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Summary Table

Category	Details
Risk Factors	Age >35 years (>40 for Indonesian population), BMI ≥23 kg/m², family history of DM in first-degree relatives, history of gestational DM, prior delivery of infant >4 kg, physical inactivity, hypertension (>140/90), dyslipidemia (HDL <35 mg/dL, TG >250 mg/dL), PCOS, history of cardiovascular disease, HIV/AIDS on antiretrovirals, low birth weight (<2.5 kg)
Etiology	Variable spectrum ranging from predominant insulin resistance with relative insulin deficiency to predominant secretory defect with insulin resistance
Patient Presentation	Classic triad: polyuria, polydipsia, unexplained weight loss. May also present with polyphagia, blurred vision, fatigue, recurrent infections (UTI, candidiasis), or slow-healing wounds. Many patients are asymptomatic and discovered incidentally
Classic Physical Exam	Obesity (especially central), acanthosis nigricans, skin tags, signs of chronic complications (diminished pedal pulses, reduced monofilament sensation, non-healing ulcers, hypertensive retinopathy or diabetic retinopathy on fundoscopy)
Key Diagnostic Results	Fasting plasma glucose (FPG) ≥126 mg/dL, 2-hour plasma glucose ≥200 mg/dL after 75g OGTT, random plasma glucose ≥200 mg/dL with classic symptoms, or HbA1c ≥6.5% (NGSP-certified method)
Management	Lifestyle modification (diet + exercise) for all patients. Metformin as first-line pharmacotherapy (unless contraindicated). Individualized add-on therapy based on comorbidities: SGLT2 inhibitors for heart failure or CKD, GLP-1 RA for ASCVD or high-risk. Insulin when HbA1c >9% with metabolic decompensation or when oral agents fail to reach target
Keywords	"Polyuria, polydipsia, weight loss," "acanthosis nigricans," "fasting glucose ≥126," "HbA1c ≥6.5%," "insulin resistance," "metabolic syndrome," "metformin first-line," "cardiorenal protection"

1. Pathophysiology

Type 2 diabetes mellitus arises from a progressive interaction between insulin resistance and beta-cell dysfunction. The pathophysiology is not a single defect but rather a collection of abnormalities often described as the "ominous octet": reduced insulin secretion from beta cells, increased glucagon secretion from alpha cells, increased hepatic glucose production, decreased peripheral glucose uptake in muscle, increased lipolysis, impaired incretin effect, increased renal glucose reabsorption, and neurotransmitter dysfunction at the hypothalamic level.

In early disease, the pancreatic beta cells compensate for peripheral insulin resistance by secreting more insulin, maintaining normoglycemia. This compensatory phase explains why many patients have hyperinsulinemia long before they develop overt hyperglycemia. Over time, beta cells undergo apoptosis and dedifferentiation, leading to a progressive decline in insulin secretion. This is the pivotal transition from prediabetes to frank diabetes. By the time a patient presents with symptoms, roughly 50% of beta-cell function has already been lost.

Insulin resistance in the liver results in unsuppressed gluconeogenesis, which is why fasting hyperglycemia is a hallmark finding. In peripheral muscle, impaired GLUT-4 translocation reduces glucose uptake, contributing to postprandial hyperglycemia. Adipose tissue resistance increases free fatty acid release (lipotoxicity), which further impairs beta-cell function and worsens hepatic insulin resistance, creating a self-perpetuating cycle.

The clinical relevance of this dual defect is directly tested on exams. Vignettes will describe a patient whose fasting glucose is elevated (hepatic resistance) versus one whose postprandial glucose is selectively high (peripheral resistance with early secretory failure). Understanding which mechanism dominates guides the choice of pharmacotherapy.

Chronic hyperglycemia drives complications through several molecular pathways: the polyol pathway (sorbitol accumulation causing osmotic damage, leading to cataracts and neuropathy), the hexosamine pathway, protein kinase C activation, and advanced glycation end-product (AGE) formation. These mechanisms unify the microvascular complications (retinopathy, nephropathy, neuropathy) and contribute to accelerated macrovascular disease (coronary artery disease, stroke, peripheral arterial disease).

