Diabetes mellitus with multimedia prototypes

Diabetes mellitus (DM) describes a group of metabolic diseases that are characterized by chronic hyperglycemia. Type 1 diabetes mellitus (T1DM) is caused by an autoimmune response that triggers the destruction of insulin-producing beta cells in the pancreas and results in an absolute insulin deficiency. It often develops during childhood, manifesting with an acute onset (e.g., diabetic ketoacidosis). Type 2 diabetes mellitus (T2DM) is much more common, has a strong genetic component, and is associated with obesity and a sedentary lifestyle. T2DM is characterized by insulin resistance and impaired insulin secretion due to pancreatic beta-cell dysfunction, resulting in relative insulin deficiency. This type of diabetes usually remains undiagnosed for many years. Testing for hyperglycemia is recommended for patients with classic symptoms of diabetes mellitus, and screening is recommended for asymptomatic patients who are at high risk of prediabetes or diabetes (e.g., patients with obesity and additional risk factors). The diagnosis is made based on blood glucose or HbA1c levels. The main goal of treatment is blood glucose control tailored to glycemic targets while avoiding hypoglycemia. Diabetes care should be comprehensive and patient-centered and should include monitoring and management of ASCVD risk factors, microvascular complications (e.g., diabetic retinopathy, diabetic nephropathy, diabetic neuropathy), and macrovascular complications (e.g., coronary artery disease, stroke, peripheral artery disease). Management should also include general lifestyle modifications (e.g., smoking cessation, exercise, nutritional support) and pharmacological treatment (e.g., antihyperglycemics, statins, ACE inhibitors or angiotensin receptor blockers, and aspirin). The management of diabetes in children is largely similar to adults, except that certain medications (sulfonylureas, dipeptidyl peptidase-4 inhibitors, SGLT-2 inhibitors, and thiazolidinediones) are not approved for use in this age group.

See also “Diabetes in pregnancy,” “Insulin,” “Hyperglycemic crises,” and "Diabetic ketoacidosis in children."

Type 1 DM

• Prevalence ^[4]
  • ∼ 1.6 million in the US
  • ∼ 5–10% of all patients with diabetes
• Age ^[4]
  • Childhood onset typically < 20 years but can occur at any age
  • Peaks at age 4–6 years and 10–14 years
• Race: highest prevalence in non-Hispanic White individuals ^[5]

Type 2 DM

• Prevalence ^[4]
  • ∼ 10.5% of adult population in the US
  • Nearly 34 million individuals in the US have diabetes with 7.3 million being undiagnosed.
• Incidence: ∼ 6.7 per 1,000 among US adults ^[4]
• Age
  • Adult onset typically > 40 years ^[5]
  • Mean age of onset is decreasing
• Gender: ♂ > ♀ ^[4]
• Race: highest prevalence in Native Americans, Hispanics, African Americans, and Asian non-Hispanic Americans ^[4]

Epidemiological data refers to the US, unless otherwise specified.

Type 1 DM ^[6][7]

• 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

“If you buy 4 DiaMonds and only pay for 3, you get 1 for free:” DR4 and DR3 are associated with Diabetes Mellitus type 1.

Type 2 DM ^[8][9][10]

• Risk factors for type 2 diabetes mellitus ^[11]
  • Family history: first-degree relative with diabetes ^[12][13][14]
  • High-risk race or ethnicity
  • Dyslipidemia
  • Prediabetes
  • Physical inactivity
  • Cardiovascular disease
  • Polycystic ovary syndrome
  • Hypertension
  • History of gestational diabetes
  • Poor sleep
  • Other conditions associated with metabolic syndrome and insulin resistance: e.g., overweight, obesity, acanthosis nigricans
  • Medications known to increase the risk of diabetes, e.g.:
    • Glucocorticoids
    • Statins
    • Thiazide diuretics
    • Some HIV medications
    • Second generation antipsychotics

Classification according to the WHO and American Diabetes Association (ADA) ^[10][15]

• Type 1: formerly known as insulin-dependent (IDDM) or juvenile-onset diabetes mellitus
  • Autoimmune (type 1A)
  • LADA: Latent autoimmune diabetes in adults, a variant of diabetes characterized by a late onset of type 1 (autoimmune) diabetes that is often mistaken for type 2 diabetes.
  • Idiopathic (type 1B)
• 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.
    • All other subtypes, including MODY III, require medical treatment either with insulin or sulfonylureas.
  • Pancreatogenic diabetes mellitus: following pancreatectomy and due to conditions that lead to destruction of pancreatic endocrine islets (e.g., hemochromatosis, cystic fibrosis)
  • Endocrinopathies: Cushing disease, acromegaly
  • Drug-induced diabetes, e.g., due to corticosteroids (steroid diabetes)
  • Genetic defects affecting insulin synthesis
  • Infections (e.g., congenital rubella infection)
  • Rare immunological diseases: stiff person syndrome
  • Other genetic syndromes that are associated with diabetes mellitus (e.g., Down syndrome)

Normal insulin physiology ^[16]

• 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: Insulin is an anabolic hormone with a variety of metabolic effects on the body, primarily contributing to the generation of energy reserves (cellular uptake and metabolism of nutrients) and glycemic control.
  • Carbohydrate metabolism: Insulin is the only hormone in the body that directly lowers the blood glucose level.
  • 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

Type 1 diabetes ^[6]

• Genetic susceptibility and environmental triggers; (often associated with previous viral infection) → autoimmune response with production of autoantibodies, e.g., anti-glutamic acid decarboxylase antibody (anti-GAD), anti-islet cell cytoplasmic antibody (anti-ICA) → progressive destruction of β cells in the pancreatic islets → absolute insulin deficiency → decreased glucose uptake in the tissues

Type 2 diabetes

Mechanisms ^[5]

• Peripheral insulin resistance ^[17]
  • 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 ^[18]
• Pancreatic β cell dysfunction: accumulation of pro-amylin (islet amyloidpolypeptide) in the pancreas → decreased endogenous insulin production ^[19]

Progression ^[1]

• 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.

