9.4 Diabetes Mellitus: Type 1, Type 2, DKA & HHS Management

Diabetes Mellitus: Type 1, Type 2, DKA & HHS Management

Clinical Core Insight: Acute glycemic emergencies represent contrasting ends of a pathophysiological spectrum. Diabetic Ketoacidosis (DKA) is driven by an absolute or near-absolute insulin deficiency leading to unrestrained lipolysis, ketogenesis, and severe metabolic acidaemia; its treatment mandates continuous fixed-rate insulin to clear ketoacids, accompanied by glucose infusions once blood sugar drops to prevent premature cessation of insulin. Conversely, Hyperosmolar Hyperglycaemic State (HHS) is driven by severe relative insulin deficiency with massive dehydration and profound hyperosmolality without ketoacidosis; its treatment prioritizes slow, gradual rehydration over 48–72 hours and mandatory thromboprophylaxis, with insulin taking a secondary role.

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Pathophysiology & Diagnostic Criteria of Diabetes Mellitus

Diabetes mellitus represents a group of metabolic diseases characterized by chronic hyperglycaemia resulting from defects in insulin secretion, insulin action, or both.

Pathophysiological Subtypes

1. Type 1 Diabetes Mellitus (T1DM):
   • Etiology: Organ-specific, T-cell mediated autoimmune destruction of insulin-producing pancreatic $\beta$-cells within the Islets of Langerhans, often associated with HLA-DR3/DR4 and autoantibodies (anti-GAD65, anti-IA2, anti-islet cell antibodies [ICA], anti-ZnT8).
   • Clinical Consequence: Absolute insulin deficiency. Without exogenous insulin replacement, patients develop unrestrained hepatic gluconeogenesis, glycogenolysis, adipose lipolysis, and life-threatening ketoacidosis.
2. Type 2 Diabetes Mellitus (T2DM):
   • Etiology: Complex multifactorial metabolic syndrome characterized by progressive peripheral insulin resistance (in skeletal muscle, liver, and adipose tissue) combined with a progressive, secretory defect of pancreatic $\beta$-cells.
   • Clinical Consequence: Relative insulin deficiency. Circulating endogenous insulin levels remain sufficient to suppress massive adipose lipolysis and hepatic ketogenesis, preventing DKA under normal conditions, but are inadequate to maintain euglycaemia, predisposing to extreme hyperglycaemia and hyperosmolality (HHS).

Formal Diagnostic Criteria (WHO & Irish HSE Guidelines)

Diagnosis is established when any one of the following laboratory criteria is fulfilled on venous plasma:

1. Fasting Plasma Glucose (FPG): $\ge 7.0$ mmol/L (126 mg/dL) [fasting defined as no caloric intake for at least 8 hours].
2. 2-Hour Post-OGTT Glucose: $\ge 11.1$ mmol/L (200 mg/dL) following a standardized 75 g oral glucose tolerance test.
3. Glycated Haemoglobin (HbA1c): $\ge 48$ mmol/mol (6.5%) [must be measured in an accredited laboratory using an IFCC-standardized assay].
4. Random Plasma Glucose: $\ge 11.1$ mmol/L (200 mg/dL) in an individual presenting with classic symptoms of hyperglycaemia (polyuria, polydipsia, unexplained weight loss, lethargy).

Diagnostic Mandate: In the absence of unequivocal symptomatic hyperglycaemia, diagnosis requires a confirmatory repeat test on a subsequent day using the same laboratory method.

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Insulin Regimens, Pharmacology & Safe Administration

Insulin is a high-risk medication requiring meticulous prescribing, dispensing, and administration. Understanding pharmacokinetic profiles is essential for glycemic management and preventing iatrogenic hypoglycemia.

Pharmacokinetic Profiles of Insulins Used in Ireland

Subcutaneous Injection Technique & Lipohypertrophy Prevention

• Needle Length: 4 mm or 5 mm needles are recommended for all adult patients regardless of Body Mass Index (BMI). Short needles reliably deposit insulin into the subcutaneous layer while virtually eliminating the risk of unintended intramuscular injection (which causes accelerated, erratic absorption and severe hypoglycemia).
• Injection Angle: Insert at a 90-degree angle to the skin surface without pinching (a skin fold pinch is required only if using needles $\ge 8$ mm or in severely cachectic individuals).
• Site Selection: Subcutaneous tissue of the abdomen (fastest, most consistent absorption rate), anterolateral thighs, and buttocks.
• Systematic Rotation: Patients must rotate injection sites systematically within the same anatomical zone (spacing injections at least 1 cm to 2 cm apart). Injecting repeatedly into the same discrete area induces lipohypertrophy—a rubbery, fibrofatty, hypertrophic dermal lesion resulting from the local lipogenic properties of insulin.