2. Classification and Clinical Manifestation

Classification of Diabetes Mellitus (Perkeni 2024)

Type	Description
Type 1	Beta-cell destruction (autoimmune or idiopathic), leading to absolute insulin deficiency
Type 2	Spectrum from predominant insulin resistance with relative insulin deficiency to predominant secretory defect with insulin resistance
Gestational DM	Diabetes first diagnosed during pregnancy without prior history of diabetes
Other Specific Types	Monogenic diabetes syndromes (neonatal DM, MODY), exocrine pancreatic disease (cystic fibrosis, pancreatitis), drug-induced (glucocorticoids, HIV therapy, post-transplant)

Prediabetes vs. Diabetes

Category	HbA1c (%)	Fasting Plasma Glucose (mg/dL)	2-hr Post-OGTT (mg/dL)	Random Plasma Glucose (mg/dL)
Normal	<5.7	70-99	70-139	--
Prediabetes	5.7-6.4	100-125 (IFG)	140-199 (IGT)	--
Diabetes	≥6.5	≥126	≥200	≥200 (with classic symptoms)

Clinical Manifestation Spectrum

Presentation	Features
Classic symptomatic	Polyuria, polydipsia, polyphagia, unexplained weight loss
Asymptomatic / incidental	Discovered on routine labs (elevated fasting glucose or HbA1c during check-up)
Complication-first presentation	Patient presents with MI, stroke, non-healing foot ulcer, visual loss, or recurrent infections before DM diagnosis is made
Metabolic decompensation	HbA1c >9%, FPG ≥250 mg/dL, or random glucose >300 mg/dL with rapid weight loss and/or ketosis; this presentation in Type 2 demands immediate insulin initiation per Perkeni guidelines
Hyperosmolar Hyperglycemic State (HHS)	Extreme hyperglycemia (>600 mg/dL), plasma osmolality >320 mOsm/L, no significant ketoacidosis, altered sensorium

3. Diagnostic Workup

Test	Role	Key Threshold
Fasting Plasma Glucose (FPG)	Best initial test for screening and diagnosis	≥126 mg/dL (after ≥8 hours fasting)
75g Oral Glucose Tolerance Test (OGTT)	More sensitive for detecting IGT and early DM; used when FPG is borderline	2-hr glucose ≥200 mg/dL
HbA1c	Reflects average glycemia over 2-3 months; used for both diagnosis and monitoring	≥6.5% (NGSP-certified, DCCT-standardized assay)
Random Plasma Glucose	Diagnostic only when accompanied by classic symptoms or hyperglycemic crisis	≥200 mg/dL with symptoms
Fructosamine / Glycated Albumin	Alternative to HbA1c when red cell turnover is abnormal	Used in hemolytic anemia, hemoglobinopathy, pregnancy, ESRD

Per the Perkeni 2024 guidelines, the recommended specimen for diagnosis is venous plasma using an enzymatic glucose assay. Capillary blood glucose (point-of-care glucometer) is acceptable for monitoring but not for establishing a diagnosis.

How to confirm the diagnosis: In an asymptomatic patient, a single abnormal result is not sufficient. Two abnormal results from different tests (or the same test on two separate occasions) are required. However, if the patient has classic hyperglycemic symptoms (polyuria, polydipsia, weight loss) or is in hyperglycemic crisis, a single random plasma glucose ≥200 mg/dL is sufficient.

HbA1c: important caveats. HbA1c is influenced by erythrocyte turnover. It should not be used as a diagnostic tool in patients with hemolytic anemia, hemoglobinopathies (sickle cell disease, HbEE), recent blood transfusion, erythropoietin-stimulating agent therapy, end-stage renal disease, or pregnancy. In these situations, use fasting or post-load glucose values, or alternative glycated protein assays such as fructosamine or glycated albumin. This is a high-yield exam trap.

Screening recommendations (Perkeni 2024): Screen any individual without symptoms who has BMI ≥23 kg/m² (note: the Asian cutoff, not 25 kg/m²) plus at least one additional risk factor (first-degree relative with DM, hypertension, dyslipidemia, PCOS, physical inactivity, HIV/AIDS). All adults aged >35 years should be screened regardless of BMI. Women with prior gestational DM should be screened every 3 years for life.

4. Management and Treatment

Glycemic Targets (Perkeni 2024)

Parameter	Target
HbA1c	<7% (or individualized)
Pre-prandial capillary glucose	80-130 mg/dL
1-2 hr post-prandial capillary glucose	<180 mg/dL
BMI	18.5-22.9 kg/m²
Systolic BP	<140 mmHg
Diastolic BP	<90 mmHg
LDL cholesterol	<100 mg/dL (moderate risk), <70 mg/dL (high risk), <55 mg/dL (very high risk)
Triglycerides	<150 mg/dL

For elderly patients with stable comorbidities and intact cognition, target HbA1c <7.0-7.5%. For elderly patients with complex health conditions, frailty, or limited life expectancy, a more relaxed target of HbA1c <8.0% is appropriate, prioritizing avoidance of hypoglycemia over strict control.