Diabetes mellitus should be suspected in patients with recurrent cellulitis, candidiasis, dermatophyte infections, gangrene, pneumonia (particularly tuberculosis reactivation), influenza, genitourinary infections (UTIs), osteomyelitis, and/or vascular dementia.

See “Hyperglycemia tests” for recommended screening methods.

Indications for diabetes screening ^[10]

The indications listed below are consistent with the 2025 ADA guidelines. The USPSTF recommends screening in adults aged 35–70 years with overweight or obesity. ^[10][24][25]

• All individuals ≥ 35 years of age
• Patients < 35 years of age who:
  • Are overweight or obese ; AND have ≥ 1 of the following risk factors:
    • First-degree relative with diabetes
    • High-risk race or ethnicity
    • Physical inactivity
    • Cardiovascular disease
    • Polycystic ovary syndrome
    • Hypertension
    • Dyslipidemia
    • Other conditions associated with insulin resistance: e.g., severe obesity and acanthosis nigricans
  • Have prediabetes or a history of gestational diabetes
  • Have any risk-enhancing comorbidities, including:
    • HIV infection: Screen before starting or switching antiretroviral therapy. ^[11]
    • Cystic fibrosis: Begin annual screening in all patients at the age of 10 years.
    • Post organ transplantation: Screen once the patient is on an immunosuppressive regimen, stable, and no infections are present.
    • Pancreatitis: Screen annually in patients with chronic pancreatitis and/or a history of acute pancreatitis
• Consider screening individuals exposed to medications known to increase the risk of diabetes, e.g., statins.
• Individuals who are planning pregnancy with any risk factor for T2DM
• See “Gestational diabetes” for testing indications during pregnancy.

If results are normal, repeat testing in asymptomatic patients at least every three years. Patients with prediabetes should be tested annually. Patients with a history of gestational diabetes should be tested every 1–3 years. ^[10]

Diagnostic criteria for diabetes mellitus ^[10]

The following tests may be performed in combination for screening and/or diagnosis. If two separate blood samples are used, the second should be obtained soon after the first.

• Random blood glucose level ≥ 200 mg/dL in patients with symptoms of hyperglycemia (i.e., polydipsia, polyuria, polyphagia, unexplained weight loss) or hyperglycemic crisis
• OR ≥ 2 abnormal test results for hyperglycemia in asymptomatic individuals

Hyperglycemia tests ^[10]

Blood glucose tests

• Random blood glucose: blood glucose measured at any time irrespective of recent meals
• Fasting plasma glucose (FPG): blood glucose measured after > 8 hours of fasting
  • Inexpensive and widely available
  • Should not be used to diagnose diabetes in hospitalized patients or in patients with critical illness
• Oral glucose tolerance test (OGTT) ^[26]
  • Most sensitive test
  • Less convenient and more expensive than other tests
  • One-step OGTT: measurement of fasting plasma glucose and blood glucose 2 hours after the consumption of 75 g of glucose
  • Two-step OGTT: used in diagnosis of gestational diabetes
    • Nonfasting patients are given 50 g of glucose and blood glucose is measured after 1 hour.
    • If values at 1 hour are ≥ 130–140 mg/dL , measure fasting plasma glucose and blood glucose 1, 2, and 3 hours after the consumption of 100 g of glucose.
    • For interpretation of results, see “Diagnosis of gestational diabetes.”

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
• Results may be impacted by a variety of conditions or treatments (e.g., sickle cell trait, chronic kidney disease). ; ^[10][27][28]
  • Factors resulting in a falsely high HbA1c
    • Increased RBC lifespan: e.g., iron and/or vitamin B₁₂ deficiency, splenectomy, aplastic anemia
    • Altered hemoglobin: chronic kidney disease
    • Assay interference: heavy alcohol use, chronic opiate use, high-dose aspirin, severe hypertriglyceridemia, uremia, hyperbilirubinemia
  • 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
    • Altered hemoglobin: high-dose vitamin C and E supplementation
    • Assay interference: low-dose aspirin

Significant discrepancy between HbA1c and glucose measurements warrants investigation of the underlying cause (e.g., sickle cell trait).

Additional recommended studies ^[30]

Perform in all patients as part of the initial diagnostic workup and reassess at least annually.

• BMP
  • Renal function
  • Electrolytes, including potassium
• Spot urinary albumin-to-creatinine ratio: to detect microalbuminuria
• CBC with platelets
• Liver chemistries
• Lipid panel
• Additionally consider: ^[30]
  • Patients with suspected or confirmed T1DM: TSH, celiac disease panel
  • Patients on metformin: vitamin B12 level
  • Selected patients: calcium, phosphorous, vitamin D level

Additional optional studies

These tests are not routinely indicated or required to establish a diagnosis.