[!WARNING] Clinical Dangers of Lipohypertrophy: Injecting insulin into lipohypertrophic nodules leads to erratic, blunted, and delayed drug absorption. Patients experience unexplained bouts of daytime hyperglycaemia alternating with sudden, unpredictable, severe nocturnal hypoglycaemia. Nurses must physically inspect and palpate injection sites at every diabetic review.

• Storage Rules: Unopened insulin vials and pens must be stored refrigerated between $2^\circ\text{C}$ and $8^\circ\text{C}$ (never frozen). In-use pens or vials may be kept at controlled room temperature (below $25^\circ\text{C} - 30^\circ\text{C}$) away from direct heat and sunlight for up to 28 days (after which they must be discarded). Injecting cold insulin from a refrigerator causes local discomfort and peripheral vasoconstriction.

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Oral & Non-Insulin Antidiabetic Pharmacotherapy

+-----------------------------------------------------------------------------+
|                   NON-INSULIN ANTIDIABETIC MEDICATIONS                      |
+-------------------+--------------------+------------------------------------+
| Class / Drug      | Primary Mechanism  | Key Clinical Considerations        |
+-------------------+--------------------+------------------------------------+
| Biguanide         | Decreases hepatic  | * First-line for T2DM              |
| (Metformin)       | gluconeogenesis;   | * Zero hypoglycaemia risk as mono  |
|                   | increases insulin  | * Lactic acidosis risk in eGFR<30  |
|                   | sensitivity        | * HOLD for iodinated contrast!     |
+-------------------+--------------------+------------------------------------+
| Sulfonylurea      | Stimulates beta    | * High risk of prolonged hypoglyc  |
| (Gliclazide)      | cells to release   | * Causes weight gain               |
|                   | insulin            | * Caution in elderly & renal decay |
+-------------------+--------------------+------------------------------------+
| SGLT2 Inhibitor   | Inhibits proximal  | * Cardio-renal protection          |
| (Empagliflozin,   | tubular glucose    | * Risk of mycotic genital infect   |
| Dapagliflozin)    | reabsorption       | * Risk of EUGLYCAEMIC DKA (euDKA)  |
|                   | (causes glycosuria)| * Hold 48-72h before surgery       |
+-------------------+--------------------+------------------------------------+
| GLP-1 Receptor Ag | Incretin mimetic:  | * Enhances glucose-dependent ins   |
| (Semaglutide,     | slows gastric      | * Promotes weight loss             |
| Liraglutide)      | emptying, satiety  | * Subcutaneous weekly / daily      |
+-------------------+--------------------+------------------------------------+
| DPP-4 Inhibitor   | Prevents incretin  | * Weight neutral                   |
| (Sitagliptin)     | breakdown          | * Very low hypoglycaemia risk      |
+-------------------+--------------------+------------------------------------+

Metformin and the Iodinated Radiocontrast Rule

Metformin is excreted unchanged by the kidneys via glomerular filtration and tubular secretion. If a patient develops contrast-induced nephropathy (CIN) following intravenous radiocontrast administration, metformin accumulates rapidly, inhibiting mitochondrial respiratory chain complex I and suppressing hepatic lactate clearance, precipitating fatal metformin-associated lactic acidosis (MALA).

[!CAUTION] Mandatory Peri-Procedural Rule: Metformin MUST BE WITHHELD on the day of procedures involving intravenous iodinated radiocontrast media and withheld for 48 hours post-procedure. It may be resumed only after repeat blood tests confirm that renal function (serum creatinine and eGFR) has remained stable at baseline.

SGLT2 Inhibitors and Euglycaemic DKA (euDKA)

Sodium-glucose co-transporter 2 inhibitors promote renal excretion of glucose, creating cardio-renal benefits. However, during acute physiological stress, sepsis, surgery, or prolonged fasting, they can trigger Euglycaemic Diabetic Ketoacidosis (euDKA). Because glucose is continually excreted in urine, circulating plasma glucose may be normal or minimally elevated ($< 14.0\text{ mmol/L}$) despite profound systemic ketoacidaemia. Nurses must check blood beta-hydroxybutyrate in any unwell patient taking an SGLT2 inhibitor, regardless of blood glucose levels.

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Diabetic Ketoacidosis (DKA)

Diabetic Ketoacidosis is an acute, life-threatening metabolic emergency occurring predominantly in Type 1 Diabetes, triggered by absolute insulin deficiency coupled with an elevation in counter-regulatory stress hormones (glucagon, cortisol, adrenaline, growth hormone). Common precipitants include infection (pneumonia, UTI), omitted insulin doses, myocardial infarction, and new-onset diabetes.