Oral Antidiabetic Drug Classes

Drug Class	Mechanism	Key Advantage	Key Side Effect / Contraindication
Metformin (biguanide)	Decreases hepatic gluconeogenesis, improves peripheral glucose uptake, activates AMPK	First-line for nearly all Type 2 DM; weight-neutral to mild weight loss; cardiovascular benefit via pleiotropic effects	GI upset (take after meals); contraindicated if eGFR <30; dose-adjust if eGFR 30-60; hold before iodinated contrast if eGFR <60
Sulfonylureas (glibenclamide, glimepirid, gliclazide)	Stimulates beta-cell insulin secretion	Potent glucose lowering, widely available, low cost	Hypoglycemia (especially in elderly, renal/hepatic impairment), weight gain
Thiazolidinedione (pioglitazone)	Decreases peripheral insulin resistance (PPAR-gamma agonist)	Cardiovascular benefit in stroke/TIA patients; resolution of NASH/MASH; durable glycemic control	Fluid retention (contraindicated in NYHA III-IV heart failure), fracture risk in women, weight gain
Alpha-glucosidase inhibitor (acarbose)	Delays carbohydrate absorption by inhibiting brush border enzymes	Targets postprandial hyperglycemia; effective with high-carbohydrate diets	GI side effects (flatulence, bloating, diarrhea); contraindicated if eGFR <30, severe liver disease, IBS
DPP-4 inhibitors (sitagliptin, vildagliptin, linagliptin, alogliptin, saxagliptin)	Prevents incretin (GLP-1, GIP) degradation	Weight-neutral, low hypoglycemia risk; linagliptin requires no renal dose adjustment	Saxagliptin increases heart failure hospitalization risk; use caution with alogliptin in NYHA III-IV
SGLT2 inhibitors (empagliflozin, dapagliflozin, canagliflozin)	Blocks renal glucose reabsorption at proximal tubule	Proven cardiorenal protection (reduces heart failure hospitalization by 32%, CV death by 15%); weight loss; BP reduction	UTI/genital infections; risk of euglycemic DKA; do not use if eGFR <20; caution with volume depletion
Oral GLP-1 RA (oral semaglutide)	GLP-1 receptor agonism (tablet form)	Glycemic control + weight loss + CV risk reduction without injection	GI side effects (nausea 25-60%, vomiting, diarrhea); start at 3 mg, titrate to 7 mg then 14 mg monthly

Injectable Therapy

Agent	Starting Dose	Key Points
Basal insulin (glargine, detemir, degludec)	10 U/day or 0.2 U/kg/day; optimize up to 0.5 U/kg/day	Titrate based on fasting glucose; target FPG within range before adding prandial insulin
Once-weekly basal insulin (icodec)	70 U/week; adjust by 20 U increments weekly	Increase if FPG/pre-prandial >130 mg/dL; decrease if <80 mg/dL
GLP-1 RA injectable (liraglutide, semaglutide, dulaglutide)	Varies by agent; titrate weekly to optimal dose	Proven 3-point MACE reduction (14%, NNT=65); reduces HF hospitalization; do not combine with DPP-4 inhibitors; limit use if eGFR <30
Dual GIP/GLP-1 RA (tirzepatide)	Titrated per protocol	Superior glycemic and weight reduction; CV safety established
Fixed-ratio combination (IDegLira, IGlarLixi)	10 U/day	Combines basal insulin with GLP-1 RA; lower hypoglycemia and weight gain vs. insulin alone
Prandial insulin (aspart, lispro, glulisine)	4 U/meal or 10% of basal dose	Added when FPG is at target but postprandial glucose remains high; start with largest meal (basal-plus strategy)

Treatment Algorithms (Perkeni 2024)

Step 1: All patients receive lifestyle modification (medical nutrition therapy + physical activity targeting 7% weight loss in 6 months).

Step 2: Determine the treatment pathway based on comorbidities.

Pathway A (Cardiorenal Risk Reduction): If the patient has established ASCVD (MI, stroke, PAD, revascularization, TIA, unstable angina), heart failure (HFrEF or HFpEF), CKD (eGFR <60 or ACR ≥30 mg/g), or high-risk features (age ≥55 with ≥2 additional risk factors), then regardless of HbA1c status, add an SGLT2 inhibitor or GLP-1 RA with proven benefit for that condition. For heart failure, SGLT2 inhibitors are preferred. For stroke/TIA, GLP-1 RA or pioglitazone is preferred. For CKD with eGFR ≥20, SGLT2 inhibitors are preferred and should be continued until dialysis initiation or transplant.

