Pancreas, Diabetes Mellitus & Hypoglycemia

Forfar & Arneil 7th Edition · Pancreatic morphology · Insulin · Glucagon · Type 1 DM · Type 2 DM · MODY · Diabetic associations (thyroid, celiac) · Hypoglycemia etiology · Endocrine pancreatic abnormalities (hyperinsulinism, insulinoma)
📌 Key principles: Insulin (beta cells) – lowers glucose; Glucagon (alpha cells) – raises glucose. Type 1 DM: autoimmune destruction, absolute insulin deficiency, DKA risk. Type 2 DM: insulin resistance, obesity, metabolic syndrome. MODY: monogenic (GCK, HNF1A, HNF4A). Hypoglycemia: hyperinsulinism commonest cause in infants.

📖 Pancreas, Diabetes Mellitus & Hypoglycemia

🩺 Pancreatic islet cells
Beta cells (70%): insulin – hypoglycemic. Alpha cells (20%): glucagon – hyperglycemic. Delta cells: somatostatin. PP cells: pancreatic polypeptide. Insulin promotes glucose uptake, glycogenesis, lipogenesis, protein synthesis.
📊 Type 1 Diabetes Mellitus (T1DM)
Autoimmune destruction of beta cells. Presents with polyuria, polydipsia, weight loss, DKA. Autoantibodies: GAD, IA-2, ZnT8, ICA. HLA-DR3/DR4 association. Requires lifelong insulin.
🍔 Type 2 Diabetes Mellitus (T2DM)
Insulin resistance with relative deficiency. Obesity, acanthosis nigricans, family history. Managed with lifestyle, metformin, then insulin if needed. Screening: fasting glucose, HbA1c.
🧬 MODY (Maturity Onset Diabetes of the Young)
Monogenic, autosomal dominant, onset <25y, non-obese, no autoantibodies. GCK (mild fasting hyperglycemia, no treatment), HNF1A/HNF4A (sulfonylurea responsive).
⚡ Hypoglycemia – etiology
Hyperinsulinism (congenital, insulinoma, exogenous), adrenal insufficiency, GH deficiency, inborn errors (fatty acid oxidation, glycogen storage, gluconeogenesis). Whipple's triad: symptoms, low glucose, relief with glucose.
📊 Associated autoimmune conditions in T1DM: Autoimmune thyroiditis (Hashimoto, Graves) – 20-30%, celiac disease – 5-10%, Addison disease – <1%. Annual screening: TSH, anti-TPO, anti-tissue transglutaminase (TTG).

🔍 Clinical approach to diabetes mellitus and hypoglycemia

1
New-onset diabetes – evaluation – Confirm hyperglycemia (fasting >7 mmol/L, random >11.1, HbA1c >48 mmol/mol). Assess for DKA (pH <7.3, bicarbonate <15, ketones). Differentiate T1 vs T2 vs MODY.
2
Type 1 diabetes – diagnostic clues – Lean, young, ketosis, autoantibodies (GAD, IA-2, ZnT8), low C-peptide. HLA typing not routine. Immediate insulin therapy.
3
Type 2 diabetes – diagnostic clues – Overweight/obese, acanthosis nigricans, family history T2DM, no ketosis, elevated C-peptide/insulin, no autoantibodies. Metformin first-line.
4
MODY suspicion – Family history of diabetes in multiple generations (autosomal dominant), onset <25y, non-obese, no autoantibodies, low insulin requirement. Genetic testing.
5
Hypoglycemia workup (non-diabetic) – Critical sample during hypoglycemia: glucose, insulin, C-peptide, cortisol, GH, β-hydroxybutyrate, lactate, acylcarnitine. High insulin suggests hyperinsulinism. Low cortisol/ACTH → adrenal insufficiency.
6
Congenital hyperinsulinism (CHI) – Presents in infancy with severe hypoglycemia, high glucose requirement (>8 mg/kg/min). Genetic testing (ABCC8, KCNJ11), diazoxide trial, FDOPA-PET for focal lesions.
📌 Clinical pearl: In a child with new-onset diabetes, HbA1c >9% (75 mmol/mol) but no ketosis and overweight – consider Type 2. Check autoantibodies; if negative and strong family history, consider MODY.