• C-peptide: can help differentiate between types of diabetes ^[31][32]
  • ↑ C-peptide levels may indicate insulin resistance and hyperinsulinemia → T2DM
  • ↓ C-peptide levels indicate an absolute insulin deficiency → T1DM
• Urinalysis
  • Glucosuria may be present if the renal threshold for glucose is reached (nonspecific for diabetes mellitus).
  • Ketone bodies: positive in acute metabolic decompensation (diabetic ketoacidosis) ^[32]
  • Microalbuminuria: early sign of diabetic nephropathy
• Islet autoantibody testing: Consider in patients with diagnosed diabetes mellitus if there is clinical suspicion for T1DM. ^[10]
  • Antiglutamic acid decarboxylase antibodies (Anti-GAD): an antibody against the enzyme glutamic acid decarboxylase responsible for the conversion of glutamic acid to GABA ^[32]
    • Positive result confirms T1DM
    • Negative result should trigger testing for other antibodies (e.g., anti-tyrosine phosphatase-related islet antigen 2 (IA-2), anti-zinc transporter 8 antibodies) and/or consultation with a specialist
  • Anti-tyrosine phosphatase-related islet antigen 2 (IA-2) ^[32]
  • Anti-zinc transporter 8 antibodies
  • Anti-insulin antibodies

Screening for T1DM with autoantibodies is not routinely recommended but can be considered in patients with presymptomatic T1DM and increased genetic risk (e.g., first-degree relatives with T1DM). ^[10]

Consider specialist consultation if the differentiation between T2DM and T1DM is unclear.

• Glucagonoma
• Somatostatinoma
• Stress-induced hyperglycemia ^[33][34]
• Medication-induced hyperglycemia

The differential diagnoses listed here are not exhaustive.

General principles ^[30][35]

• Main goal: blood glucose control (tailored to glycemic targets and regularly monitored) ^[30]
  • Patients with T1DM always require insulin therapy.
  • T2DM may be managed with noninsulin diabetes medications and/or insulin therapy.
  • Acute illness may require temporary changes in treatment (e.g., increased insulin demand due to acute stress reaction).
• Comprehensive diabetes care (all patients)
  • Diabetes self-management education and support; see “Managing chronic conditions.” ^[35]
  • Lifestyle modifications, including:
    • Weight reduction
    • Balanced diet and nutrition; (including a high-fiber diet)
    • Regular exercise
    • Smoking cessation
  • Routine screening for microvascular complications of diabetes
  • Evaluation for and management of common comorbidities as indicated (e.g., psychiatric disorders, autoimmune diseases, NAFLD, obstructive sleep apnea, dental or periodontal disease, sexual dysfunction) ^[30][36]
  • Vaccinations; (e.g., influenza, hepatitis B, zoster, COVID-19, and pneumococcal vaccines) ^[30][36]
• ASCVD risk assessment and ASCVD prevention, including: ^[37]
  • Hypertension management
  • Management of hypercholesterolemia
    • Patients aged 40–75 years with diabetes mellitus: Initiate moderate-intensity statin therapy regardless of lipid levels.
    • Assess indications for high-intensity statins. ^[38]
  • Management of obesity ^[39]
  • Diagnostic studies for coronary artery disease in patients with clinical features of CAD ^[37]
  • Antiplatelet therapy if indicated (see “Primary prevention of ASCVD” and “Management of ASCVD”)
• Follow-up
  • Periodically re-evaluate the need for further education and support. ^[35]
  • Check HbA1c at least every 3–6 months (see “Glycemic monitoring for DM”).
  • For patients requiring lipid-lowering therapy, repeat lipid panel yearly and 4–12 weeks after any medication changes. ^[37]

Diabetes care should be patient-centered and comprehensive and include lifestyle modifications and assessment of psychosocial health. Consider social determinants of health and formulate a treatment plan together with the patient.

The goals of diabetes management include eliminating symptoms of hyperglycemia, reducing or eliminating complications, and enabling as healthy a lifestyle as possible. ^[25]

Physical exercise reduces blood glucose and increases insulin sensitivity.

Lifestyle modifications ^[35]

Glycemic targets in diabetes ^[41][42]

• Consider the following patient factors when setting a glycemic target:
  • Risk of hypoglycemia or other adverse effects
  • Presence of vascular complications and comorbidities
  • Patient preferences and resources
  • Disease duration
  • Life expectancy
• Re-evaluate glycemic targets continuously and adjust if necessary.

Glycemic targets should be individualized. A target of HbA1c < 7% is usually suitable for most nonpregnant adults. ^[41]

Glycemic monitoring for diabetes ^[41][43]

HbA1c monitoring

HbA1c is measured at fixed intervals.

• At least every 6 months if targets are met
• At least every 3 months in the following situations:
  • If targets are not met
  • If treatment has recently been modified
  • If the patient is undergoing intensive insulin therapy
  • Repeated or significant hyperglycemia or hypoglycemia
  • Rapid growth in children
  • Health changes

Fructosamine or continuous glucose monitoring may be used as alternatives to HbA1c if needed.

Home glucose monitoring

Glucose levels can be used to evaluate treatment and prevent hypoglycemia and hyperglycemia, especially in patients using insulin.

• Self-monitoring of blood glucose: at fixed times or as needed
  • Indication: insulin therapy (particularly for intensive regimens)
  • Consider for any patient to assess for hypoglycemia or the impact of diet and/or exercise.
• Continuous glucose monitoring: Interstitial glucose levels are measured continuously or intermittently using a subcutaneous device. ^[43]
  • Improves glycemic monitoring, which reduces the risk of hypoglycemia
  • Early use is recommended for adults with T1DM (can be used in combination with an insulin pump).
  • Advised for use in patients with diabetes on any form of insulin therapy
  • Consider in:
    • Patients with T2DM on noninsulin glucose-lowering drugs
    • Patients not meeting HbA1c targets

Hypoglycemia

• Assess for episodes of hypoglycemia (symptomatic or asymptomatic) at every follow-up visit.
• Prescribe glucagon for individuals taking insulin or at high-risk for hypoglycemic events
• In patients with at least one clinically significant hypoglycemia event or asymptomatic hypoglycemia:
  • Check for possible contributors (e.g., medication interaction or errors).
  • Consider relaxing the glycemic targets and adjusting management.

