Section 8.3: Diabetes Mellitus & Metabolic Syndrome

Diabetic Ketoacidosis and Hyperosmolar Hyperglycemic State

Diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic state (HHS) are life-threatening acute complications of diabetes mellitus. DKA is characterized by a triad of hyperglycemia (typically glucose > 250 mg/dL), metabolic acidosis (arterial pH < 7.30 and serum bicarbonate < 18 mEq/L), and ketonemia/ketonuria (marked by elevated beta-hydroxybutyrate and acetoacetate). DKA occurs primarily in type 1 diabetes due to absolute insulin deficiency, which promotes lipolysis, fatty acid transport to the liver, and subsequent ketogenesis. Conversely, HHS occurs predominantly in type 2 diabetes and is defined by severe hyperglycemia (glucose > 600 mg/dL), high serum osmolality (> 320 mOsm/kg), and minimal or absent ketosis (pH > 7.30, bicarbonate > 18 mEq/L). In HHS, residual insulin secretion is sufficient to suppress lipolysis and ketogenesis but insufficient to prevent profound hyperglycemia and osmotic diuresis, leading to severe dehydration.

The management protocol for both DKA and HHS requires a highly structured approach:

1. Intravenous Fluids: Fluid resuscitation is the initial priority. Administer 1–1.5 L of 0.9% normal saline in the first hour. Subsequent fluid selection is based on corrected sodium and volume status. If corrected sodium is normal or high, switch to 0.45% saline. When serum glucose falls to 200 mg/dL in DKA (or 300 mg/dL in HHS), change the IV fluid to 5% dextrose in 0.45% saline. This allows the continuation of the insulin infusion to resolve ketosis (in DKA) or hyperosmolality (in HHS) while preventing hypoglycemia and cerebral edema.
2. Potassium Management: Before initiating insulin, serum potassium must be evaluated. Insulin drives potassium intracellularly, which can cause fatal cardiac arrhythmias. If potassium is < 3.3 mEq/L, hold insulin and administer potassium chloride (20–30 mEq/h) until the potassium is > 3.3 mEq/L. If potassium is 3.3–5.2 mEq/L, administer potassium (20–30 mEq per liter of IV fluid) concurrently with insulin to maintain potassium between 4.0–5.0 mEq/L. If potassium is > 5.2 mEq/L, insulin can be started immediately, and potassium should be monitored closely without supplement.
3. Insulin Administration: Administer a continuous regular insulin infusion at 0.1 units/kg/h (or a 0.1 unit/kg bolus followed by 0.1 units/kg/h). In DKA, do not stop the insulin infusion based on glucose levels alone; the infusion must continue until the anion gap closes (AG < 12), pH > 7.30, and bicarbonate ≥ 18 mEq/L.
4. Transition to Subcutaneous Insulin: When the patient is hemodynamically stable, tolerating oral intake, and DKA has resolved (or osmolality has normalized in HHS), transition to a subcutaneous insulin regimen. To prevent immediate relapse into ketosis, administer the first dose of subcutaneous basal insulin 2 hours before discontinuing the intravenous insulin infusion.

Step-wise Management of Type 2 Diabetes

Pharmacotherapy for type 2 diabetes has evolved from a glucose-centric model to a risk-stratified, cardiorenal-protective framework:

• First-line Therapy: Metformin is the first-line agent due to high efficacy, weight-neutral profile, low hypoglycemia risk, and low cost. It decreases hepatic gluconeogenesis and improves peripheral insulin sensitivity. Metformin is contraindicated if eGFR is < 30 mL/min/1.73m2 due to lactic acidosis risk. Renal function must be monitored annually.
• Cardiorenal Protection: In patients with established atherosclerotic cardiovascular disease (ASCVD), heart failure (HF), or chronic kidney disease (CKD) with albuminuria, specific agents should be added independent of baseline HbA1c:
  • SGLT-2 Inhibitors (e.g., empagliflozin, dapagliflozin): Block renal glucose reabsorption in the proximal convoluted tubule. They are preferred in patients with heart failure (reduced or preserved ejection fraction) and CKD progression (slowing GFR decline and reducing proteinuria). Side effects include genitourinary candidiasis, urinary tract infections, euglycemic DKA, and volume depletion.
  • GLP-1 Receptor Agonists (e.g., semaglutide, liraglutide, dulaglutide): Mimic incretin hormones to enhance glucose-dependent insulin secretion and delay gastric emptying. They are preferred in patients with predominant ASCVD or a high need for weight loss. Side effects include gastrointestinal distress and a risk of pancreatitis; they are contraindicated in patients with a history of medullary thyroid carcinoma or Multiple Endocrine Neoplasia type 2.
• Other Adjunctive Agents: Other agents include DPP-4 inhibitors (weight-neutral), sulfonylureas (high hypoglycemia risk), and thiazolidinediones (cause fluid retention, contraindicated in advanced heart failure).
• Insulin Initiation: Indicated for severe hyperglycemia (glucose > 300 mg/dL or HbA1c > 10%) or symptomatic patients (weight loss, polyuria, polydipsia). Begin with basal insulin (10 units daily or 0.1–0.2 units/kg/day) and titrate based on fasting glucose.

Chronic Diabetic Complications and Metabolic Syndrome

Microvascular complications require strict screening and management:

• Diabetic Kidney Disease: Screen annually with a urine albumin-to-creatinine ratio (UACR). If UACR is ≥ 30 mg/g, initiate an ACE inhibitor (e.g., lisinopril) or ARB (e.g., losartan), even in normotensive patients, to slow progression.
• Diabetic Retinopathy: Screen with a dilated eye exam annually starting at diagnosis for type 2 diabetes (or 5 years after diagnosis for type 1).
• Diabetic Neuropathy: Diabetic Neuropathy requires annual 10-g monofilament testing. Management of painful neuropathy includes pregabalin, duloxetine, or gabapentin. Gastroparesis presents with delayed gastric emptying; treat with small, low-fat meals and prokinetic agents like metoclopramide (limit use due to tardive dyskinesia risk) or erythromycin.
• Macrovascular Risk: Patients aged 40–75 with diabetes require a moderate- to high-intensity statin for primary cardiovascular prevention, regardless of baseline LDL cholesterol.

Metabolic Syndrome: A cluster of risk factors predisposing to cardiovascular disease and type 2 diabetes. Diagnosis requires at least 3 of the following 5 criteria:

1. Waist Circumference: > 102 cm (40 inches) in men, or > 88 cm (35 inches) in women.
2. Triglycerides: ≥ 150 mg/dL (or on pharmacotherapy for hypertriglyceridemia).
3. HDL Cholesterol: < 40 mg/dL in men, or < 50 mg/dL in women (or on therapy).
4. Blood Pressure: Systolic ≥ 130 mmHg and/or diastolic ≥ 85 mmHg (or on antihypertensives).
5. Fasting Glucose: ≥ 100 mg/dL (or on glucose-lowering therapy).