📋 Stepwise management of diabetes & hypoglycemia

1
Type 1 diabetes – insulin regimen – Multiple daily injections (MDI): basal (glargine/detemir) + prandial (aspart/lispro). Insulin pump (CSII) for eligible. Target HbA1c <7.5% (58 mmol/mol). Carbohydrate counting and CGM recommended.
2
Diabetic ketoacidosis (DKA) management – IV 0.9% saline (20 ml/kg), then 0.45% saline with 5% dextrose. Insulin infusion 0.1 U/kg/h. Potassium replacement when K+ <5.5. Monitor for cerebral edema (risk factors: urea <3.5, bicarbonate <5, severe acidosis, initial treatment with bicarbonate).
3
Type 2 diabetes – pharmacotherapy – Metformin first-line (lifestyle modification). Add insulin, GLP-1 agonists (liraglutide) or SGLT2 inhibitors if uncontrolled. Monitor for hypertension, dyslipidemia, NAFLD.
4
MODY treatment – GCK: no treatment (benign fasting hyperglycemia). HNF1A/HNF4A: low-dose sulfonylureas (glibenclamide). Dietary management. Avoid insulin unless pregnancy.
5
Congenital hyperinsulinism – treatment – Diazoxide (first-line, 5-15 mg/kg/day), chlorothiazide (synergistic). Octreotide if refractory. Pancreatectomy for focal lesion (FDOPA-PET guided). Glucose infusion (IV) acutely.
6
Hypoglycemia prevention & screening – T1DM: CGM with low-glucose suspend; education on hypoglycemia awareness. Adrenal insufficiency: stress dose glucocorticoids.
⚠️ DKA cerebral edema – risk factors: Severe acidosis (pH <7.1), low PaCO2, high BUN, delayed correction of hypernatremia, bicarbonate administration. Prevention: gradual correction, avoid rapid fluid shifts.

🧠 Reflex prompts: diabetes & hypoglycemia

👧 A 9-year-old with polydipsia, polyuria, weight loss, glucose 22 mmol/L, pH 7.25, bicarbonate 14 mmol/L, ketones present. Diagnosis?
Diabetic ketoacidosis (DKA). Type 1 diabetes. IV fluids, insulin infusion, monitor for cerebral edema.
🍔 A 14-year-old obese girl (BMI 32) with acanthosis nigricans, HbA1c 8.5%, no ketones, GAD antibodies negative. Diagnosis?
Type 2 diabetes. Metformin, lifestyle modification, screen for comorbidities (hypertension, dyslipidemia).
👪 A 12-year-old lean boy with fasting glucose 7.5 mmol/L, HbA1c 6.8%, no autoantibodies, mother and grandmother also diabetic diagnosed <25y. Most likely?
MODY (likely GCK mutation). Genetic testing; usually no treatment required.
🍬 A 3-month-old with severe hypoglycemia (glucose 1.2 mmol/L), requiring 14 mg/kg/min glucose. Insulin elevated. Diazoxide trial ineffective. Next step?
Congenital hyperinsulinism (diffuse vs focal). FDOPA-PET scan; if focal lesion, pancreatectomy.
🩺 A 5-year-old with T1DM and poor growth, fatigue, HbA1c 7.2%, TSH 12 mIU/L, fT4 low. Diagnosis?
Autoimmune hypothyroidism (Hashimoto) – association with T1DM. Start levothyroxine.
🌾 A 7-year-old with T1DM, recurrent abdominal pain, bloating, diarrhea, weight loss. Anti-TTG antibodies positive. Diagnosis?
Celiac disease (association with T1DM). Gluten-free diet.
🩸 A 2-year-old with fasting hypoglycemia, ketosis, hepatomegaly, elevated lactate, normal insulin. Glucagon test shows no glucose rise. Diagnosis?
Glycogen storage disease type I (G6Pase deficiency). Cornstarch therapy.
⚕️ A 4-year-old with hypoglycemia, vomiting, hyperpigmentation, hyponatremia, hyperkalemia. Cortisol low, ACTH high. Diagnosis?
Primary adrenal insufficiency (Addison disease). Hydrocortisone + fludrocortisone.
🧪 What are the three most common autoantibodies in type 1 diabetes?
GAD65 (glutamic acid decarboxylase), IA-2 (islet antigen-2), ZnT8 (zinc transporter 8). ICA (islet cell) also used.
💊 Which oral agent is first-line for type 2 diabetes in children?
Metformin. Start 500 mg daily, titrate to 2000 mg/day. Contraindicated in renal impairment.