Reassess and adjust treatment at regular intervals (e.g., every 3–6 months).

Early morning hyperglycemia

• Early morning hyperglycemia may be caused by:
  • Dawn phenomenon
    • A physiological increase of growth hormone levels in the early morning hours stimulates hepatic gluconeogenesis and leads to a subsequent increase in insulin demand that cannot be met in insulin-dependent patients, resulting in elevated blood glucose levels.
    • Consider measurement of nocturnal blood glucose levels before initiating insulin therapy.
    • Long-acting insulin dose may be given later or increased under careful glycemic control.
  • Somogyi effect (widely taught but unproven hypothesis)
    • Description: Nocturnal hypoglycemia due to evening insulin injection triggers a counterregulatory secretion of hormones , leading to elevated blood glucose levels in the morning.
    • There is no evidence to support the existence of this effect. ^[44][45][46]

Do not assume that early morning hyperglycemia is due to nocturnal hypoglycemia. It is more likely caused by nocturnal hyperglycemia with or without hypoinsulinemia and/or early morning secretion of counterregulatory hormones (e.g., cortisol). ^[44][45][46]

Assess for past hypoglycemic episodes or risk of hypoglycemia regularly and adjust glycemic goals accordingly. Hypoglycemia is one of the major limitations to adequate glycemic control. ^[41]

In patients that meet preprandial glucose targets, HbA1c above target may be due to postprandial hyperglycemia, requiring prandial insulin dose adjustments.

This section outlines the approach to pharmacological treatment of diabetes mellitus.

• See “Inpatient management of hyperglycemia” for details, including management of hyperglycemia in critically ill patients.
• See also “Perioperative medication management” for adjustments to insulin and oral diabetes medications prior to surgery.

Type 1 diabetes mellitus

Insulin replacement therapy ^[47]

• Treatment options
  • Insulin pump: Consider for most patients.
  • Multiple daily insulin injections; see “Full basal-bolus insulin regimen” for details.
• Starting dose calculation ^[47]
  • Exogenous insulin requirements will depend on the residual insulin production of the pancreas.
  • Total daily dose (TDD) of insulin is usually 0.4–1.0 units/kg per day, divided into 50% basal and 50% prandial insulin.
  • Consider starting treatment with 0.5 units/kg per day.
• Dose titration
  • After beginning insulin treatment, exogenous insulin demand is temporarily reduced. ^[48]
  • Dosage should be adjusted according to glycemic monitoring.

Educate patients on calculating insulin requirements throughout the day based on activities and meals. ^[47]

Other treatment strategies ^[47]

• Noninsulin diabetes medications: not generally used in T1DM treatment
• Pancreas and/or islet transplantation
  • May improve glucose control but is not standard treatment due to the need for lifelong immunosuppressive therapy
  • May be considered in patients:
    • With recurrent episodes of diabetic ketoacidosis or severe hypoglycemia despite adequate treatment
    • Undergoing simultaneous renal transplantation or patients with a previous renal transplantation

Type 2 diabetes mellitus

Approach ^[47]

• Start treatment in all patients at diagnosis. ; ^[47][49]
  • Start therapy with a glucose-lowering medication based on patient factors (e.g., ASCVD, CKD).
  • Metformin is the first-line initial therapy for most patients; without cardiovascular or kidney risk factors.
• Consider initial combination pharmacological treatment in selected patients, e.g., those with: ^[36][47]
  • Clinical ASCVD, high ASCVD risk, heart failure, or CKD
  • HbA1c above the glycemic target
  • Indications for insulin therapy for T2DM at time of diagnosis
• Re-evaluate treatment and treatment adherence every 3–6 months. ^[47]
  • Sequentially add noninsulin diabetes medications until glucose targets are met.
  • Consider insulin therapy if targets are not met despite adequate treatment.

Noninsulin diabetes medications

• Other drugs that are not part of the therapy algorithms for T2DM according to the ADA guideline include:
  • Meglitinides (e.g., nateglinide )
  • Alpha-glucosidase inhibitors: acarbose
  • Amylin analogs: injectable pramlintide
• See “Overview of diabetes medications” for details on side effects and contraindications.

Oral monotherapy usually lowers HbA1c levels by ∼ 1%. Every noninsulin drug added to metformin will lower the HbA1c by an additional 0.7–1.0%. ^[47]

Beware of drug interactions and drug incompatibilities; combining sulfonylureas with insulin increases the risk for hypoglycemia. ^[51]

Many oral diabetes medications should be avoided in patients undergoing surgery or experiencing severe illness; consider insulin therapy instead.

Indications for insulin therapy in T2DM ^[47]

• Patients whose glycemic targets are not met despite sufficient noninsulin diabetes medications
• Patients with contraindications for noninsulin diabetes medications (e.g., patients with end-stage renal failure)
• Pregestational and gestational diabetes ^[52]
• Hyperglycemic crisis
• Consider in patients with ≥ 1 of the following:
  • Initial glucose ≥ 300 mg/dL or HbA1c > 10%
  • Symptoms of hyperglycemia
  • Signs of a continued catabolic state (e.g., weight loss)

Approach to insulin treatment in T2DM ^[47]

• Start with the simplest insulin regimen (i.e., a basal insulin regimen with once-daily injections).
• Titrate the insulin dose according to individualized glycemic targets and tolerance.
• Consider adding prandial insulin or switching to a mixed insulin regimen as needed.
• Noninsulin diabetes medications may be continued once insulin treatment is started.
• See “Insulin regimens” for details.

Include GLP-1 receptor agonists in the treatment strategy prior to starting insulin therapy in patients with T2DM, unless they are inappropriate or insulin therapy is preferred.

