenolysis maintains blood glucose. Muscle glycogen fuels muscle locally.
Prolonged fasting
Make new glucose
Gluconeogenesis rises from lactate, alanine and glycerol while fatty acids fuel many tissues.
Starvation
Shift toward ketones
Ketogenesis supplies brain fuel after adaptation and reduces muscle protein breakdown.
07
Alternative fuel production
Gluconeogenesis and ketogenesis solve different fasting problems.
Gluconeogenesis
New glucose from non-carbohydrate precursors
Lactate from RBCs and exercising muscle.
Alanine from muscle protein breakdown.
Glycerol from adipose triglyceride breakdown.
Glucagon and cortisol support hepatic glucose production; insulin suppresses it.
Ketogenesis
Liver turns excess acetyl-CoA into ketones
Trigger: low insulin, high glucagon, high fatty acid delivery and high beta-oxidation.
Ketones: acetoacetate, beta-hydroxybutyrate and acetone.
The liver makes ketones but does not use them because it lacks thiophorase.
08
Fuel use by tissue
Each organ follows a different fuel hierarchy.
Brain
Glucose early; ketones during prolonged fasting; still needs some glucose.
RBCs
Only glucose, no mitochondria, produce lactate.
Muscle
Uses glucose fed, fatty acids fasting, and preserves ketones for brain in starvation.
Heart
Prefers fatty acids; can use lactate and ketones.
Liver
Makes glucose and ketones; uses fatty acids; does not use ketones.
09 / Diabetes mellitus
Chronic hyperglycemia from impaired insulin secretion, impaired insulin action, or both.
Type 1 diabetes
Autoimmune beta-cell destruction → absolute insulin deficiency → requires insulin → high DKA risk.
Autoantibodies: anti-GAD65, anti-insulin, anti-IA-2 and anti-ZnT8.
Type 2 diabetes
Insulin resistance plus progressive beta-cell dysfunction. Early insulin may be high; later secretion becomes inadequate.
10
Acute metabolic emergencies
DKA and HHS diverge at ketogenesis.
DKA
Insulin deficiency unlocks lipolysis and ketogenesis.
Hormonal drive: severe insulin deficiency plus glucagon, epinephrine, cortisol and growth hormone increases hepatic glucose production.
Acidosis: lipolysis sends fatty acids to liver; ketones cause high anion gap metabolic acidosis.
Findings: hyperglycemia, ketones, dehydration, Kussmaul respirations, abdominal pain, vomiting, fruity breath and altered mental status.
HHS
Enough insulin to limit ketosis, not enough to control glucose.
Typical pattern: usually type 2 diabetes, gradual onset, severe hyperglycemia and hyperosmolality.
Ketones: minimal, with no major acidosis or only mild acidosis.
Neurologic effect: altered mental status is driven by hyperosmolality and dehydration.
11
Osmotic diuresis and potassium in DKA
Serum potassium can hide a profound total-body deficit.
Glucose spills
Filtered glucose exceeds renal transport maximum, remains in tubule and pulls water with it.
Classic symptoms
Polyuria, polydipsia, weight loss and sometimes polyphagia.
K+ trap
Total body K+ is depleted in DKA even if serum K+ is normal or high before insulin treatment.
12
Chronic complications
Hyperglycemia damages vessels, nerves and specialized tissues.
Microvascular
Retinopathy, nephropathy and neuropathy.
Macrovascular
Coronary artery disease, stroke and peripheral artery disease.
Tissue damage
AGEs, oxidative stress, PKC activation, polyol pathway, endothelial dysfunction and inflammation.
Nephropathy
Hyperfiltration, microalbuminuria, proteinuria, GBM thickening, mesangial expansion and Kimmelstiel-Wilson nodules.
Retinopathy
Microaneurysms, hemorrhages, hard exudates, cotton wool spots, macular edema and neovascularization.
Neuropathy
Distal symmetric polyneuropathy, autonomic neuropathy, foot ulcers and gastroparesis.
13
Treatment physiology map
Each therapy targets a different control point.
Insulin
Replaces or supplements insulin; required in type 1 diabetes.
Metformin
Decreases hepatic gluconeogenesis and improves insulin sensitivity.
GLP-1 agonists
Increase glucose-dependent insulin, decrease glucagon, slow gastric emptying and increase satiety.
SGLT2 inhibitors
Decrease renal glucose reabsorption and increase urinary glucose excretion.
Sulfonylureas
Close beta-cell KATP channels and increase insulin secretion; hypoglycemia risk.
DPP-4 inhibitors
Increase endogenous incretin levels.
TZDs
Activate PPAR-gamma and improve insulin sensitivity; weight gain and fluid retention risk.
Glucagon
Treats severe hypoglycemia when oral glucose cannot be given.
14
Two high-yield patterns
The incretin effect and hypoglycemia symptoms.
Incretin effect
Oral glucose triggers more insulin than IV glucose.
GLP-1 and GIP enhance glucose-dependent insulin secretion. GLP-1 also decreases glucagon, slows gastric emptying and increases satiety.
Hypoglycemia pattern
Autonomic warning, then brain dysfunction.
Adrenergic: sweating, tremor, palpitations, anxiety, hunger.
Neuroglycopenic: confusion, weakness, behavior change, seizures, coma.
15 / Final synthesis
Metabolism question
Ask whether the body is fed, fasting, exercising or stressed, then predict insulin, glucagon, storage and mobilization.
Diabetes question
Ask whether insulin action is absent, insufficient or resisted, then predict hepatic glucose output, lipolysis, ketogenesis, osmolality and K+ shifts.