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Endocrinology - Diabetes - Fast Facts | NEJM Resident 360

Diabetes is a common condition that is managed in both the inpatient and outpatient settings. The two main types of diabetes are type 1 and type 2. Highlighted below are some of the classic characteristics of type 1 and type 2 diabetes. However, these characteristics often overlap, and patients may present with mixed features.

Distinguishing Features of Type 1 and Type 2 Diabetes

	Type 1 Diabetes	Type 2 Diabetes
Etiology	Autoimmune destruction of pancreatic β-cells	Insulin resistance with inadequate compensatory β-cell function
Insulin levels	Absent or negligible	Typically, higher than normal
Insulin action	Absent or negligible	Decreased
Insulin resistance	Not part of syndrome but may be present (e.g., in patients with obesity)	Yes
Age of onset	Typically <30 years	Typically, >40 years
Acute complications	Ketoacidosis
Wasting	Hyperglycemia (can lead to hyperosmotic seizures and coma)
Chronic complications	Neuropathy
Retinopathy
Nephropathy
Peripheral vascular disease
Coronary artery disease	(Same as type 1)
Pharmacologic interventions	Insulin	Multiple drug classes are available, including insulin

(Adapted from: Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy. Fourth edition. Philadelphia: Wolters Kluwer 2017).

• Type 1 diabetes is due to autoimmune beta-cell destruction that leads to insulin deficiency. Patients typically present with symptomatic hyperglycemia (e.g., polyuria, polydipsia, and weight loss) or with DKA. Often antibodies can be detected early in the disease, including islet cell antibodies (ICA, against cytoplasmic proteins in the beta cell), antibodies to glutamic acid decarboxylase (GAD-65), insulin autoantibodies (IAA) or IA-2A (against protein tyrosine phosphatase). These antibodies might help distinguish type 1 from type 2 diabetes in certain circumstances.

• Type 2 diabetes is due to insulin resistance and progressive loss of beta-cell insulin secretion. Onset is usually gradual, with milder forms of hyperglycemia, termed prediabetes, eventually leading to symptomatic hyperglycemia.

• Other causes of diabetes include:

• • monogenic diabetes syndromes (presenting as neonatal diabetes or maturity-onset diabetes of the young [MODY])

  • drug- or chemical-induced diabetes (e.g., steroid-induced diabetes)

  • diabetes due to diseases of the exocrine pancreas (e.g., cystic fibrosis, chronic pancreatitis, post-pancreatectomy)

Key concerns in diabetes care include:

• screening and diagnosis of prediabetes/diabetes

• phenotyping (determining the type of diabetes)

• long-term (outpatient) management of blood-glucose levels and glycated hemoglobin (HbA1c)

• prevention and management of diabetic complications

• management of diabetes in hospitalized patients with infection, acute illness, and varying nutritional status

• management of glycemic emergencies (hypoglycemia, hyperglycemia, diabetic ketoacidosis, and hyperosmolar hyperglycemic nonketotic syndrome)

Screening and Diagnosis

Screening: Given the high prevalence of impaired glucose tolerance (IGT or prediabetes) and type 2 diabetes, an informal assessment of risk factors or validated tools (e.g., CANRISK diabetes risk calculator) should be considered in the screening of asymptomatic adults at risk of developing diabetes.

The American Diabetes Association (ADA) recommendations for diabetes screening in asymptomatic adults are outlined in the following table:

(Source: Classification and Diagnosis of Diabetes: Standards of Medical Care in Diabetes-2022. American Diabetes Association. Diabetes Care 2022.)

*The United States Preventive Services Task Force (USPSTF) recommends screening for prediabetes and type 2 diabetes in all adults aged 35 to 70 years who have overweight or obesity.

Diagnosis: Diagnosis of type 2 diabetes requires two abnormal test results from the same blood sample (e.g., abnormal HbA1c and fasting plasma glucose) or in two separate test samples. If the patient presents with a clear clinical picture of hyperglycemia (e.g., polyuria, polydipsia), then a single abnormal test is sufficient to make the diagnosis.

The following tests can be used to both screen for and diagnose diabetes:

• fasting plasma glucose (FPG)

• 2-hour plasma glucose concentration during a 75-g oral glucose tolerance test (OGTT)

• HbA1c

Thresholds for diagnosis of IGT and type 2 diabetes based on each of these tests are provided in the following table:

Thresholds for Diagnosis of IGT and Type 2 Diabetes

Test	Normal	IFG or IGT	Type 2 Diabetes
Hemoglobin A1c level, %	<5.7	5.7–6.4	≥6.5
Fasting plasma glucose level
mmol/L
mg/dL
<5.6
<100
5.6–6.9
100–125
≥7.0
≥126
OGTT results
mmol/L
mg/dL
7.8
<140
7.8–11.0
140–199
≥11.1
≥200

Abbreviations: IGT, impaired glucose tolerance; IFG, impaired fasting glucose; OGTT, oral glucose tolerance test

(Reference: American Diabetes Association Standards of Medical Care in Diabetes—2022. Diabetes Care 2022.)

