Diabetes mellitus

Diabetes mellitus (DM) describes a group of metabolic diseases that are characterized by chronic hyperglycemia. Type 1 diabetes mellitus (T1DM) is the result of an autoimmune response that triggers the destruction of insulin-producing β 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), which is much more common, has a strong genetic component as well as a significant association with obesity and a sedentary lifestyle. T2DM is characterized by insulin resistance and impaired insulin secretion due to pancreatic β-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 glucose targets while avoiding hypoglycemia. Diabetes care should be comprehensive and patient-centered, and it should include monitoring and management of ASCVD risk factors, microvascular complications (e.g., diabetic retinopathy, diabetic nephropathy, diabetic neuropathy), and macrovascular complications (e.g., CAD, stroke, PAD). Management should also include general lifestyle modifications (e.g., smoking cessation, exercise, nutritional support) and pharmacotherapy (e.g., antihyperglycemics, statins, ACE inhibitors or angiotensin receptor blockers, and aspirin). The management of diabetes in children is largely similar to adults, except certain medications (sulfonylureas, dipeptidyl peptidase-4 inhibitors, SGLT-2 inhibitors, and thiazolidinediones) are not licensed for use in this age group.

See also “Diabetes in pregnancy,” “Insulin,” and “Hyperglycemic crises.”

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
  • Near 34 million individuals in the US have diabetes with 7.3 million being undiagnosed.
• Incidence: ∼ 6.7 per 1,000 among the 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 ^[10]
  • Family history: first-degree relative with diabetes ^[11][12][13]
  • High-risk race or ethnicity
  • Dyslipidemia
  • Prediabetes
  • Physical inactivity
  • Cardiovascular disease
  • Polycystic ovary syndrome
  • Hypertension
  • History of gestational diabetes
  • Other conditions associated with metabolic syndrome and insulin resistance: e.g., severe 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][14]

• 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 HbA_1C 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 ^[15]

• 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 ^[16]
  • 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 ^[17]
• Pancreatic β cell dysfunction: accumulation of pro-amylin (islet amyloid polypeptide) in the pancreas; → decreased endogenous insulin production ^[18]

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.

Indications for diabetes screening ^[10]

The indications listed below are consistent with the 2024 ADA guidelines. The 2021 USPSTF guideline recommends screening in adults aged 35–70 years with overweight or obesity. ^[10][23][24]

• 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. ^[10]
    • 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.

Method of screening

• See “Hyperglycemia tests” below.

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 at least every three years. ^[10]

Diagnostic criteria for diabetes mellitus ^[10]

A combination of either of the tests described below may be performed to confirm the diagnosis and the same test can be used both for screening and 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]

• 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) ^[25]
  • 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 altered by a variety of conditions or treatments, e.g., sickle cell trait, chronic kidney disease. ; ^[10][26][27]
    • 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 evaluation ^[28]

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: ^[28]
  • Patients with suspected or confirmed T1DM: TSH
  • Patients on metformin: vitamin B12 level
  • Select 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 ^[29][30]
  • ↑ 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) ^[30]
  • 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, which is responsible for the conversion of glutamic acid to GABA ^[30]
    • 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) ^[30]
  • Anti-zinc transporter 8 antibodies

While screening for T1DM with autoantibodies is not routinely recommended, it can be considered for patients with first-degree relatives with T1DM or in the setting of research trials. ^[10]

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

• Glucagonoma
• Somatostatinoma

The differential diagnoses listed here are not exhaustive.

General principles ^[31]

• Main goal: blood glucose control, tailored to glycemic targets and regularly monitored ^[31]
  • Patients with T1DM always require insulin therapy.
  • T2DM may be managed with noninsulin antidiabetics 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)
  • Continuous patient education ; see “Managing chronic conditions.”
  • 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, OSA) ^[28][32]
  • Vaccinations: e.g., influenza, hepatitis B, pneumococcal vaccines, zoster vaccine, and COVID-19. ^[32][33]
• ASCVD risk assessment and ASCVD prevention, including ^[34]
  • Hypertension management ^[34]
  • 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. ^[35]
  • Management of obesity ^[36]
  • Diagnostic studies for coronary artery disease in patients with clinical features of CAD ^[34]
  • Use of antiplatelet therapy, if indicated (see “Primary prevention of ASCVD” and “Management of ASCVD”)
• Follow-up
  • Periodically reevaluate the need for further diabetes self-management education and support (DSMES). ^[37]
  • Check HbA1c at least every 3–6 months (see “Glycemic monitoring for DM”).
  • For patients requiring lipid-lowering therapy, repeat yearly and 4–12 weeks after any medication changes. ^[34]

Diabetes care should be patient-centered and comprehensive, including 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. ^[24]

Physical exercise reduces blood glucose and increases insulin sensitivity.

