Epidemiology

Type 2 DM

• Age
  • Adult onset typically > 40 years
  • Mean age of onset is decreasing
• Race: highest prevalence in Native Americans, Hispanics, African Americans, and Asian non-Hispanic Americans

Etiology

Type 1 DM

• Autoimmune destruction of pancreatic β cells in genetically susceptible individuals
• HLA association: HLA-DR3 and HLA-DR4 positive patients are at increased risk of developing T1DM.
• Associated with other autoimmune conditions
  • Hashimoto thyroiditis
  • Type A gastritis
  • Celiac disease
  • Primary adrenal insufficiency

Classifications

• Type 1: formerly known as insulin-dependent (IDDM) or juvenile-onset diabetes mellitus
• Type 2: formerly known as non-insulin-dependent (NIDDM) or adult-onset diabetes mellitus
• Gestational diabetes
• Other types of diabetes mellitus
  • MODY (maturity-onset diabetes of the young): genetic defects leading to β-cell dysfunction
  • Different forms of autosomal dominant inherited diabetes mellitus that manifest before the age of 25 years and are not associated with obesity or autoantibodies
  • Multiple monogenic subtypes (most common: MODY II due to glucokinase gene defect, and MODY III, due to hepatocyte nuclear factor-1-α gene defect)
  • MODY II
    • A single mutation leads to impaired insulin secretion due to altered glucokinase function.
    • Glucokinase is the glucose sensor of the β cell, facilitating storage of glucose in the liver, especially at high concentrations.
    • There is no increased risk of microvascular disease.
    • Despite stable hyperglycemia and chronically elevated HbA1C levels, MODY II can be managed with diet alone.

Pathophysiology

Normal insulin physiology

• Secretion: Insulin is synthesized in the β cells of the islets of Langerhans. The cleavage of proinsulin (precursor molecule of insulin) produces C-peptide (connecting peptide) and insulin, which consists of two peptide chains (A and B chains).
• Action
  • Carbohydrate metabolism
  • Protein metabolism: insulin inhibits proteolysis, stimulates protein synthesis, and stimulates cellular uptake of amino acids
  • Lipid metabolism: maintains a fat depot and has an antiketogenic effect
  • Electrolyte regulation:
    • Stimulates intracellular potassium accumulation
      • Directly stimulates Na⁺/K⁺ ATPase and promotes intracellular alkalosis, reduces phosphate levels (glucose binds to phosphate in the cell), and stimulates magnesium uptake into cells
      • Insulin boosts glucose uptake into cells through two linked processes:
        1. Direct effect: Insulin stimulates GLUT transporters to move glucose into cells through facilitated diffusion
        2. Indirect effect: Insulin activates Na⁺/K⁺-ATPase pumps, which:
           • Pump Na⁺ out of cells → Creates high Na⁺ outside
           • This Na⁺ gradient powers SGLT transporters
           • SGLT uses Na⁺ flow into cells to drag glucose in with it (co-transport)
    • Reduces phosphate levels: When insulin promotes glucose uptake, glucose must be phosphorylated to glucose-6-phosphate
• Those with long-standing diabetes (ie, >5 years) frequently also have alpha cell failure with decreased glucagon secretion and therefore have an even greater risk of rapid hypoglycemia.

Type 2 diabetes

• Mechanisms
  • Peripheral insulin resistance
    • Numerous genetic and environmental factors
      • Central obesity → increased plasma levels of free fatty acids → impaired insulin-dependent glucose uptake into hepatocytes, myocytes, and adipocytes
      • Increased serine kinase activity in fat and skeletal muscle cells → phosphorylation of insulin receptor substrate (IRS)-1 → decreased affinity of IRS-1 for PI3K → decreased expression of GLUT4 channels → decreased cellular glucose uptake
  • Pancreatic β cell dysfunction: accumulation of pro-amylin (islet amyloid polypeptide) in the pancreas → decreased endogenous insulin production
• Progression
  • Initially, insulin resistance is compensated by increased insulin and amylin secretion.
  • Over the course of the disease, insulin resistance progresses, while insulin secretion capacity declines.
  • After a period of impaired glucose tolerance with isolated postprandial hyperglycemia, diabetes manifests with fasting hyperglycemia.

Clinical features

Onset

Type 1 DM

• Often sudden
• Diabetic ketoacidosis (DKA) is the first manifestation in approx. one-third of cases.

Type 2 DM

• Typically gradual
• The majority of patients are asymptomatic.
• Some patients may present with a hyperglycemic crisis.
  • Elderly patients especially may present in a hyperosmolar hyperglycemic state.
  • Occasionally, patients with T2DM present with DKA , which mostly affects black and Hispanic individuals.
• Symptoms of complications may be the first clinical sign of disease.

