Step 1 · Endocrine

Diabetes Mellitus & Glucose Regulation

Name: Diabetes Mellitus & Glucose Regulation
Creator: Veli Bakalov, MD

Two roads to hyperglycemia, and the acute crises that follow

Endocrine·Endocrine Pancreas & Diabetes·6 min read·9 high-yield points·Reviewed by Veli Bakalov, MD @HemeOncBuddy

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Type 1 DM (~5–10%): autoimmune β-cell destruction, HLA-DR3/DR4, anti-GAD65/IA-2/insulin/ZnT8 antibodies, absent C-peptide, DKA-prone; type 2 DM (~90%): insulin resistance plus β-cell exhaustion, islet amyloid (amylin/IAPP), HHS-prone.
Glucose closes β-cell ATP-sensitive K+ channels, depolarizing the cell so calcium entry triggers insulin release; sulfonylureas close the same channel.
Insulin acts through a receptor tyrosine kinase (IRS-1 → PI3K → Akt) to move GLUT4 into muscle and adipose membranes; GLUT4 is the only insulin-responsive transporter.
Insulin is the only glucose-lowering hormone and shifts K+ into cells; glucagon, cortisol, epinephrine and GH all raise glucose.
Diagnose diabetes with HbA1c ≥6.5%, fasting glucose ≥126, 2-hour OGTT ≥200, or random glucose ≥200 mg/dL with symptoms; prediabetes is A1c 5.7–6.4%, FPG 100–125, OGTT 140–199.
High insulin with high C-peptide = insulinoma or sulfonylurea; high insulin with low C-peptide = injected insulin.
DKA: insulin lack → lipolysis → β-hydroxybutyrate → anion-gap acidosis, Kussmaul breathing and hyperkalemia despite total-body K+ depletion; treat with fluids, insulin and potassium, holding insulin if K+ <3.3.
HHS: elderly type 2 patient, glucose often >600 mg/dL, osmolality >320 mOsm/kg, minimal ketosis because residual insulin blocks ketogenesis; mortality exceeds DKA.
Glycation and the sorbitol pathway cause retinopathy, nephropathy (Kimmelstiel-Wilson nodules; microalbuminuria first) and neuropathy; tight control prevents microvascular disease, but MI is the leading cause of death.

Insulin, glucagon and glucose transport

Insulin secretion. β cells make proinsulin, which is cleaved into insulin and C-peptide in equimolar amounts. Glucose enters the β cell through GLUT2 and is metabolized; the rising ATP/ADP ratio closes ATP-sensitive K+ channels, depolarizing the cell, opening voltage-gated calcium channels and triggering exocytosis of insulin granules. Sulfonylureas act by closing the same K+ channel.

Insulin is anabolic; glucagon is catabolic. Insulin lowers glucose by driving uptake through GLUT4, glycogenesis, lipogenesis and protein synthesis, and it shifts K+ into cells via the Na+/K+-ATPase. Glucagon, from α cells, raises glucose through glycogenolysis, gluconeogenesis, lipolysis and ketogenesis. The insulin-to-glucagon ratio, not either absolute level, sets the fed versus fasting state.

Insulin is the only hormone that lowers glucose; many hormones raise it (glucagon, cortisol, epinephrine, GH).

Insulin signaling. Insulin binds a receptor tyrosine kinase, which autophosphorylates and recruits IRS-1. The PI3K–Akt arm translocates GLUT4 vesicles to the membrane of muscle and adipose cells; a parallel RAS/MAP-kinase arm drives growth and mitogenesis.

Insulin binds its receptor tyrosine kinaseAutophosphorylation
IRS-1 → PI3KSecond messengers generated
Akt (protein kinase B)Downstream kinase
GLUT4 to the membraneGlucose uptake into muscle and fat

Insulin signaling to GLUT4

Know your GLUT transporters.

GLUT1: red cells, brain and cornea; basal, insulin-independent uptake.
GLUT2: β cells and liver (also kidney and intestine); a low-affinity, bidirectional transporter that lets β cells sense glucose.
GLUT4: skeletal muscle and adipose; the only insulin-responsive transporter. Its failure to reach the membrane underlies type 2 hyperglycemia.
GLUT5: a fructose transporter in the intestine.

Tissues that take up glucose without insulin: BRICK LIPS (Brain, RBCs, Intestine, Cornea, Kidney, Liver, Islet β cells, Placenta, Spermatocytes).

Type 1 and type 2 diabetes

Type 1 (~5–10%). Autoimmune T-cell destruction of β cells causes absolute insulin deficiency. It is linked to HLA-DR3 and DR4 and marked by autoantibodies to GAD65, IA-2, insulin (IAA) and ZnT8; histology shows lymphocytic insulitis. C-peptide is absent, patients are typically young and lean, and the disease is ketosis-prone, often presenting in childhood or adolescence.

Type 2 (~90%). Peripheral insulin resistance, driven by visceral obesity, combines with progressive β-cell exhaustion to cause relative deficiency. Islets contain amyloid deposits of amylin (islet amyloid polypeptide, IAPP). Acanthosis nigricans signals insulin resistance. C-peptide is present and DKA is uncommon; the risk of HHS is higher. Genetic and lifestyle influences are strong.