Lifestyle modifications ^[37]

Glycemic targets in diabetes ^[38][39]

• 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 and life expectancy
• Reevaluate glycemic targets continuously and adjust if necessary.

Glycemic targets should be individualized. A target of HbA1c < 7% is generally suitable for most nonpregnant adults. ^[38]

Assess for past episodes or risk of hypoglycemia regularly and adjust glycemic goals accordingly. Hypoglycemia is one of the major limitations for adequate glycemic control. ^[38]In patients that meet preprandial glucose targets, HbA1c above target may be due to postprandial hyperglycemia that requires prandial insulin dose adjustments.

Glycemic monitoring for DM ^[38][40]

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

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 (SMBG): at fixed times or as necessary
  • 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 (CGM): Interstitial glucose levels are measured continuously or intermittently using a device. ^[40]
  • 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)
  • Consider in:
    • Patients with T2DM using intensive insulin therapy or those with a high risk of hypoglycemia
    • Any patient 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-riks 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. ^[41][42][43]

As there is little to no evidence to support the existence of the Somogyi effect, it should not be assumed that early morning hyperglycemia is due to nocturnal hypoglycemia. Rather, it is more likely caused by nocturnal hyperglycemia with or without hypoinsulinemia and/or the early morning secretion of counterregulatory hormones (e.g., cortisol). ^[41][42][43]

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

• See “Inpatient management of hyperglycemia” for details regarding, e.g., management of hyperglycemia in critically ill patients.
• See also “Perioperative medication management” for the adjustments to insulin and oral antidiabetics prior to surgery.

Type 1 diabetes mellitus

Insulin replacement therapy ^[31]

• Treatment options
  • Multiple daily insulin injections (see “Full basal-bolus insulin regimen” for details)
  • Insulin pump (consider for most patients)
• Starting dose calculation ^[31]
  • 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 initiating treatment with 0.5 units/kg per day.
• Dose titration
  • After beginning insulin treatment, there is often a temporary reduction in exogenous insulin demand. ^[44]
  • Dosage should be adjusted according to glycemic monitoring.

Educate patients on calculating insulin requirements throughout the day and in accordance with activities and meals. ^[31]

Other treatment strategies ^[31]

• Noninsulin antidiabetics: not generally used in T1DM treatment
• Pancreas and islet transplantation
  • Can improve glucose control but are not standard treatments because of 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 transplant

Type 2 diabetes mellitus

Approach ^[31]

• Start treatment in all patients at diagnosis. ; ^[31][45]
  • Monotherapy with metformin is the first-line initial treatment for most patients.
  • If there are contraindications for metformin, choose a different noninsulin antidiabetic, depending on patient factors.
• Consider early combination pharmacological therapy in select patients, e.g., those with: ^[31][32]
  • Clinical ASCVD, high ASCVD risk, heart failure, or CKD
  • HbA1c ≥ 1.5% above the glycemic target
  • Indications for insulin therapy for T2DM at time of diagnosis
• Reevaluate treatment and treatment adherence every 3–6 months. ^[31]
  • Sequentially add noninsulin antidiabetic drugs until glucose targets are met.
  • If targets are still not met despite adequate treatment:
    • Add an injectable GLP-1 receptor agonist.
    • Consider insulin therapy.

Metformin should be part of every patient's treatment, unless contraindicated, and continued for as long as it is tolerated, as it is safe, effective, widely available, and has been shown to reduce cardiovascular events and mortality. ^[31]

Noninsulin antidiabetics

• 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 antidiabetic drugs” 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%. ^[31]

Beware of drug interactions and drug incompatibilities; combining sulfonylureas with insulin increases the risk of hypoglycemia. ^[46]

Many oral antidiabetic drugs should be avoided in patients undergoing surgery or experiencing severe illness. Instead, insulin therapy may be initiated.

Indications for insulin therapy in T2DM ^[31]

• Patients whose glycemic targets are not met despite sufficient antidiabetic treatment
• Patients with contraindications for noninsulin antidiabetic drugs, e.g., patients with end-stage renal failure
• Pregestational and gestational diabetes ^[47]
• Hyperglycemic crisis
• Consider in newly diagnosed patients with any 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 ^[31]

• Start with the simplest insulin regime, 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 antidiabetics may be continued when insulin treatment is started.
• See “Insulin regimens” for details.

GLP-1 receptor agonists should be part of the treatment strategy prior to starting insulin treatment in patients with T2DM, unless they are not appropriate or insulin therapy is preferred.

If treatment goals are not met in a patient on a basal insulin regimen, combination therapy with basal insulin and injectable GLP-1 receptor agonists may be considered.