Common clinical features

• Classic symptoms of hyperglycemia
  • Polyuria, which can lead to secondary enuresis and nocturia in children
  • Polydipsia
  • Polyphagia
• Nonspecific symptoms
  • Unexplained weight loss
  • Visual disturbances, e.g., blurred vision
  • Fatigue

Specific clinical features

Type 2 DM

• Possible cutaneous signs of insulin resistance
  • Benign acanthosis nigricans
  • Acrochordons

Complications

Microvascular disease

• Onset: typically arises 5–10 years after onset of disease
• Pathophysiology: chronic hyperglycemia → nonenzymatic glycation of proteins and lipids → thickening of the basal membrane with progressive function impairment and tissue damage
• Manifestations
  • Diabetic nephropathy
  • Diabetic retinopathy, glaucoma
  • Diabetic neuropathy including diabetic gastroparesis
  • Diabetic foot

Other complications

• Osmotic damage: occurs in tissues with high aldolase reductase activity and low/absent sorbitol dehydrogenase activity (e.g., eyes, peripheral nerves) → diabetic cataracts, neuropathy

Diagnostics

Diagnostic criteria for diabetes mellitus

Hyperglycemia tests

• Hemoglobin A1C (HbA1c or A1C): glycated hemoglobin, which reflects the average blood glucose levels of the prior 8–12 weeks
  • Can be measured at any time, not required to fast and the results are independent of time of day
  • Results may be altered by a variety of conditions or treatments, e.g., sickle cell trait, chronic kidney disease.
  • Factors resulting in a falsely high HbA1c
    • Increased RBC lifespan: e.g., iron and/or vitamin B12 deficiency, splenectomy, aplastic anemia
    • Assay interference: heavy alcohol use
  • Factors resulting in a falsely low HbA1c
    • Decreased RBC lifespan: e.g., due to acute blood loss, hemoglobinopathies such as sickle cell trait/disease, thalassemia, G6PD deficiency, cirrhosis, hemolytic anemia, splenomegaly, antiretroviral drugs
    • Increased erythropoiesis: e.g., due to EPO therapy, reticulocytosis, pregnancy (second and third trimesters), iron supplementation

Additional studies

• C-peptide: can help differentiate between types of diabetes
  • ↑ C-peptide levels may indicate insulin resistance and hyperinsulinemia → T2DM
  • ↓ C-peptide levels indicate an absolute insulin deficiency → T1DM

Treatment

Approach

• Guiding Principles (ADA/EASD): Initial therapy is lifestyle modification + Metformin. Subsequent agent selection is based on patient comorbidities (ASCVD, HF, CKD), risk of hypoglycemia, impact on weight, and cost.

• First-Line (Type 2 DM):

  • Metformin:
    • MOA: ↓ Hepatic gluconeogenesis, ↑ peripheral insulin sensitivity.
    • Benefits: Weight neutral/modest loss, low hypoglycemia risk, proven efficacy.
    • SE/CI: GI distress (diarrhea), lactic acidosis (do not use if eGFR <30), B12 deficiency. Hold for IV contrast procedures.

• Second-Line Selection (after Metformin):

  • If patient has ASCVD, HF, or CKD: Choose an agent with proven cardiorenal benefit, regardless of A1c.

    • ASCVD Dominant: GLP-1 RA (e.g., Liraglutide, Semaglutide) > SGLT2i (e.g., Empagliflozin).
    • HF or CKD: SGLT2i is preferred (reduces HF hospitalizations & CKD progression). GLP-1 RA is a secondary option if SGLT2i is CI/not tolerated.

  • If compelling need to minimize hypoglycemia:

    • Use DPP-4i, GLP-1 RA, SGLT2i, or TZD. Avoid Sulfonylureas & Insulin.

  • If compelling need for weight loss:

    • Use GLP-1 RA (most effective) or SGLT2i.

  • If cost is a major issue:

    • Use Sulfonylurea or TZD. Be mindful of side effect profiles.

• If Glucose Control Remains Suboptimal (Third-Line Therapy):

  • Action: Add a third agent with a complementary mechanism of action.
  • Selection: Re-evaluate and prioritize based on patient comorbidities (ASCVD, HF, CKD), hypoglycemia risk, and weight goals.
  • High-Benefit Combo: For patients with ASCVD/HF/CKD, combining Metformin + SGLT2i + GLP-1 RA offers maximal cardiorenal protection and potent glucose lowering.
  • Intensification: If triple therapy fails or A1c remains significantly elevated, initiate/intensify injectable therapy, typically starting with basal insulin once daily.