Type 1 vs type 2 diabetes

Feature	Type 1	Type 2
Defect	Autoimmune β-cell destruction; absolute deficiency	Insulin resistance plus relative deficiency
Patient	Young, lean	Older, obese
Genetics	HLA-DR3/DR4; weaker twin concordance	Polygenic; strong twin concordance
Markers	Anti-GAD65, IA-2, IAA, ZnT8; C-peptide absent	No islet antibodies; C-peptide present
Islet histology	Lymphocytic insulitis	Amyloid (amylin, IAPP)
Acute crisis	DKA	HHS

Diagnosis and C-peptide

Four ways to diagnose. Any one criterion establishes diabetes; confirm on a repeat test unless the patient is unequivocally symptomatic. HbA1c reflects average glucose over roughly the preceding 3 months (red cells live about 120 days).

Diagnostic thresholds

Test	Prediabetes	Diabetes
HbA1c	5.7–6.4%	≥6.5%
Fasting plasma glucose	100–125 mg/dL	≥126 mg/dL
2-hour OGTT (75 g)	140–199 mg/dL	≥200 mg/dL
Random glucose	—	≥200 mg/dL with classic symptoms

C-peptide separates real from injected insulin. Because proinsulin yields insulin and C-peptide in equal amounts, endogenous insulin carries C-peptide but pharmaceutical insulin does not. In a hypoglycemic patient, high insulin with high C-peptide means an insulinoma or a sulfonylurea (a drug screen separates the two); high insulin with low C-peptide means exogenous (factitious or surreptitious) insulin.

Acute crises: DKA and HHS

Diabetic ketoacidosis. Mostly type 1, often triggered by infection, stress or missed insulin. Insulin deficiency plus a surge of counter-regulatory hormones drives lipolysis; free fatty acids reach the liver, which converts them to ketoacids, chiefly β-hydroxybutyrate and acetoacetate. The result is an anion-gap metabolic acidosis with Kussmaul breathing, fruity (acetone) breath, abdominal pain, vomiting, dehydration and a glucose of about 250–600 mg/dL. Serum K+ is often high despite total-body K+ depletion, because insulin lack and acidosis shift potassium out of cells while osmotic diuresis wastes it.

Insulin deficiencyPlus stress hormones
LipolysisFree fatty acids rise
Hepatic ketogenesisβ-hydroxybutyrate
Anion-gap acidosisKussmaul breathing, fruity breath

Pathogenesis of DKA

Hyperosmolar hyperglycemic state. Typically an elderly type 2 patient with profound hyperglycemia (often >600 and sometimes >1000 mg/dL) and serum osmolality >320 mOsm/kg, but no significant ketoacidosis, because residual insulin still suppresses ketogenesis. Severe dehydration and altered mental status dominate, and mortality exceeds that of DKA.

DKA vs HHS

Feature	DKA	HHS
Typical patient	Type 1, often young	Type 2, elderly
Insulin	Absent	Residual, enough to block ketogenesis
Glucose	~250–600 mg/dL	Often >600, may exceed 1000 mg/dL
Ketones and pH	High ketones; anion-gap acidosis	Minimal ketosis; little acidosis
Osmolality	Mildly raised	>320 mOsm/kg
Dominant picture	Kussmaul breathing, fruity breath	Profound dehydration, stupor

Managing DKA. Give IV fluids first, then insulin, with aggressive potassium repletion because insulin drives K+ into cells from an already depleted total-body store. Hold insulin if K+ is below 3.3 mEq/L until it is repleted. Add dextrose as glucose falls and continue insulin until the anion gap closes. In children, correcting too quickly risks cerebral edema. DKA also predisposes to rhinocerebral mucormycosis.

Serum K+ may look high at presentation but plummets once insulin starts; always replace potassium.

Chronic complications

Mechanisms. Chronic hyperglycemia damages tissue in two main ways. Nonenzymatic glycation of proteins forms advanced glycation end products that thicken basement membranes and cause hyaline arteriolosclerosis. The sorbitol (aldose reductase) pathway traps osmotically active sorbitol in cells that lack sorbitol dehydrogenase, such as the lens, Schwann cells and retina.

Retinopathy: microaneurysms, hemorrhages and exudates, progressing to VEGF-driven neovascularization in proliferative disease; osmotic damage to the lens causes cataracts.
Nephropathy: glomerular basement membrane thickening, mesangial expansion and Kimmelstiel-Wilson nodular glomerulosclerosis, with hyaline arteriolosclerosis of the efferent arteriole driving hyperfiltration. Microalbuminuria is the first sign; ACE inhibitors or ARBs slow progression.
Neuropathy: symmetric distal "stocking-glove" sensory loss and autonomic neuropathy (gastroparesis, orthostatic hypotension, erectile dysfunction), which together with vascular disease set up foot ulcers.

Micro versus macro. Tight glucose control chiefly prevents microvascular disease. Accelerated atherosclerosis drives coronary disease, stroke and peripheral arterial disease, and myocardial infarction is the leading cause of death in diabetes; statins and blood-pressure control, not glucose alone, target this macrovascular risk. Patients also have impaired resistance to infection.