Type 2 Diabetes

Results from a combination of insulin resistance and less severe insulin deficiency

Aetiology

Accounts for 90-95% of diabetes

Greatest prevalence is in lower and middle income countries

T2DM is thought to be polygenic - contribution of environmental influences, usually the development of insulin resistance and obesity

Non-modifiable risk factors

Usually occurs later in life (> 45 years)

β-cell function declines with age

Genetics - polygenetic disease with 400 genetic varients identified to date ('common complex disease')

Ethnicity - individuals of South Asian, African and Afro-Carribean descent are at greater risk

Modifiable risk factors

Obesity - 9 out of 10 people with T2DM are overweight/obese (BMI of 25 or above)

Diet - high dietary fat, particularly saturated fat, red and processed meat, fried food, increased intake of white rice and sugary drinks

Physical inactivity and sedentary behaviours

Pathophysiology

Autoimmune destruction of the beta-cell does not occur

Patients do not have any other known cause for their diabetes

Ranges from predominantly insulin resistance with relative insulin deficiency to predominantly an insulin secretory defect with insulin resistance

Abnormalities of insulin action

Insulin action is diminished in T2DM through the development of insulin resistance

Central obesity → increased plasma levels of free fatty acids → impaired insulin-dependent glucose uptake into hepatocytes, myocytes and adipocytes
Increased tyrosine kinase activity in liver, fat and skeletal muscle cells → decreased activation of downstream proteins → decreased expression of GLUT channels → decreased cellular glucose uptake

Insulin resistance occurs in genetically susceptible individuals due to modifiable lifestyle related factors

Insulin resistance occurs when fat can no longer be stored in subcutanous adipose tissue causing spill over of FFA to the viscera, which explains why not everyone with obesity develops diabetes
People with 'healthy' obesity are able to safely store lots of fat, whereas others have a low fat storage threshold and these are the people who develop T2DM

Abnormalities of insulin secretion

As insulin resistance develops, the body's response is to increase insulin secretion and so early T2DM is often associated with insulin hypersecretion

An early sign is the loss of the first phase of the normal biphasic insulin secretion

The compensatory increased insulin is still insufficient to restore glucose homeostasis, so hyperglycaemia persists

Hyperglycaemia and the increased levels of FFAs and adipokines are toxic to the β-cells

The hyperglycaemia and lipid excess damage the β-cells → decrease in insulin production

People with increased genetic risk of T2DM have β-cells which are less able to cope with the lipotoxicity and glucotoxicity - another explanation for why not all obese people are diabetic

Other hormonal abnormalities

Glucagon secretion is increased in T2DM due to decreased intra-islet insulin → increased gluconeogenesis (further increases blood glucose)

Incretin effect is decreased in T2DM

Clinical presentation

Classic Symptoms

Polyuria

Polydipsia

Polyphagia

Unintentional weight loss

Signs

Acanthosis nigricans - insulin-driven epithelial overgrowth seen in hyperinsulinaemic states (severe insulin resistance)

Investigations

Blood glucose

Diagnostic Criteria (Any One of the Following):

Fasting plasma glucose ≥ 126 mg/dL (7.0 mmol/L)

2-hour plasma glucose ≥ 200 mg/dL during OGTT

HbA1c ≥ 6.5%

Random plasma glucose ≥ 200 mg/dL with classic symptoms

Other investigations

Ketones - if random blood glucose > 15 mM

Cholesterol

(Pancreatic autoantibodies)

Management

Lifestyle change - at diagnosis, 10-15% weight loss can result in remission

Pharmacological management

First-Line Therapy

Lifestyle Modification + Metformin (Biguanide)

Indication:

First-line drug for most patients unless contraindicated

Contraindications:

eGFR <30 mL/min/1.73 m²

Severe hepatic failure

Risk of lactic acidosis

Dual Therapy (If HbA1c Above Target After 3 Months)

Metformin + selected drugs depends on comorbidities and patient factors.