Pathway B (Glycemic and Weight Control): If no cardiorenal comorbidity is present, start metformin (unless contraindicated) and individualize add-on therapy based on:

If avoiding hypoglycemia is the priority: add GLP-1 RA, SGLT2 inhibitor, DPP-4 inhibitor, or TZD (avoid sulfonylureas)
If weight loss is needed: add GLP-1 RA, dual GIP/GLP-1 RA (tirzepatide), or SGLT2 inhibitor (avoid sulfonylureas, TZD, insulin if possible)
If cost/access is a barrier: sulfonylurea or TZD may be appropriate

Combination therapy from the start is recommended when HbA1c at diagnosis is >7% (dual combination) or >9% / >1.5% above target (triple combination), always using agents with different mechanisms.

Step 3: Insulin initiation. Per Perkeni 2024, insulin should be started in the following situations:

HbA1c >9%, FPG ≥250 mg/dL, or random glucose >300 mg/dL with metabolic decompensation (rapid weight loss, severe hyperglycemia with ketosis)
HbA1c remains above 7% despite 2-3 oral agents at optimized doses
Hyperglycemic crisis (DKA, HHS)
Acute severe illness (systemic infection, surgery, MI, stroke)
Severe renal or hepatic impairment precluding oral agents
Perioperative setting

Insulin intensification: If basal insulin achieves target fasting glucose but postprandial glucose remains high, add prandial insulin at the largest meal first ("basal-plus"), then extend to basal-plus-2 or full basal-bolus as needed.

Monitoring (Perkeni 2024)

HbA1c should be checked every 3 months until target is achieved, then every 3-6 months for stable patients.

Self-monitoring of blood glucose (SMBG): For patients on insulin, structured monitoring should include fasting, pre-meal, post-meal, bedtime, and overnight values. For patients on non-insulin therapy, SMBG is useful for dietary adjustments and detecting hypoglycemia (especially with sulfonylureas).

Continuous Glucose Monitoring (CGM): CGM metrics include Time in Range (TIR, goal >70% between 70-180 mg/dL), Time Above Range (TAR <25% for 181-250, <5% for >250), and Time Below Range (TBR <4% for 54-69, <1% for <54). For elderly patients, the target is more lenient: TIR >50%, TBR <1% for both levels.

HbA1c-to-glucose correlation (Perkeni 2024):

HbA1c (%)	Estimated Mean Glucose (mg/dL)
6	126 (100-152)
7	154 (123-185)
8	183 (147-217)
9	212 (170-249)
10	240 (193-282)
11	269 (217-314)
12	298 (240-347)

Annual screening for complications:

Eye exam by ophthalmologist at diagnosis, then every 1-2 years if no retinopathy (annually if retinopathy detected)
Urine albumin-to-creatinine ratio (ACR) and eGFR annually
Foot examination with 10g monofilament and 128 Hz tuning fork annually
Lipid panel, liver function, cardiovascular risk assessment annually