The Pathophysiological Triad & Diagnostic Criteria

Diagnosis requires fulfillment of all three components of the DKA triad:

$\text{DKA Triad} = \text{Hyperglycaemia} + \text{Ketonaemia} + \text{Acidosis}$

1. Hyperglycaemia: Blood glucose $> 11.0$ mmol/L (or known history of diabetes mellitus).
2. Ketonaemia: Capillary blood beta-hydroxybutyrate $\ge 3.0$ mmol/L (or significant ketonuria $\ge 2+$ on dipstick).
3. Acidosis: Venous blood $\text{pH} < 7.30$ OR serum bicarbonate $< 15.0$ mmol/L.

Clinical Presentation

• Dehydration & Shock: Polyuria, polydipsia, dry mucus membranes, decreased skin turgor, tachycardia, hypotension, prolonged capillary refill.
• Respiratory: Kussmaul breathing (deep, rapid, sighing hyperventilation compensatory for metabolic acidosis), sweet "pear drop" or acetone breath odour.
• Gastrointestinal: Nausea, intractable vomiting, diffuse abdominal pain (simulating an acute surgical abdomen due to gastric stasis and mesenteric hypoperfusion).
• Neurological: Lethargy, drowsiness, progressive confusion, stupor.

Evidence-Based DKA Management Protocol

Management follows national Irish and joint British endocrine guidelines:

+-----------------------------------------------------------------------------+
|                        EVIDENCE-BASED DKA PROTOCOL                          |
+-----------------------------------------------------------------------------+
| 1. INTRAVENOUS FLUID RESUSCITATION (0.9% Sodium Chloride)                   |
|    * Hour 1: 1,000 mL over 1 hour                                           |
|    * Hours 2-4: 1,000 mL with KCl over 2 hours, then 1,000 mL over 2 hours  |
|    * Subsequent: 1,000 mL with KCl over 4h, then 4h, then 6h                |
+-----------------------------------------------------------------------------+
| 2. FIXED-RATE INTRAVENOUS INSULIN INFUSION (FRIII)                          |
|    * Infuse Soluble Insulin (Actrapid) at exactly 0.1 units/kg/hour         |
|    * CONTINUE patient's baseline long-acting basal insulin (Lantus/Tresiba) |
|    * Target: Ketone clearance >= 0.5 mmol/L/hr; HCO3- rise >= 3 mmol/L/hr   |
+-----------------------------------------------------------------------------+
| 3. AGGRESSIVE POTASSIUM REPLACEMENT PROTOCOL                                |
|    * Serum K+ > 5.5 mmol/L  --> NO potassium added; recheck K+ in 2 hours   |
|    * Serum K+ 3.5 - 5.5     --> Add 20 to 40 mmol KCl per litre of fluid    |
|    * Serum K+ < 3.5 mmol/L  --> DO NOT START INSULIN! Infuse K+ first!      |
+-----------------------------------------------------------------------------+
| 4. SUBSTRATE REPLACEMENT (10% DEXTROSE)                                     |
|    * When Blood Glucose drops < 14.0 mmol/L, start 10% Dextrose at 125 mL/hr|
|    * NEVER stop or drastically cut the FRIII just because glucose falls!    |
|    * Insulin is needed to turn off ketogenesis until DKA fully resolves     |
+-----------------------------------------------------------------------------+

[!IMPORTANT] The Potassium Cardinal Rule: Insulin drives potassium into cells by stimulating the $\text{Na}^+/\text{K}^+$ ATPase pump, causing a precipitous drop in circulating serum potassium. If a patient's baseline serum potassium is $< 3.5\text{ mmol/L}$, DO NOT START INSULIN (or suspend insulin). Replace potassium intravenously until $\text{K}^+ > 3.5\text{ mmol/L}$ before initiating insulin, preventing fatal cardiac dysrhythmias and cardiac arrest.

Criteria for Resolution of DKA

DKA is resolved when:

• Blood beta-hydroxybutyrate $< 0.6$ mmol/L
• Venous $\text{pH} > 7.30$
• Serum bicarbonate $> 18.0$ mmol/L
• Patient is alert, haemodynamically stable, and able to eat and drink.

Transition to Subcutaneous Insulin: Administer a subcutaneous dose of rapid-acting insulin and meal, and continue the intravenous insulin infusion for 30 to 60 minutes after the subcutaneous dose to avoid rebound ketoacidosis.

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Hyperosmolar Hyperglycaemic State (HHS)

Hyperosmolar Hyperglycaemic State is a life-threatening emergency occurring predominantly in older individuals with Type 2 Diabetes. It evolves insidiously over several days to weeks, driven by profound relative insulin deficiency and severe dehydration.