T1DM

Insulin

• Types

• Regulation
  • Insulin release is primarily stimulated by the parasympathetic nervous system.
  • Parasympathetic stimulation of muscarinic M3 receptors promotes insulin secretion and is induced by the smell and/or sight of food.
  • In contrast, sympathetic stimulation is more complex, since both alpha-2 and beta-2 adrenergic receptors are present on pancreatic beta cells and exert opposite effects.
    • Alpha-2 receptor activation (dominant) inhibits insulin release during stress to maintain high glucose levels for vital tissues (brain, heart, etc.).
    • Beta-2 receptor activation modestly promotes insulin secretion, fine-tuning glucose regulation and preventing excessive hyperglycemia under moderate stress.
    • However, the alpha-2-mediated inhibitory effect is predominant, causing sympathetic stimulation to lead to overall inhibition of insulin secretion.
    • Alpha-2 inhibits NA reuptake
• Adverse effects
  • Weight gain
    • Due to physiologic factors (increased glucose uptake and lipid synthesis) and behavioral factors (less dietary adherence and eating snacks when hypoglycemia)
    • Should review for changes in diet
• Regimens
  • 
  • 
  • 

T2DM

Metformin

• Mechanism of action: enhances the effect of insulin
  • Reduction in insulin resistance via modification of glucose metabolic pathways
    • Inhibits mitochondrial glycerophosphate dehydrogenase (mGPD) → ↓ hepatic gluconeogenesis and intestinal glucose absorption
    • Increases peripheral insulin sensitivity → ↑ peripheral glucose uptake and glycolysis
  • Lowers postprandial and fasting blood glucose levels
  • Reduces LDL, increases HDL
• Important side effects
  • Metformin-associated lactic acidosis
    • High-risk groups
      • Elderly individuals
      • Patients with renal insufficiency or CHF
        • So check serum creatinine before initiation of metformin
• Contraindications
  • Renal failure, heart failure (NYHA III and IV), respiratory failure, shock, sepsis
    • Decreased renal blood flow, cannot be excreted

Sulfonylureas

• Close K⁺ channels in pancreatic B cell membrane → cell depolarizes → insulin release via ↑ Ca²⁺ influx.
• Side effects
  • Life-threatening hypoglycemia
    • Due to excessive insulin secretion, which occurs independent of blood glucose concentrations (ie, even when blood glucose concentrations are low).
    • Increased risk under the following circumstances:
      • Simultaneous intake of CYP2C9 inhibitors (e.g., amiodarone, trimethoprim, fluconazole)
      • Patients with renal failure
        • Because sulfonylureas are excreted via the kidneys, renal failure can result in accumulation. Hypoglycemia due to accumulation of long-acting glyburide may persist for several days, requiring extensive glucose substitution.
      • Decreased carbohydrate intake (diets or periods of fasting)
      • Elevated glucose utilization (e.g., unaccustomed physical activity)
      • Sulfonylurea overdose
  • Alcohol intolerance (first-generation agents): disulfiram-like reaction
  • Weight gain
  • Hematological changes: granulocytopenia, hemolytic anemia

Meglitinides

• Same with Sulfonylureas

DPP-4 inhibitor and GLP-1 analogs

• Although Glucagon-like peptide-1 (GLP-1) and glucagon share similar structure, they perform opposite functions.
  • Glucagon-like peptide-1 (GLP-1) is an incretin hormone, meaning it's produced in the gut after eating and signals the pancreas to increase insulin secretion.
• 

SGLT-2 inhibitors

• Sodium-dependent glucose cotransporter (SGLT)
  • SGLT1 is responsible for almost all sodium-dependent glucose uptake in the small intestine
  • SGLT2 is responsible for almost all sodium-dependent glucose reabsorption in the proximal tubule.
• Contraindications
  • Chronic kidney disease: If GFR decreases, drug efficacy decreases and adverse effects increase.
    • Because SGLT-2 inhibitors rely on adequate renal glucose filtration to exert their antihyperglycemic effect, they become less effective or ineffective as renal function declines (eg, when estimated glomerular filtration rate (eGFR) falls <30-45 mL/min/1.73 m2). Therefore, checking serum creatinine (used to calculate eGFR) is recommended prior to medication initiation.
  • Recurrent urinary tract infections (e.g., in patients with anatomical or functional anomalies of the urinary tract)

α-glucosidase inhibitors

Pioglitazone

• Mechanism of action: activation of the transcription factor PPARγ (peroxisome proliferator-activated receptor of gamma type in the nucleus) → ↑ transcription of genes involved in glucose and lipid metabolism → ↑ levels of adipokines such as adiponectin and insulin sensitivity → ↑ storage of fatty acids in adipocytes, ↓ products of lipid metabolism (e.g., free fatty acids) → ↓ free fatty acids in circulation → ↑ glucose utilization and ↓ hepatic glucose production
• Clinical characteristics
  • Glycemic efficacy: lowers HbA1c by 1% in 3 months
  • Favorable effect on lipid metabolism: ↓ triglyceride, ↓ LDL, ↑ HDL
  • No risk of hypoglycemia
  • Onset of action is delayed by several weeks.
    • because it acts at the level of transcription
• Important side effects
  • ↑ Risk of heart failure
  • ↑ Risk of bone fractures (osteoporosis)
  • Fluid retention and edema
  • Weight gain

• Amylin analogs (Pramlintide)
  • Works with insulin to ↓ glucagon release, ↓ gastric emptying.

Screening

• All individuals ≥ 35 years of age
• Patients < 35 years of age who:
  • Are overweight or obese AND have ≥ 1 additional risk factor for T2DM
    • BMI of ≥ 23 kg/m² in Asian American individuals or a BMI of ≥ 25 kg/m² in all other individuals