5. Differential Diagnosis and Distractors

Differential	Why It Looks Similar	Key Discriminator
Type 1 DM	Also presents with polyuria, polydipsia, weight loss, and hyperglycemia	Type 1 presents in younger patients (typically <30, though LADA can occur later), has rapid progression to insulin dependence, positive anti-GAD/anti-IA2 antibodies, low C-peptide, and frequently presents with DKA as first episode. Type 2 patients are typically older, overweight, with signs of insulin resistance (acanthosis nigricans), and have preserved or elevated C-peptide
LADA (Latent Autoimmune Diabetes in Adults)	Adult onset with initially mild presentation resembling Type 2	Progressive beta-cell failure within months despite oral agents; positive autoantibodies (anti-GAD); low or declining C-peptide. The vignette clue is a "lean adult who fails oral therapy within 1-2 years"
MODY (Maturity-Onset Diabetes of the Young)	Mild fasting hyperglycemia in a young, non-obese patient with strong family history	Autosomal dominant inheritance across ≥3 generations; negative autoantibodies; normal or mildly reduced C-peptide; does not require insulin initially. MODY2 (glucokinase) presents as stable, mild fasting hyperglycemia that does not progress
Cushing Syndrome	Hyperglycemia + central obesity + hypertension	Look for moon facies, buffalo hump, violaceous striae (>1 cm wide), proximal muscle weakness, easy bruising. Confirm with 24-hr urinary free cortisol or overnight dexamethasone suppression test
Acromegaly	Hyperglycemia + insulin resistance due to excess GH/IGF-1	Coarsened facial features, frontal bossing, enlarged hands/feet/jaw (prognathism), skin tags, visual field defects from pituitary mass. Confirm with IGF-1 level and oral glucose suppression test
Pheochromocytoma	Episodic hyperglycemia with paroxysmal hypertension and sweating	Classic triad: headache, diaphoresis, palpitations (episodic, not continuous). Catecholamine excess inhibits insulin secretion and stimulates glycogenolysis. Diagnose with plasma free metanephrines
Drug-induced hyperglycemia	New-onset hyperglycemia temporally related to medication initiation	Common offenders: glucocorticoids, thiazide diuretics, atypical antipsychotics (olanzapine, clozapine), calcineurin inhibitors (tacrolimus), protease inhibitors. Temporal relationship between drug initiation and glucose elevation is the key clue
Hemochromatosis	"Bronze diabetes": hyperglycemia + skin hyperpigmentation	Iron overload damages beta cells. Look for hepatomegaly, arthropathy, hypogonadism, elevated ferritin, high transferrin saturation. Liver biopsy or MRI for iron quantification. HFE gene testing

6. Traps and High-Yield Pearls

Trap 1: Using HbA1c to diagnose diabetes when it is unreliable. A common exam question will present a patient with sickle cell trait, hemolytic anemia, recent transfusion, or end-stage renal disease and ask you to choose the best diagnostic test. HbA1c is invalid in these settings because altered red blood cell lifespan falsifies the result. Use fasting glucose, OGTT, or fructosamine/glycated albumin instead. This tests your understanding that HbA1c is a surrogate marker dependent on erythrocyte turnover, not a direct glucose measurement.

Trap 2: Forgetting the Asian BMI cutoff. The Perkeni 2024 guideline uses BMI ≥23 kg/m² (not 25) as the threshold for overweight and screening. A vignette featuring an Asian patient with BMI 24 who "appears normal weight" is already above the screening threshold. The standard WHO cutoff of 25 does not apply in Southeast Asian populations.

Trap 3: Ordering metformin in a patient with eGFR <30. Metformin is contraindicated when eGFR falls below 30 mL/min/1.73m². Between 30 and 60, the dose must be adjusted. Additionally, metformin must be withheld before any iodinated contrast procedure (for IV contrast, hold if eGFR <60; for intra-arterial contrast, hold regardless of eGFR) and resumed 48 hours later only if renal function is stable.

Trap 4: Choosing a sulfonylurea in an elderly patient with CKD. Sulfonylureas are metabolized hepatically but several have active metabolites cleared renally. In elderly patients or those with renal impairment, accumulated active metabolites cause prolonged, dangerous hypoglycemia. If a vignette describes an elderly patient found unresponsive with glucose of 35 mg/dL who takes glibenclamide, this is the expected scenario. The lesson: avoid sulfonylureas in this population, or choose gliclazide (which has no active renal metabolites) if one must be used.

Trap 5: Missing the cardiorenal-first pathway. A frequent testing concept is the patient with established ASCVD or CKD whose HbA1c is already at target (say 6.8%) but who is not yet on an SGLT2 inhibitor or GLP-1 RA. The correct answer is to add one of these agents for organ protection regardless of glycemic control. Students often skip this because "the HbA1c is fine." The Perkeni 2024 algorithm and all major international guidelines explicitly state that cardiorenal-protective agents should be prescribed independently of glycemic status when the comorbid condition is present.

Trap 6: Not recognizing when to start insulin immediately. If HbA1c >9% with metabolic decompensation (rapid weight loss, ketosis), or FPG ≥250 mg/dL, or random glucose >300 mg/dL with symptoms, the answer is not "start metformin and reassess in 3 months." The correct answer is insulin initiation, with possible de-escalation later once the glucose toxicity resolves and beta-cell function recovers.

Core competency being tested: Licensing exams assess three main skills with this diagnosis. First, the ability to apply diagnostic criteria correctly and to know when HbA1c is unreliable. Second, the ability to individualize therapy based on the patient's comorbidity profile (cardiorenal risk vs. glycemic-weight target pathway) rather than reflexively choosing metformin for everyone. Third, the ability to recognize the threshold for insulin initiation and the stepwise intensification from basal to basal-plus to basal-bolus regimens.

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