Screening for microvascular complications of diabetes

• Initial screening ^[53][54][55]
  • Type 1 DM: 5 years after the onset of diabetes ^[56]
  • Type 2 DM: at the time of diabetes diagnosis
• Frequency ^[53][54][55]
  • Perform at minimum every 12 months.
  • More frequent screening may be necessary for:
    • Pregnant individuals
    • Patients with a history of microvascular complications
• Modalities
  • Screening for diabetic kidney disease: spot urine albumin to creatinine ratio (UACR) and serum glomerular filtration rate ^[55][57]
  • Screening for diabetic retinopathy: comprehensive eye exam with dilation or retinal photography (if available) ^[53]
  • Screening for diabetic peripheral neuropathy with a focused examination of sensation, e.g.: ^[53][57]
    • Monofilament test
    • Pinprick sensation or temperature sensation
    • Vibration sense (using a tuning fork)
  • Screening for diabetic autonomic neuropathy by recording resting heart rate, orthostatic vital signs, and heart rate variability.
  • Screening for diabetic foot: comprehensive foot exam ^[53][58][59]

Screening for macrovascular complications of diabetes ^[37]

• Check BP at every clinic appointment and encourage patients with elevated BP to measure blood pressure at home.
• Obtain a lipid panel at the time of diabetes diagnosis and repeat every 5 years for patients < 40 years.
• Screening for cardiovascular disease is not recommended for asymptomatic individuals. ^[37]
• Consider screening asymptomatic individuals for cardiovascular disease on a case-by-case basis:
  • BNP or NT-proBNP for patients without known structural heart disease ^[60]
  • Ankle-brachial index testing for patients ≥ 65 years of age with microvascular disease, diabetic foot complications, and/or any end-organ damage from diabetes ^[37]

T2DM (outpatient management)

Assessment: This is a @AGE@-year-old @SEX@ with T2DM diagnosed in [**year] presenting for routine management.

–Current glycemic control: [HbA1c **%, fasting glucose mg/dL]

–Symptoms: [**asymptomatic, polyuria, polydipsia, fatigue]

–Complications: [**none, neuropathy, nephropathy, retinopathy]

–Comorbidities: [**hypertension, dyslipidemia, obesity]

Plan

Glycemic management

–Target HbA1c: < [**%]

–Nutrition counseling

–≥ 150 minutes of moderate-intensity aerobic activity per week

Current medications

–Metformin [** mg **FREQUENCY]

–GLP-1 receptor agonist: [**liraglutide or semaglutide] for cardiovascular benefit, weight loss

–SGLT2 inhibitor: [empagliflozin or dapagliflozin [** mg] once daily] for renal and cardiovascular benefit

–DPP-4 inhibitor (if GLP-1 not available or tolerated): [sitagliptin]

–Basal insulin (consider if HbA1c remains > 10% or significant symptoms of hyperglycemia)

–Sulfonylureas: e.g., glimepiride (cheaper option; monitor for hypoglycemia)

Monitoring for complications

–HbA1c: every 3–6 months [**last date]

–Fasting lipid panel: annually [**last date]

–BMP: annually, or more frequently if CKD is present [**last date]

–Urine ACR: annually [**last date]

–Comprehensive foot exam: annually [**last date]

–Dilated eye exam: annually or every 2 years if low risk [**last date]

–BP, weight, BMI: every visit

–ECG [for patients with cardiovascular risk factors]: [**last date]

Cardiovascular risk management

–Target blood pressure: < [**140/90] mm Hg

–[Lisinopril ** mg PO once daily] for patients with albuminuria or hypertension

–High-intensity statin: [atorvastatin ** mg once daily] for all patients with diabetes aged ≥ 40 years

–Ezetimibe or PCSK9 inhibitors for LDL ≥ 70 mg/dL despite maximally tolerated statin

–[Aspirin ** mg once daily] for ASCVD prevention

Education and support

–Glucose monitoring: Review frequency and goals for self-monitoring.

–Reinforce signs of hypoglycemia and hyperglycemia and when to seek care.

Immunizations

–Influenza: annually

–Pneumococcal: for all adults with diabetes

–Hepatitis B: series for all adults with diabetes aged ≤ 59 years

Follow-up

–Routine follow-up in [** months] for glycemic control

–Follow-up sooner if symptomatic hyperglycemia or significant therapy adjustments.

Acute complications

• Hyperglycemic crisis: undiagnosed or insufficiently treated diabetes mellitus may result in severe hyperglycemia, potentially culminating in a crisis
  • Hyperglycemic hyperosmolar state (HHS)
  • Diabetic ketoacidosis (DKA)
• Life-threatening hypoglycemia: secondary to inappropriate insulin therapy

Long-term complications ^[61]

Macrovascular complications of diabetes (atherosclerosis)

• Prevalence: more common in patients with type 2 diabetes
• Risk factors: : The major determinants are metabolic risk factors, which include obesity, dyslipidemia, and arterial hypertension. Hyperglycemia may be less related to the development of macrovascular disease.
• Manifestations
  • Coronary heart disease (most common cause of death)
  • Cerebrovascular disease
  • Peripheral artery disease (possible loss of limb)
  • Monckeberg arteriosclerosis
  • Gangrene

Microvascular complications of diabetes

• 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

Gastroparesis can complicate the management of diabetes by causing poor absorption of oral antidiabetic drugs and difficulties with timing insulin doses due to delayed food absorption. ^[62]

Strict glycemic control is crucial in preventing microvascular disease.