Screening for microvascular complications of diabetes

• Initial screening ^[48][49][50]
  • Type 1 DM: 5 years after the onset of diabetes ^[51]
  • Type 2 DM: at the time of diabetes diagnosis
• Frequency ^[48][49][50]
  • Perform at minimum every 12 months.
  • More frequent screening may be necessary for:
    • Pregnant patients
    • 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 ^[50][51]
  • Screening for diabetic retinopathy: comprehensive eye exam with dilation or retinal photography (if available) ^[49]
  • Screening for diabetic peripheral neuropathy with a focused examination of sensation, e.g.: ^[49][51]
    • 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 ^[49][52][53]

Screening for macrovascular complications of diabetes ^[54]

• 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. ^[34]
• Consider screening asymptomatic individuals for cardiovascular disease on a case-by-case basis:
  • BNP or NT-proBNP without known structural heart disease ^[54]
  • Ankle-brachial index testing for patients ≥ 50 years of age with microvascular disease, diabetic foot complications, and/or any end-organ damage from diabetes. ^[54]

Acute complications

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

Long-term complications ^[55]

Macrovascular disease (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 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

Strict glycemic control is crucial in preventing microvascular disease.

Necrobiosis lipoidica ^[56]

• 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 ^[57]
  • 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 ^[58]
  • 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) ^[59]
  • 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 ^[60]
  • 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 ^[61]

• 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 management in pregnancy, see “Diabetes in pregnancy.”

Diabetes mellitus in children

The following recommendations are for children and adolescents with T1DM and T2DM. Management of other forms of diabetes in children (e.g., diabetes associated with transplantation or cystic fibrosis) is not addressed here.

Screening indications ^[10][51][62]

For screening modalities, see “Diagnostics” below.

• T1DM: Consider for children with first-degree relatives with T1DM.
• T2DM: Consider for children meeting all of the criteria below; repeat every 3 years or sooner in high risk patients. ^[10]
  • Age ≥ 10 years OR after puberty begins
  • BMI ≥ 85^th percentile
  • ≥ 1 additional risk factor for T2DM:
    • Children born to mothers with pregestational diabetes mellitus or gestational diabetes mellitus
    • Conditions associated with insulin resistance
    • Race/ethnicity
    • Family history of T2DM

Diagnostics ^[10]

• Diagnostic criteria for diabetes mellitus and prediabetes are similar to the adult population.
• Perform antibody testing for all children diagnosed with diabetes. ^[32][51]
• FPG, OGTT, or HbA1c may be used to assess for hyperglycemia ^[10]

Management ^[32][51]

Diabetes management in children is generally similar to adults, with the following modifications.

Screening and management of associated conditions ^[51]

• Screening for thyroid disease and celiac disease is recommended for all children with T1DM.
• Dyslipidemia screening is recommended for children who are at least 2 years old and have acceptable glycemic control.
• Assess for changes in anthropometric measurements and deviation from growth trajectory.
• Screen children annually for associated mental health problems. ^[63][64][65]
  • From age 7–8 years old: Screen for psychosocial distress.
  • From 10–12 years old: Screen children with T1DM for disordered eating.
• Provide preconception counseling for adolescent girls.
• For treatment of hypertension in children: Goal blood pressure is < 90th percentile or < 130/80 mm Hg for children ≥ 13 years of age.

Educate all individuals involved in the care of the patient (e.g., family members, school, and childcare personnel) about the treatment plan. ^[51]

Antidiabetic treatment ^[51]

• T1DM: insulin pump OR full basal-bolus insulin regimen ^[31][51]
• T2DM: The following regimens are suitable for children ≥ 10 years of age; for whom metformin, insulin, and GLP-1 receptor agonists are approved for use.
  • Initial treatment varies based on laboratory findings and presence of acidosis and/or ketosis.
    • Acidosis or hyperosmolar hyperglycemic state: See “Management of hyperglycemic crises.”
    • HbA1c < 8.5%, no ketosis, and normal renal function: metformin ^[51]
    • HbA1c ≥ 8.5%, blood glucose ≥ 250 mg/dL without acidosis, and symptomatic: initiate metformin PLUS basal insulin regimen while uptitrating metformin ^[51]
  • If glycemic targets are not achieved with metformin AND basal insulin, switch to an insulin pump or consider the addition of:
    • Prandial insulin
    • GLP-1 receptor agonists (e.g., exenatide extended-release, liraglutide)
  • Metabolic surgery can be considered for adolescents with a BMI of > 35 kg/m² with either of the following despite lifestyle and pharmacological management:
    • Elevated HbA1c
    • Serious comorbidities

Patients with T2DM presenting with diabetic ketoacidosis should be treated with insulin alone. Metformin may be added after acidosis resolves. ^[51]

T2DM is rare in children under 10 years of age; consider consulting a specialist to determine treatment, as neither metformin nor GLP-1 receptor agonists are FDA-approved for use in this age group.

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