The Diagnostic Triad of HHS

1. Severe Hyperglycaemia: Blood glucose $\ge 30.0$ mmol/L (frequently $> 40 - 50\text{ mmol/L}$).
2. Profound Hyperosmolality: Effective serum osmolality $> 320$ mOsm/kg. $\text{Effective Serum Osmolality} = 2 \times [\text{Na}^+] + \text{Glucose (mmol/L)}$
3. Profound Dehydration & Absence of Significant Ketoacidosis:
   • Venous blood $\text{pH} > 7.30$
   • Serum bicarbonate $> 15.0$ mmol/L
   • Serum beta-hydroxybutyrate $< 3.0$ mmol/L (absent or mild ketonuria).

Clinical Presentation & Thromboembolism Hazard

• Extreme fluid deficit (typically 8 to 12 litres, representing $10% - 22%$ of total body water)
• Severe hypernatraemia, hyperviscosity, and prerenal acute kidney injury
• Impaired consciousness, delirium, focal neurological deficits (hemiparesis, seizures mimicking stroke), and coma
• Massive Thromboembolic Risk: Severe dehydration and hyperviscosity create extreme vulnerability to deep vein thrombosis, pulmonary embolism, stroke, and myocardial infarction.

Management Principles of HHS

1. Gradual Fluid Rehydration (0.9% Sodium Chloride):
   • Restore intravascular volume slowly. The fluid deficit must be replaced gradually over 48 to 72 hours.
   • Target Rate of Osmolality Decline: Reduce effective serum osmolality by 3 to 8 mOsm/kg/hour. Precipitous declines in osmolality or glucose cause water to shift rapidly into brain cells, triggering fatal cerebral edema or central pontine myelinolysis.
2. Mandatory Pharmacological Thromboprophylaxis:
   • Administer prophylactic Low-Molecular-Weight Heparin (LMWH) (e.g., enoxaparin) to all patients unless contraindicated by active haemorrhage.
3. Cautious, Delayed Insulin Administration:
   • Fluid resuscitation alone significantly lowers blood glucose (by increasing renal perfusion and glycosuria).
   • Do NOT start insulin immediately unless fluid replacement alone fails to reduce glucose, or significant ketonaemia is present.
   • If indicated, infuse low-dose insulin at 0.05 units/kg/hour only after fluid resuscitation is well established.

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Sick Day Rules: Managing Diabetes During Illness

RCSI lists Diabetes Ireland's material on managing diabetes during an illness and general sick day management, and this is the education that prevents most of the DKA and HHS admissions described above. Intercurrent illness raises counter-regulatory hormones - cortisol, glucagon, catecholamines, growth hormone - which drive gluconeogenesis and insulin resistance, so blood glucose usually rises even when the person is eating little or nothing.

The Core Rules

When the Person Must Seek Urgent Help

Teach these as explicit red flags rather than as general advice to "see how you get on":

• Persistent vomiting or inability to keep fluids down
• Moderate or large ketones, or ketones that are not falling despite extra insulin and fluids
• Blood glucose persistently high despite correction doses
• Breathlessness, deep sighing (Kussmaul) breathing, abdominal pain, or a fruity smell on the breath
• Drowsiness or confusion
• Signs of dehydration - dry mouth, reduced urine output, dizziness on standing
• Nobody at home to monitor them, or the person is unsure what to do

Teaching It

Use teach-back: ask the person to explain what they would do tomorrow morning if they woke with vomiting and a glucose of 18 mmol/L. Give written information to take home, check they have in-date ketone strips and know how to use them, and confirm who they would ring and when. Involve the family or carer, and ensure the plan is documented and shared with the GP and practice nurse.

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Comparison Matrix: DKA versus HHS

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Clinical Traps & Safety Pearls

• Trap 1: Stopping Insulin When Glucose Normalizes in DKA. Stopping the insulin infusion when glucose drops below 14.0 mmol/L results in rapid rebound ketoacidosis. The nurse must start 10% Dextrose and continue the insulin infusion until ketoacids are fully cleared.
• Trap 2: Starting Insulin in DKA with Hypokalaemia. Never start IV insulin if serum potassium is $< 3.5\text{ mmol/L}$. Administering insulin without potassium replacement will shift potassium intracellularly, causing lethal arrhythmias.
• Trap 3: Dropping Osmolality Too Rapidly in HHS. Aggressive hydration or large insulin boluses in HHS can cause a rapid drop in extracellular osmolality, driving water into brain cells and causing fatal cerebral edema. Rehydrate slowly over 48–72 hours.
• Trap 4: Missing Euglycaemic DKA in SGLT2 Users. A patient on empagliflozin presenting with vomiting, tachypnoea, and normal glucose can still be in life-threatening DKA. Always test blood ketones.