Necrobiosis lipoidica ^[63]

• Definition: inflammatory granulomatous disorder of the skin; characterized by collagen degeneration and lipid accumulation in the surface of the skin.
• Epidemiology
  • > 60% association with DM
  • ♀ >> ♂
• Clinical features
  • Rash: circumscribed, erythematous plaques with atrophic centers and irregular margins
  • Common sites: pretibial region
  • Usually asymptomatic
  • Ulcerations with subsequent scarring may occur.
• Histopathology: necrobiotic palisading granuloma
  • Lymphohistiocytic infiltration with plasma cells, foam cells, and giant cells
  • Wall thickening and occlusion of small blood vessels
  • Destruction of collagen fibers in the entire corium
• Treatment: Corticosteroids may be effective (e.g., intralesional corticosteroid injections).

Other complications

• Mucormycosis (zygomycosis)
• Diabetic cardiomyopathy: a disorder of the myocardium seen in patients with diabetes ^[64]
  • Chronic hyperglycemia results in altered metabolism of glucose and fatty acids, microangiopathy with endothelial dysfunction, and autonomic neuropathy, which collectively results in cardiomyocyte hypertrophy, myocardial fibrosis, ventricular dilation, and ultimately in systolic and/or diastolic heart failure.
  • This disorder may or may not be accompanied by CVD and hypertension.
• Osmotic damage: occurs in tissues with high aldolase reductase activity and low/absent sorbitol dehydrogenase activity (e.g., eyes, peripheral nerves) → cataracts, neuropathy
• Diabetic fatty liver disease
• Hyporeninemic hypoaldosteronism ^[65]
  • Hypoaldosteronism that is caused by decreased renin activity
  • Most commonly caused by diabetic nephropathy or chronic interstitial nephritis
  • Patients present with features of hypoaldosteronism, i.e., hypotension, hyponatremia, and type 4 renal tubular acidosis.
• Limited joint mobility syndrome (formerly known as diabetic cheiroarthropathy) ^[66]
  • Manifested as stiffness of the small joints of the hand
  • Tight waxy skin, particularly on the dorsal surface of the fingers, is common.
  • Positive prayer sign: inability to approximate the palms due to flexion contractures of the PIP and MCP joints ^[67]
  • Positive tabletop test: inability to flatten the palm against the surface of a table due to the contractures in the metacarpophalangeal joints
• Sialadenosis
• Increased risk of infection

Insulin purging ^[68]

• Definition: attempting to lose weight by purposefully not injecting insulin after meals
• Population: young patients with type 1 diabetes with eating disorders use insulin purging as an alternative to fasting, vomiting, and other methods of weight loss
• Result: self-induced insulin deficiency → ↓ insulin-dependent glucose uptake in cells → ↓ anabolic effect of insulin → weight loss (no weight gain)
  • Poor glycemic control
  • Increased risk of hyperglycemic crises

We list the most important complications. The selection is not exhaustive.

• Diabetes mellitus is one of the leading causes of death in the US; common complications that result in death are myocardial infarction and end-stage renal failure. ^[4]
• One of the leading causes of blindness, nontraumatic lower limb amputation, end-stage renal failure, and cardiovascular disease ^[4]
• The prognosis primarily depends on glycemic control and treatment of comorbidities (e.g., hypertension, dyslipidemia).

For information on screening, see "Screening for diabetes."

Primary prevention

• Recommend a healthy lifestyle, including: ^[69][70]
  • Balanced diet
  • Maintenance of a healthy weight
  • Exercising for ≥ 150 minutes a week
  • 6–9 hours of sleep per night ^[29][69]
• Address modifiable risk factors for T2DM and prediabetes, e.g.: ^[29][69]
  • Management of obesity: Encourage reduction of at least 7% of body weight. ^[69][70]
  • Management of hypertension
  • Management of hyperlipidemia
  • Management of polycystic ovary syndrome
  • Medication review and use of lower-risk alternatives where possible (e.g., steroid-sparing agents)
• For adults at high risk of prediabetes or diabetes: ^[69]
  • Refer to a diabetes prevention program.
  • Consider metformin in consultation with an endocrinologist.
• Manage prediabetes promptly upon identification.

Prediabetes is defined as elevated glucose and/or HbA1c levels that do not meet the criteria for T2DM. ^[11][71]

Epidemiology

• Prevalence: Approx. 38% of adults in the US (97.6 million individuals) have prediabetes. ^[72]
• Sex: ♂ > ♀ ^[72]

Etiology

• Risk factors for prediabetes are the same as risk factors for T2DM.
• Overweight and obesity are the most common risk factors. ^[24][71]

Pathophysiology ^[71]

• Impaired glucose tolerance: The pancreas cannot secrete enough insulin to overcome peripheral insulin resistance, resulting in decreased glucose uptake after ingestion of a glucose load.
• Impaired fasting glucose: Hepatic insulin resistance, inappropriate endogenous glucose production, and impaired insulin secretion from the pancreas lead to elevated fasting blood glucose.

Diagnosis of prediabetes ^[10][24][69]

• Usually diagnosed during routine screening for diabetes
• Prediabetes is confirmed if any of the following values are obtained:
  • 2-hour OGTT: 140–199 mg/dL
  • FPG: 100–125 mg/dL
  • HbA1c: 5.7–6.4% ^[10][24][29]
  • See also "Interpretation of hyperglycemia tests."

