Diabetes mellitus (DM) describes a group of metabolic diseases that are characterized by chronic 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 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 “ .”
|Type 1 vs Type 2 diabetes mellitus|
|Features||Type 1 DM||Type 2 DM |
|Association with obesity|| || |
|Onset|| || |
|C-peptide (insulin)|| || |
|Glucose intolerance|| || |
|Insulin sensitivity|| || |
|Risk of ketoacidosis|| || |
|β-cells in the islets|| || |
| || |
- ∼ 1.6 million in the US
- ∼ 5–10% of all patients with diabetes
- 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 
- ∼ 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 
- Adult onset typically > 40 years 
- Mean age of onset is decreasing
- Gender: ♂ > ♀ 
- Race: highest prevalence in Native Americans, Hispanics, African Americans, and Asian non-Hispanic Americans 
Epidemiological data refers to the US, unless otherwise specified.
Type 1 DM 
- Autoimmune destruction of pancreatic β cells in genetically susceptible individuals
- HLA association: HLA-DR3 and HLA-DR4 positive patients are at increased risk of developing T1DM.
Associated with other autoimmune conditions
“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 
- Hereditary and environmental factors 
- Associated with : e.g., high waist-to-hip ratio (visceral fat accumulation) 
- Risk factors for type 2 diabetes mellitus 
Classification according to the WHO and American Diabetes Association (ADA) 
- Type 1: formerly known as insulin-dependent (IDDM) or juvenile-onset diabetes mellitus
- Type 2: formerly known as non-insulin-dependent (NIDDM) or adult-onset diabetes mellitus
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)
- 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.,
- Rare immunological diseases:
- Other genetic syndromes that are associated with diabetes mellitus (e.g., Down syndrome)
- MODY (maturity-onset diabetes of the young): genetic defects leading to β-cell dysfunction
Normal insulin physiology 
- Secretion: Insulin is synthesized in the β cells of the islets of Langerhans; . The cleavage of proinsulin (precursor molecule of insulin) produces C-peptide (connecting peptide) and insulin, which consists of two peptide chains (A and B chains).
Action: 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 
- 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
Peripheral insulin resistance 
- Numerous genetic and environmental factors
- Central obesity → increased plasma levels of free fatty acids → impaired insulin-dependent glucose uptake into hepatocytes, myocytes, and adipocytes
- Increased serine kinase activity in fat and skeletal muscle cells → phosphorylation of insulin receptor substrate (IRS)-1 → decreased affinity of IRS-1 for → decreased expression of → decreased cellular glucose uptake channels
- Numerous genetic and environmental factors
- Pancreatic β cell dysfunction: accumulation of pro-amylin (islet amyloid polypeptide) in the pancreas; → decreased endogenous insulin production 
- 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 with isolated postprandial hyperglycemia, diabetes manifests with fasting hyperglycemia.
|Clinical features of diabetes mellitus|
|Type 1 DM||Type 2 DM |
|Onset|| || |
|Clinical features|| |
Indications for testing 
- > 45 years of age
- History of prediabetes or gestational diabetes
- Patients < 45 years of age with both
- Presence of risk enhancing comorbidities, including:
- Consider in women who are planning pregnancy with any risk factor for T2DM (e.g., overweight or obesity).
- See “pregnancy. ” for testing indications during
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. 
Diagnostic criteria for diabetes mellitus 
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
- ≥ 2 abnormal test results for hyperglycemia in asymptomatic individuals
Hyperglycemia 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): 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. ; 
- Factors resulting in a falsely high HbA1c
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
|Interpretation of diagnostic tests |
|FPG||2-hour glucose value after OGTT||HbA1c|
|Diabetes mellitus||≥ 126 mg/dL (≥ 7.0 mmol/L)||≥ 200 mg/dL (≥ 11.1 mmol/L)||≥ 6.5%|
|Prediabetes||100–125 mg/dL (5.6–6.9 mmol/L) = impaired fasting glucose||140–199 mg/dL (7.8–11.0 mmol/L) = impaired glucose tolerance||5.7–6.4%|
|Normal||< 100 mg/dL (< 5.6 mmol/L)||< 140 mg/dL (< 7.8 mmol/L)||< 5.7%|
Perform in all patients as part of the initial diagnostic workup and reassess at least annually.
- Renal function
- Electrolytes, including potassium
- Liver chemistries
- Lipid panel
- Spot urinary albumin-to-creatinine ratio: to detect microalbuminuria
These tests are not routinely indicated or required to establish a diagnosis.
- C-peptide: can help differentiate between types of diabetes 
Antibody testing: Consider in patients with diagnosed diabetes mellitus if there is clinical suspicion for T1DM. 
- Antiglutamic acid decarboxylase antibodies (Anti-GAD)
- Anti-tyrosine phosphatase-related islet antigen 2 (IA-2) 
- Islet cell antibody (ICA) 
General principles 
- Main goal: blood glucose control, tailored to glycemic targets and regularly monitored
Comprehensive diabetes care (all patients)
- Continuous patient education
- Lifestyle modifications, including:
- 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 
- Follow-up: Periodically reevaluate the need for further diabetes self-management education and support (DSMES). 
Diabetes care should be patient-centered and comprehensive, including lifestyle modifications and assessment of psychosocial health. Consider and formulate a treatment plan together with the patient.
Lifestyle modifications 
|Lifestyle recommendations for patients with diabetes mellitus |
|Physical activity|| |
|Balanced diet and nutrition|| |
|Weight management |
Physical exercise reduces blood glucose and increases insulin sensitivity.
Glycemic targets in diabetes 
- Consider the following patient factors when setting a glycemic target:
- Reevaluate glycemic targets continuously and adjust if necessary.
|Common glycemic targets |
< 7%: suitable for most patients 
|Preprandial capillary glucose|| |
|Peak postprandial capillary glucose|| |
< 180 mg/dL
Glycemic targets should be individualized. A target of HbA1c < 7% is generally suitable for most nonpregnant adults. 
Glycemic 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
- Self-monitoring of blood glucose (SMBG): at fixed times or as necessary
- Continuous glucose monitoring (CGM): Interstitial glucose levels are measured continuously or intermittently using a device. 
- Assess for episodes of (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:
- 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)
- Dawn phenomenon
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). 
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.
Insulin replacement therapy 
- Treatment options
- Starting dose calculation 
- Dose titration
Educate patients on calculating insulin requirements throughout the day and in accordance with activities and meals. 
Other treatment strategies 
- Noninsulin : 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:
- Start treatment in all patients at diagnosis. 
- Monotherapy with 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:
- or high
- 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. 
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. 
|Noninsulin antidiabetics for the treatment of type 2 diabetes mellitus |
|Drug class|| |
| || |
|GLP-1 receptor agonists|
- Other drugs that are not part of the therapy algorithms for T2DM according to the American Diabetes Association guideline include:
- See “ ” for details on side effects and contraindications.
Indications for insulin therapy in T2DM 
- Patients whose glycemic targets are not met despite sufficient antidiabetic treatment
- Patients with contraindications for noninsulin antidiabetic drugs, e.g., patients with
- Pregestational and gestational diabetes
- Hyperglycemic crisis
- Consider in newly diagnosed patients with any of the following:
Approach to insulin treatment in T2DM 
- 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.
- Diabetes mellitus is one of the leading causes of death in the US; common complications that result in death are and . 
- One of the leading causes of blindness, nontraumatic lower limb amputation, end stage renal failure, and cardiovascular disease 
- The prognosis primarily depends on glycemic control and treatment of comorbidities (e.g., hypertension, dyslipidemia).
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