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).

For more information on the complications of type 1 and type 2 diabetes, see “Complications of diabetes mellitus.”

See also “Gestational diabetes mellitus,” “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]

• Hereditary and environmental factors ^[11][12][13]
• Associated with metabolic syndrome: e.g., high waist-to-hip ratio (visceral fat accumulation) ^[14]
• Risk factors for type 2 diabetes mellitus ^[10]
  • Positive family history
  • Race/ethnicity (high risk factor)
  • Physical inactivity
  • History of cardiovascular disease
  • Polycystic ovary syndrome
  • Conditions associated with insulin resistance: e.g., severe obesity and high-calorie diet
  • Hypertension
  • Dyslipidemia
  • History of gestational diabetes

Classification according to the WHO and American Diabetes Association (ADA) ^[15][16]

• 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 ^[17]

• 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 ^[18]
  • 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 ^[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.

Indications for testing ^[10][24]

The indications listed below are consistent with the 2021 ADA guidelines. The 2021 USPSTF guideline recommends screening in adults aged 35–70 years with overweight or obesity. ^[10][24][25]

• > 45 years of age
• History of prediabetes or gestational diabetes
• Patients < 45 years of age with both
  • Overweight or obesity ^[25]
  • AND ≥ 1 additional risk factor for T2DM
• Presence of risk enhancing comorbidities, including:
  • HIV infection: Screen before starting or switching antiretroviral therapy. ^[26]
  • 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.
• Consider in women who are planning pregnancy with any risk factor for T2DM (e.g., overweight or obesity).
• 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 at least annually to detect progression to diabetes. ^[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): measurement of fasting plasma glucose and blood glucose 2 hours after the consumption of 75 g of glucose
  • Most sensitive test
  • Less convenient and more expensive than other 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
  • Results may be altered 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).

Routine studies

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

• BMP
  • Renal function
  • Electrolytes, including potassium
• Liver chemistries
• Lipid panel
• Spot urinary albumin-to-creatinine ratio: to detect microalbuminuria

Additional 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
• Antibody 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
    • Seen in ∼ 60–80% of patients with new-onset T1DM ^[30]
  • Anti-tyrosine phosphatase-related islet antigen 2 (IA-2) ^[30]
  • Islet cell antibody (ICA) ^[30]

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
  • 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
  • Lifestyle modifications, including:
    • Weight reduction
    • Balanced diet and nutrition; (including a high-fiber diet)
    • Regular exercise
    • Smoking cessation
  • Routine screening for and management of common comorbidities and complications
  • Vaccinations in line with the ACIP immunization schedule, including influenza, hepatitis B, pneumococcal vaccines, and COVID-19
• Risk assessment and prevention ^[32][33]
  • Control of blood pressure and blood lipids
  • ASCVD risk assessment and ASCVD prevention
    • Patients aged 40–75 years with diabetes mellitus: Initiate moderate-intensity statin therapy, regardless of lipid levels.
    • Assess indications for high-intensity statins.
• Follow-up: Periodically reevaluate the need for further diabetes self-management education and support (DSMES). ^[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]

Lifestyle modifications ^[34]

Physical exercise reduces blood glucose and increases insulin sensitivity.

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 ^[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

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
  • Consider in:
    • Patients with T1DM (can be used in combination with an insulin pump)
    • 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.
• 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.
  • Prescribing glucagon may be beneficial for some patients.

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 initial or early dual therapy with a noninsulin antidiabetic in certain patients, e.g., those with:
  • Clinical ASCVD or high ASCVD risk
  • HbA1c ≥ 1.5–2.0% above the glycemic target
• Consider the necessity for early combination therapy with insulin (see “Indications for insulin therapy for T2DM” below).
• 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 American Diabetes Association 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 GLP-1 receptor agonists with DPP4 inhibitors is not beneficial. Sulfonylureas should not be used together with insulin.

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
• 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.
• 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.

• 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).

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