Management of prediabetes ^[29][69]

• Address risk factors for T2DM and perform an ASCVD risk assessment. ^[29]
• Recommend lifestyle modifications for patients with DM, including ≥ 7% weight loss for patients with overweight or obesity. ^[24][69][69]
• Refer to a diabetes prevention program , and provide resources for support (e.g., local support groups). ^[24]
• Consider pharmacological treatment for prediabetes.
• Regularly assess treatment response (e.g., every 3 months), and adjust the plan accordingly.
• Monitor for progression to diabetes annually; see “Screening for diabetes.” ^[29][69]

Adults aged > 70 years with prediabetes are less likely to develop diabetes than younger adults; tailor management based on shared decision-making and life expectancy. ^[69]

Pharmacological treatment for prediabetes ^[29][69][71]

• Indications
  • Patients at high-risk for progression to T2DM, e.g.: ^[69][71]
    • Age 25–59 years with BMI ≥ 35 kg/m²
    • History of gestational diabetes
    • Higher glucose levels on prediabetes diagnostic labs (e.g., fasting glucose ≥ 110 mg/dL, HgbA1c ≥ 6%)
  • Patients with an inadequate response to lifestyle modifications
• Consider off-label use of one of the following: ^[24][29][69]
  • Preferred: metformin ^[69][73]
  • Alternative: pioglitazone OR acarbose
• Consider vitamin D supplementation. ^[69][74]

While metformin, pioglitazone, and acarbose are usually recommended to prevent progression in prediabetes, other antihyperglycemic medications (e.g., GLP-1 receptor agonists, insulin) may be used in specific patient populations (e.g., individuals with obesity). ^[29][69]

Prognosis ^[71]

• Approx. 10% of untreated individuals with prediabetes progress to T2DM annually. ^[71]
• Increased risk for ASCVD and microvascular complications (e.g., retinopathy, neuropathy, nephropathy) compared to normoglycemic individuals ^[71]

• Diabetes in children and adolescents is covered in the relevant section.
• See “Diabetes in pregnancy” for information on gestational diabetes mellitus and pregestational diabetes mellitus.
• Diabetes in other special patient groups (e.g., transplant-associated diabetes, cystic fibrosis-related diabetes, neonatal diabetes) is rare and is typically managed by specialists.

Management of hyperglycemic crises in children is covered separately.

Epidemiology

• Over 90% of diabetes in children and adolescents is T1DM, but incidence of T2DM is rising. ^[75][76]
• Prevalence in the US
  • T1DM: 2.15 per 1000 individuals aged < 20 years ^[76]
  • T2DM: 0.67 per 1000 adolescents aged 10–19 years ^[76]

Clinical features

• Clinical features of diabetes mellitus are similar in children and adults.
• Distinguishing between T1DM and T2DM can be challenging; the following features suggest T1DM in children: ^[77]
  • DKA or cerebral edema at presentation
  • Early age of onset (< 10 years old or before puberty)
  • BMI < 85th percentile
  • No risk factors for T2DM
  • No signs of insulin resistance (e.g., acanthosis nigricans)

Screening for diabetes mellitus in children

There are two screening types for diabetes mellitus in children: screening for hyperglycemia (designed to detect prediabetes and T2DM) and screening for elevated risk of T1DM.

Screening for prediabetes or T2DM ^[10][57][78]

• Indications: children who meet all of the following criteria
  • Aged ≥ 10 years or after puberty (whichever occurs earlier)
  • With overweight or obesity
  • And ≥ 1 of the following risk factors for diabetes in children: ^[10]
    • Maternal diabetes in pregnancy during the child's gestation
    • First or second-degree relative with T2DM
    • High-risk race and/or ethnicity ^[10]
    • Large-for-gestational-age or small-for-gestational-age infants
    • Conditions associated with insulin resistance ^[10]
    • Signs of insulin resistance (e.g., acanthosis nigricans)
    • Use of atypical antipsychotics causing rapid weight gain ^[77]
• Modality: one-step OGTT, FPG, or HbA1c (see also “Interpretation of hyperglycemia tests”) ^[10]
• Intervals: Repeat at least every 2 years. ^[10][57]

Regular monitoring and lifestyle changes are the mainstay of management of prediabetes in children and adolescents. There is insufficient data to support the use of medications to delay or prevent progression to T2DM in this age group. ^[77]

Screening for elevated risk of T1DM

• Indication: normoglycemic children with increased genetic risk (e.g., first-degree relative with T1DM) ^[10][79]
• Modality: islet autoantibody testing; repeat test to confirm result if any antibodies are positive ^[10][80][81]
• Follow-up for patients with positive antibodies:
  • 1 autoantibody: Repeat testing of autoantibodies, random glucose, and HbA1c at set intervals. ^[10][79][80]
    • Every 6 months for children < 3 years of age for 3 years, then annually for another 3 years
    • Every 12 months for children ≥ 3 years of age for 3 years
  • ≥ 2 autoantibodies
    • Refer patient to endocrinology for the management of presymptomatic T1DM. ^[10][79][80]
    • Provide home glucose monitoring and regularly check HbA1c. ^[80]

Educate caregivers of children with antibodies on the signs and symptoms of diabetes and diabetic ketoacidosis. ^[79]

Diagnostics

• Diagnostic criteria for diabetes mellitus are the same in children and adults. ^[10]
• Assess for hyperglycemia with FPG, OGGT, and/or HbA1c (for results, see "Interpretation of hyperglycemia tests"). ^[57]
• In case of diagnostic uncertainty, obtain: ^{[36][57][75][82]}
  • Islet autoantibody testing
  • Urine and plasma C-peptide
• Refer for genetic testing if features of monogenic diabetes are present, e.g.: ^[57]
  • Onset in the first 6 months of life
  • Features that are atypical for T1DM and T2DM
  • Family history of diabetes in successive generations
  • Mild fasting hypoglycemia

Diabetes management is similar in adults and children.