Phenotyping of diabetes: All patients with new-onset diabetes should be evaluated to determine the type of diabetes. To identify less-common forms of diabetes, the patient should be evaluated for symptoms, medications, family history, and physical examination findings that may suggest genetic or secondary causes of diabetes. Targeted laboratory evaluation can be performed to further evaluate for conditions suspected after this initial clinical assessment.

Patients who present with features most consistent with type 1 diabetes (e.g., before puberty, with diabetic ketoacidosis, and/or without the typical findings of type 2 diabetes, including obesity or acanthosis nigricans) should be tested for islet autoantibodies. This typically involves measurements of antibodies directed against glutamic acid decarboxylase 65 (GAD65), the 40K fragment of tyrosine phosphatase (IA2), insulin, and/or zinc transporter 8 (ZnT8). Levels of C peptide can also be useful. In older patients with typical features of type 2 diabetes, no additional testing is needed. Autoantibody and C-peptide testing as described above can be helpful in patients with atypical features.

Management of Blood Glucose in Diabetes

Blood-glucose testing: It is helpful for patients with diabetes to regularly engage in blood glucose monitoring (BGM). This is typically done through measurements of capillary blood glucose using lancets and glucometers (fingerstick glucose measurements), although measurement of interstitial fluid glucose levels using continuous glucose monitors (CGMs) is becoming increasing popular both in patients with type 1 and type 2 diabetes.

All patients with diabetes should check their blood glucose level when they are unwell or feel symptomatic for hyper- or hypoglycemia. Frequency of BGM will depend on the individual patient’s medication regimen (e.g., testing may be omitted altogether in patients who are not taking medications that cause hypoglycemia, while patients requiring insulin may need to test ≥4 times per day).

Glycated hemoglobin targets: In patients with diabetes, HbA1c should be tested at least twice annually. In general, the HbA1c target for people with diabetes is <7.0% and ideally around 6.5%. However, goals should be individualized and based on the patient’s age, comorbidities, resources, and risk for hypoglycemia. For example, in an elderly patient with established cardiovascular disease or multiple other comorbidities, the HbA1c target is less stringent (HbA1c of 7.5% to 8.5%) because the risk of harm associated with hypoglycemia outweighs the benefits gained from glycemic control.

The following figure shows the factors to consider when setting a specific glycemic target:

Patient and disease factors used to determine optimal glycemic targets. Characteristics and predicaments toward the left justify more stringent efforts to lower A1C; those toward the right suggest less stringent efforts. A1C 7% = 53 mmol/moL.
(Source: Glycemic Targets: Standards of Medical Care in Diabetes—2022. American Diabetes Association. Diabetes Care 2022.)

General Glycemic Targets for Adults with Diabetes

Management of Type 1 Diabetes

Patients with type 1 diabetes have absolute insulin deficiency due to beta-cell destruction. Therefore, all patients with type 1 diabetes require insulin. Omission of insulin places patients with type 1 diabetes at risk of hyperglycemia and diabetic emergencies (e.g., diabetic ketoacidosis).

Insulin is usually administered via multiple daily injections (MDI) or continuous subcutaneous insulin infusion (CSII) via an insulin pump. Although insulin regimens vary, the primary principles for insulin administration in patients with type 1 diabetes are:

• basal insulin to cover baseline metabolic requirements (long-acting insulin analogue such as insulin glargine or via insulin pump)

• bolus insulin to cover meal-time carbohydrate intake and prevent postprandial hyperglycemia (short-acting insulin such as insulin aspart)

• correctional insulin to bring a high blood glucose level down into the target range

• newer closed-loop systems (“artificial pancreas”) integrate the insulin pump with a continuous glucose monitor (CGM). The system adjusts basal insulin based on real-time glucose levels, but still requires manual entry of prandial insulin doses for meal-time coverage.

Noninsulin pharmacologic treatments (e.g., metformin and sodium–glucose cotransporter-2 [SGLT-2] inhibitors) have been investigated in many trials as potential adjuncts for treatment in type 1 diabetes. However, these adjuncts are not approved for use in type 1 diabetes at this time.

Surgery: Pancreas transplantation or islet cell transplantation are two options for management of type 1 diabetes offered to very select patients and should not be considered part of routine care.

