Type 2 Diabetes Mellitus (T2DM)

A 52 year old obese male presents with progressive fatigue, increased thirst, frequent urination, and blurred vision for several months. He has a history of hypertension and dyslipidemia. Physical examination reveals central obesity and acanthosis nigricans. Laboratory investigations show fasting plasma glucose of 156 mg/dL and HbA1c of 8.2%. Renal function is normal. Diagnosis?

Diagnosis is type 2 diabetes mellitus (T2DM).

1. Definition

Type 2 diabetes mellitus is a chronic metabolic disorder caused by insulin resistance and progressive pancreatic β-cell dysfunction resulting in persistent hyperglycemia.

2. Epidemiology

1. Accounts for approximately 90% of diabetes cases
2. Increasing prevalence worldwide
3. Commonly associated with obesity and sedentary lifestyle
4. Strong familial predisposition
5. Increasingly recognized in younger populations

3. Pathophysiology

1. Peripheral insulin resistance develops
2. Initial compensatory hyperinsulinemia occurs
3. Progressive pancreatic β-cell dysfunction develops
4. Hepatic glucose production increases
5. Chronic hyperglycemia results
6. Persistent hyperglycemia causes vascular injury leading to complications

4. Risk Factors

1. Obesity
2. Physical inactivity
3. Family history of diabetes
4. Increasing age
5. Hypertension
6. Dyslipidemia
7. Previous gestational diabetes
8. Polycystic ovary syndrome
9. Conditions associated with insulin resistance

5. Clinical Features

5.1 Classic Symptoms

1. Polyuria
2. Polydipsia
3. Polyphagia
4. Fatigue
5. Blurred vision
6. Weight loss in advanced disease

5.2 Signs of Insulin Resistance

1. Central obesity
2. Acanthosis nigricans
3. Skin tags

5.3 Features Suggesting Complications

1. Recurrent infections
2. Peripheral neuropathy
3. Foot ulcers
4. Erectile dysfunction
5. Visual impairment

6. Screening

1. Screen all adults beginning at age 35 years
2. Screen earlier in overweight or obese individuals with risk factors
3. Repeat screening every 3 years if normal or more frequently in high-risk patients

7. Diagnosis

Diagnosis requires one of the following:

1. HbA1c ≥6.5%
2. Fasting plasma glucose ≥126 mg/dL
3. 2-hour plasma glucose ≥200 mg/dL after 75 g OGTT
4. Random plasma glucose ≥200 mg/dL with classic symptoms

For asymptomatic patients, diagnosis should be confirmed with repeat testing

Prediabetes

1. HbA1c: 5.7–6.4%
2. Fasting plasma glucose: 100–125 mg/dL
3. 2-hour OGTT: 140–199 mg/dL

8. Initial Evaluation

History

1. Hyperglycemic symptoms
2. Family history
3. Diet and exercise habits
4. Medication review
5. Cardiovascular and renal history

Examination

1. BMI and waist circumference
2. Blood pressure
3. Foot examination
4. Signs of insulin resistance

Baseline Investigations

1. HbA1c
2. Renal function and eGFR
3. Lipid profile
4. Liver function tests
5. Urine albumin-to-creatinine ratio
6. Consider TSH when indicated

9. Complications

9.1 Microvascular

1. Diabetic retinopathy
2. Diabetic nephropathy
3. Diabetic neuropathy

9.2 Macrovascular

1. Coronary artery disease
2. Cerebrovascular disease
3. Peripheral arterial disease

9.3 Acute Complications

1. Hyperosmolar hyperglycemic state (HHS)
2. Hypoglycemia related to therapy
3. Diabetic ketoacidosis may rarely occur

10. Glycemic Targets

Most Adults

1. HbA1c <7%

Selected Patients

1. HbA1c <6.5% if safely achievable

Older Adults / Significant Comorbidity

1. Less stringent targets such as ≤8% may be appropriate

Targets should be individualized based on hypoglycemia risk, comorbidities, and life expectancy

11. Management

11.1 Lifestyle Therapy

1. Lifestyle modification for all patients
2. Weight reduction improves glycemic control and may induce remission, especially with substantial early weight loss
3. Whole-food dietary pattern with reduced refined carbohydrates
4. ≥150 minutes/week moderate exercise
5. Resistance training at least 2 days/week

11.2 Pharmacologic Therapy

Drug selection should be individualized based on:

1. ASCVD
2. Heart failure
3. Chronic kidney disease
4. Obesity
5. Hypoglycemia risk
6. Cost and patient preference

Metformin

1. Common preferred initial therapy if tolerated
2. Improves insulin sensitivity
3. Weight neutral
4. Avoid if eGFR <30 mL/min

GLP-1 Receptor Agonists and Dual GIP/GLP-1 Agonists

1. Preferred particularly in obesity and established ASCVD
2. Promote substantial weight loss
3. Provide cardiovascular and renal benefit

SGLT2 Inhibitors

1. Preferred in CKD and heart failure regardless of HbA1c in appropriate patients
2. Reduce cardiovascular and renal events
3. May cause genital infections and volume depletion

Other Options

1. DPP-4 inhibitors
2. Sulfonylureas
3. TZDs
4. Insulin

11.3 When to Start Insulin

1. HbA1c ≥10%
2. Fasting glucose ≥300 mg/dL
3. Symptomatic hyperglycemia
4. Catabolic features such as weight loss or ketosis

12. Monitoring

1. HbA1c every 3 months until stable, then every 6 months
2. Dilated retinal examination at diagnosis and repeat every 1–2 years if normal or more frequently if retinopathy is present
3. Annual urine albumin and eGFR assessment
4. Annual comprehensive foot examination
5. More frequent foot assessment in high-risk patients
6. Blood pressure at every visit

13. Cardiovascular and Renal Protection

1. Blood pressure control
2. Statin therapy when indicated
3. Smoking cessation
4. ACE inhibitor or ARB for albuminuria
5. Early use of SGLT2 inhibitors and GLP-1 receptor agonists in appropriate patients
6. Vaccination including influenza, pneumococcal, hepatitis B, and COVID where appropriate

14. Key Clinical Insight

Middle-aged or obese patient with polyuria, polydipsia, acanthosis nigricans, and elevated HbA1c strongly suggests type 2 diabetes mellitus

15. Key Exam Points

1. Most common type of diabetes mellitus
2. Core defects are insulin resistance and progressive β-cell failure
3. HbA1c ≥6.5% is diagnostic
4. Diagnosis in asymptomatic patients requires confirmation
5. Treatment is individualized and organ-protective
6. Metformin remains a common preferred initial therapy
7. GLP-1 receptor agonists are preferred in obesity and ASCVD
8. SGLT2 inhibitors are preferred in CKD and heart failure
9. Lifestyle therapy is essential for all patients
10. Early cardiovascular and renal protection improves long-term outcomes