At diagnosis ^[57]

• Stabilize the patient.
  • Treat any diabetic ketoacidosis.
  • Start insulin replacement therapy. ^[83]
• Refer to a multidisciplinary pediatric diabetes team for individualized comprehensive diabetes care, including: ^[57]
  • Glycemic monitoring for diabetes
  • Glycemic treatment for diabetes
  • Setting glycemic targets in diabetes
• Refer to a registered dietitian nutritionist to teach appropriate diet and carbohydrate monitoring.
• Encourage a healthy lifestyle to reduce cardiovascular risk factors.
  • Encourage ∼ 60 minutes of moderate to vigorous activity daily and resistance activity at least 3 days per week. ^[57]
  • Manage overweight and obesity in children. ^[57]
• Initiate initial screening for comorbidities.
• Include caregivers in self-management education. ^[57]

Initial screening for comorbidities

• Additional autoimmune disease, i.e.: ^[57]
  • Thyroid disease: Obtain TSH levels and consider measuring antithyroid peroxidase and antithyroglobulin levels.
  • Celiac disease: IgA tissue transglutaminase (tTG) and total IgA
• Pediatric dyslipidemia in patients ≥ 2 years of age: Obtain a lipid panel.
  • Initiate treatment of dyslipidemia in children if elevated.
  • Aim for an LDL cholesterol target of < 100 mg/dL.
• Hypertension: Measure blood pressure.
  • Initiate treatment of hypertension in children if elevated.
  • Aim for a target blood pressure of:
    • < 13 years of age: < 90^th percentile for age, height, and sex and of < 120/80 mm Hg for children
    • ≥ 13 years of age: < 120/80 mm Hg
• Psychosocial factors
  • Screen children for psychosocial disorders (including diabetes distress).
  • Assess children and caregivers for risk factors for poor adherence.

Ongoing management

• Assess whether glycemic goals are being met. ^[83]
  • Assess for risk factors for poor adherence.
  • Consider if insulin requirements have increased (e.g., at puberty).
  • Consider a higher HbA1c goal (e.g., < 7.5%) for children at risk for hypoglycemia. ^[57]
• Screen for complications and comorbidities as needed (see "Repeat screenings for children with T1DM").
• Advise reviews at least annually with a registered dietitian nutritionist.
• Encourage younger children to assume self-management tasks as they mature.
• For adolescents: ^[57][84]
  • Screen regularly for psychosocial distress including disordered eating.
  • Offer preconception counseling at puberty.
  • Support transition to adult care.

Worsening of diabetes control is common during adolescence as individuals learn to self-manage their chronic disease; support and educate adolescents and their caregivers. ^[84]

Screening

Diabetes management is similar in adults and children.

At diagnosis ^[57]

• Refer to a multidisciplinary pediatric diabetes team for individualized comprehensive diabetes care, including: ^[57]
  • Glycemic monitoring for diabetes
  • Glycemic treatment for diabetes
  • Setting glycemic targets in diabetes
• Start lifestyle management. ^[57]
  • Initiate weight management: Aim for a weight loss of at least 7–10%. ^[57]
  • Encourage ∼ 60 minutes of moderate to vigorous activity daily and resistance activity at least 3 days per week. ^[57]
• Base initial pharmacological treatment on HbA1c, usually aiming for a target HbA1c of < 6.5%. ^[57][77]
  • < 8.5%: metformin
  • ≥ 8.5%: metformin and basal insulin
• Include caregivers in self-management education.

Initial screening for comorbidities

• Dyslipidemia: Obtain a lipid panel.
  • Initiate treatment of dyslipidemia in children if elevated.
  • Aim for an LDL cholesterol target of < 100 mg/dL, HDL > 35 mg/dL, and triglycerides < 150 mg/dL. ^[57]
• Hypertension: Measure blood pressure.
  • Initiate treatment of hypertension in children if elevated.
  • Aim for target blood pressure of:
    • < 13 years of age: < 90^th percentile for age, height, and sex and of < 120/80 mm Hg for children
    • ≥ 13 years of age: < 120/80 mm Hg
• Common comorbidities of T2DM
  • Metabolic dysfunction-associated steatotic liver disease (MASLD): Obtain AST and ALT.
  • Obstructive sleep apnea: Screen for symptoms.
  • Polycystic ovary disease (PCOS): Screen for symptoms and consider laboratory studies.
• Microvascular complications of diabetes
  • Retinopathy: comprehensive dilated eye examination
  • Nephropathy: spot urine albumin-to-creatinine ratio and eGFR
  • Neuropathy: comprehensive foot examination
• Psychosocial factors
  • Screen children for psychosocial disorders (including diabetes distress).
  • Assess children and caregivers for risk factors for poor adherence.

Ongoing management

• Review glycemic control.
• Screen for comorbidities and complications of diabetes.
• Support children to assume self-management tasks as they mature. ^[57]
• Provide preconception counseling from puberty. ^[57]
• Support adolescents to transition to adult care. ^[57]

Glycemic control

• Measure HbA1c every 3 months with a target of < 6.5%.
• HbA1c < 6.5%: Continue metformin and consider weaning insulin or additional medications. ^[57]
• HbA1c ≥ 6.5%: Add therapies in a stepwise manner. ^[57][77]
  • Review adherence.
  • Maximize metformin.
  • Add a GLP-1 receptor agonist or a SGLT-2 inhibitor (e.g., empagliflozin) approved for use in children.
  • Add or increase long-acting insulin.
  • Add prandial insulin.
  • Refractory hyperglycemia or serious comorbidities: Consider referral for metabolic surgery. ^[57]

Screening

• Every visit ^[57]
  • Measure blood pressure.
  • Screen for symptoms of sleep apnea and PCOS.
  • Screen for psychosocial distress and social determinants of health (see "Psychosocial screening for adolescents"). ^[77]
• Screen annually for: ^[57]
  • Microvascular complications of diabetes with foot examination, spot urine albumin-to-creatinine ratio and eGFR, and dilated comprehensive eye examination
  • Dyslipidemia: Obtain a lipid panel.
  • MASLD: Obtain AST and ALT.

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