Management of Type 2 Diabetes

The three main approaches to managing diabetes and blood-glucose levels are:

• comprehensive lifestyle management

• pharmacologic therapy

• surgery

Lifestyle management: Lifestyle management is a key component of diabetes management, and all patients diagnosed with diabetes should make lifestyle changes, including the following:

• diabetes self-management education and support

• nutritional/dietary changes

• increase of physical activity and weight loss (when appropriate)

• smoking-cessation counseling (when applicable)

• psychosocial care

Pharmacologic therapy: Types of pharmacologic treatment for type 2 diabetes include:

• oral agents (e.g., metformin, SGLT-2 inhibitors, sulfonylureas, and meglitinides)

• injectable agents that are not insulin (e.g., glucagon-like peptide-1 [GLP-1] analogues)

• insulin

As with glycemic targets, choice of pharmacologic agents should be individualized. Metformin is typically recommended as the first-line agent, with more individualization possible when choosing second-line therapies. For example, an overweight 60-year-old man with heart failure will derive greater benefit from an SGLT-2 inhibitor than a sulfonylurea.

Comparison of Pharmacologic Treatments for Type 2 Diabetes

| Drug | Mechanism
of Action | Efficacy  | Hypoglycemia Risk | Effect on Weight | Effect on
CVD Risk | Comments | | --- | --- | --- | --- | --- | --- | --- | | Oral Agents | | Metformin | Not fully understood, but
primarily by
reducing hepatic
gluconeogenesis | High | None | Neutral or reduction | Potential benefit for atherosclerotic disease | GI adverse effects

Start at low dose, with gradual up-titration

Potential B₁₂ deficiency | | SGLT-2 inhibitor (empagliflozin, dapagliflozin, canagliflozin, ertugliflozin) | Prevents renal
tubule glucose
reabsorption
by inhibiting
SGLT-2 activity | Medium | None | Reduction | ↓ CVD risk
(atherosclerotic disease and CHF) | Also has renal benefit

↑ risk of fractures

↑ risk of DKA

↑ risk of amputation
(canagliflozin only) | | DPP-4 inhibitor (sitagliptin, linagliptin, saxagliptin, alogliptin, vildagliptin) | Blocks enzyme
(DPP-4) that causes
breakdown of incretins
that stimulate
insulin secretion | Medium | None | Neutral | No benefit | ↑ risk of acute pancreatitis | | Sulfonylurea (glipizide, gliclazide, glyburide, glimepiride) | Increases
beta-cell
insulin secretion | High | ↑ risk in patients with impaired liver or kidney function | Increase | No benefit | Dose reduction needed in elderly
due to hypoglycemia risk | | Thiazolidinediones (pioglitazone, rosiglitazone) | Bind to peroxisome
proliferator-
activated receptor
gamma in
adipocytes

Promotes
adipogenesis and
lipid availability | High | None | Increase | Potential ↑ risk of CHF

Potential benefit for atherosclerotic disease (pioglitazone) | Generally reserved as last-line treatment

Possible ↑ risk of edema and CHF

Uncertain benefit in NASH | | Injectable Agents | | GLP-1 analogues (dulaglutide, exenatide, liraglutide, semaglutide*) | Synthetic incretins
that stimulate insulin
secretion | High | None | Reduction | Cardiovascular benefit  | Uncertain risk of thyroid C-cell tumor

GI adverse effects

Injection-site reactions | | Insulin analogues | Synthetic insulin | High | ↑ risk in patients with impaired kidney function | Increase | No benefit | |

*Semaglutide is also available in a once-daily oral formulation

Abbreviations: CVD, cardiovascular disease; GI, gastrointestinal; SGLT-2, sodium–glucose cotransporter-2; CHF, congestive heart failure; DKA, diabetic ketoacidosis; DPP-4, dipeptidyl peptidase 4; NASH, nonalcoholic steatohepatitis; GLP-1, glucagon-like peptide-1
(Reference: Pharmacologic Approaches to Glycemic Treatment: Standards of Medical Care in Diabetes—2022. American Diabetes Association. Diabetes Care 2022.)

Glucose-Lowering Medication in Type 2 Diabetes

(Source: American Diabetes Association. Pharmacologic Approaches to Glycemic Treatment: Standards of Medical Care in Diabetes—2022. American Diabetes Association Diabetes Care 2022.)

Surgery: Metabolic surgery is a potential treatment option in patients with type 2 diabetes and BMI ≥40 kg/m² (BMI ≥37.5 in Asian Americans) and in adults with BMI 35.0–39.9 (32.5–37.4 in Asian Americans) who do not achieve durable weight loss and improvement in comorbidities (including hyperglycemia) with reasonable nonsurgical methods. In the appropriate patient, increasing evidence indicates that metabolic surgery is associated with improved cardiovascular outcomes and sustained glycemic control, compared with lifestyle and pharmacologic treatments alone.