Established ASCVD or High CV Risk

GLP-1 receptor agonist (liraglutide, semaglutide)
SGLT-2 inhibitor (empagliflozin, dapagliflozin)

Heart Failure (Especially HFrEF)

SGLT-2 inhibitor (empagliflozin, dapagliflozin)

Chronic Kidney Disease

SGLT-2 inhibitor (preferred if eGFR allows)
GLP-1 receptor agonist (alternative)

Triple Therapy

Combine metformin + two agents from different classes

Avoid combining:

DPP-4 inhibitor + GLP-1 receptor agonist

Insulin Therapy

Indications in T2DM

Severe hyperglycemia (HbA1c ≥10–11%)
Symptomatic hyperglycemia
Failure of oral/injectable agents
Acute illness, surgery, pregnancy

Insulin Initiation

Basal insulin (glargine, degludec, detemir)
Start: 0.1–0.2 U/kg/day
Titrate based on fasting glucose

Non-insulin Antidiabetic Drugs

Table 1. Classification and Mechanism of Non-Insulin Antidiabetic Drugs

Drug Class	Mechanism of Action	Primary Glycemic Effect
Biguanides	↓ Hepatic gluconeogenesis, ↑ insulin sensitivity	↓ Fasting plasma glucose
Sulfonylureas	↑ Insulin secretion (β-cell K⁺-ATP channel closure)	↓ Fasting & post-prandial glucose
Meglitinides (Glinides)	Rapid, short-acting insulin secretagogues	↓ Post-prandial glucose
Thiazolidinediones (TZDs)	PPAR-γ agonists → ↑ insulin sensitivity	↓ Fasting glucose
Alpha-glucosidase inhibitors	Delay intestinal carbohydrate absorption	↓ Post-prandial glucose
DPP-4 inhibitors	↑ Endogenous incretins (GLP-1, GIP)	↓ Fasting & post-prandial glucose
GLP-1 receptor agonists	↑ Glucose-dependent insulin, ↓ glucagon	↓ Fasting & post-prandial glucose
SGLT-2 inhibitors	↓ Renal glucose reabsorption	↓ Fasting glucose
Amylin analogs	↓ Glucagon, delayed gastric emptying	↓ Post-prandial glucose

Table 2. Drug Classes and Examples

Drug Class	Examples
Biguanide	Metformin
Sulfonylureas	Glimepiride, Gliclazide, Glipizide, Glyburide
Meglitinides	Repaglinide, Nateglinide
TZDs	Pioglitazone, Rosiglitazone
Alpha-glucosidase inhibitors	Acarbose, Miglitol
DPP-4 inhibitors	Sitagliptin, Saxagliptin, Linagliptin, Vildagliptin
GLP-1 receptor agonists	Exenatide, Liraglutide, Dulaglutide, Semaglutide
SGLT-2 inhibitors	Empagliflozin, Dapagliflozin, Canagliflozin
Amylin analog	Pramlintide

Table 3. Efficacy, Weight Effect, and Hypoglycemia Risk

Drug Class	HbA1c Reduction	Weight Effect	Hypoglycemia Risk
Biguanide	1–1.5%	Neutral / ↓	Low
Sulfonylureas	1–1.5%	↑	High
Meglitinides	0.5–1%	↑	Moderate
TZDs	0.5–1.4%	↑	Low
Alpha-glucosidase inhibitors	0.5–0.8%	Neutral	Low
DPP-4 inhibitors	0.5–0.8%	Neutral	Low
GLP-1 receptor agonists	1–1.5%	↓	Low
SGLT-2 inhibitors	0.5–1%	↓	Low
Amylin analog	0.3–0.6%	↓	Moderate

Table 4. Major Adverse Effects and Key Clinical Notes

Drug Class	Major Adverse Effects	Important Clinical Considerations
Biguanide	GI upset, lactic acidosis (rare)	Contraindicated in severe CKD with GFR <30
Sulfonylureas	Hypoglycemia, weight gain	Caution in elderly, renal disease
Meglitinides	Hypoglycemia, weight gain	Taken before meals
TZDs	Weight gain, edema, HF risk	Contraindicated in HF
Alpha-glucosidase inhibitors	Flatulence, diarrhea	Avoid in IBD
DPP-4 inhibitors	URTI, pancreatitis (rare)	Weight neutral
GLP-1 RAs	Nausea, vomiting, pancreatitis	CV benefit (liraglutide, semaglutide)
SGLT-2 inhibitors	Genital infections, euglycemic DKA	Strong benefit in HF & CKD
Amylin analog	Nausea, hypoglycemia	Used with insulin

Targets

Parameter	Target
HbA1c	< 7% (individualized)
FPG	80–130 mg/dL
Post-prandial glucose	< 180 mg/dL
BP	< 140/90 mmHg
LDL-C	< 70 mg/dL (high risk)
Weight loss	5–10%
Albuminuria	< 30 mg/g
Pregnancy	Fasting glucose: < 95 mg/dL 1-hour post-prandial: < 140 mg/dL 2-hour post-prandial: < 120 mg/dL HbA1c: ideally < 6.0%

Prevention

Domain	Target
Diet	Individualized, calorie-controlled
Physical activity	≥150 min/week moderate-intensity
Smoking	Complete cessation
Alcohol	Limited / none