For more information on metabolic surgery, see the Obesity section in this rotation guide.

Diabetic Complications

Diabetic complications can be classified as microvascular and macrovascular disease. Microvascular disease comprises nephropathy, retinopathy, and neuropathy. Macrovascular complications include coronary artery disease, cerebrovascular disease, and peripheral vascular disease.

Management of patients with diabetes requires regular assessment for potential complications and management of cardiovascular risk factors. Due to the autoimmune nature of type 1 diabetes, additional screening should be performed in this patient group for other autoimmune diseases.

Routine Follow-up in Patients with Diabetes

Clinical Concern	Examination/ Testing	Target	Follow-up	Treatment	Comments
Hypertension	Measure BP	≤120/80 mm Hg	Every clinic visit	First-line: ACE inhibitors or ARBs due to renoprotective effects	Consider 24h BP monitoring
Overweight/Obesity	Measure weight and height	BMI:
18.5–24.9 kg/m2
(lower for Asians)	Every clinic visit	Target: achieve and maintain

5% weight loss

Encourage balanced diet and regular physical activity

Pharmacotherapy and metabolic surgery for certain patients | High-intensity diet, physical and behavioral therapy (>16 sessions in 6 months) aimed to achieve 500–750 kcal/day energy deficit | | Dyslipidemia | Fasting lipids | LDL cholesterol <100 mg/dL (2.6 mmol/L) OR <70 mg/dL if high cardiac risk

Triglycerides
<150 mg/dL
HDL >40 mg/dL | At least every 5 years (if no statin therapy)

Annually, if treated | Patients aged <40 years: Commence statin treatment based on previous ASCVD event 

Patients aged >40 years: Start primary prevention with moderate-intensity statin for lower ASCVD risk and high-intensity statin for higher risk

Triglyceride-lowering agents (e.g., icosapent ethyl) can be considered in
high-risk patients with triglyceride levels ≥150 mg/dL) | In patients aged >75 years with no history of cardiac event, consider risk-benefit profile of statin therapy | | Lipohypertrophy | Skin exam | No lipohypertrophy | Every clinic visit | Avoid insulin injection into sites of lipohypertrophy | | | Peripheral neuropathy | Comprehensive foot exam | Maintain overall foot health | Annually | Adequate glycemic control

Regular podiatry review if neuropathy present | Foot exam: inspection, pedal pulses, and sensation (pin prick, vibration, 10-g monofilament) | | Retinopathy | Fundal exam | Maintain vision | Annually | Adequate glycemic control

Consider fibrates with comorbid dyslipidemia | | | Nephropathy | UACR

eGFR | <30 mg/gCr
Moderately increased albuminuria (microalbuminuria)
UACR: 30–299 mg/gCr

Severely increased albuminuria (macroalbuminuria)
UACR >300 mg/gCr

90 mL/min/
1.73 m² | At least annually | Adequate glycemic control

Control blood pressure (ACE inhibitor or ARB)

Consider adjunct of SGLT-2 inhibitor in type 2 diabetes | UACR can be falsely elevated within 24 hours of exercise and with fever, infection, CHF, menstruation, and marked hypertension | | Nonalcoholic steatohepatitis | Liver-function tests

Hepatic transaminases | Within normal range | At least annually | Weight loss
Glycemic control | Consider further investigation with liver ultrasound | | Type 1 Diabetes Only | | Other autoimmune disease | Celiac serology

Thyroid function

| Negative

Within normal range | Ask about symptoms annually

Test at diagnosis and then  periodically thereafter | Treat individual autoimmune condition | No specific guidelines on frequency of screening |

Abbreviations: BP, blood pressure; ACE, angiotensin-converting–enzyme; ARBs, angiotensin II–receptor blockers; ASCVD, arteriosclerotic cardiovascular disease; UARC, urine albumin-to-creatinine ratio (UACR); eGFR, estimated glomerular filtration rate

Hypoglycemia in Diabetes

Hypoglycemia is defined as blood-glucose concentration below 72 mg/dL. However, some patients experience symptoms before blood-glucose concentrations are so low. Symptoms can be classified as adrenergic (autonomic; e.g., sweating, shaking, palpitations) or neuroglycopenic (due to alterations in brain function; e.g., hunger, difficulty concentrating, confusion).

Common Precipitating Factors

Hypoglycemia can be caused by:

• incorrect insulin or long-acting sulfonylurea administration

• variation in carbohydrate intake

• suppression of glucose production in the liver by alcohol

• vigorous or prolonged exercise

• intercurrent illness

Hypoglycemic unawareness occurs when patients no longer experience adrenergic symptoms but directly experience neuroglycopenic symptoms. Usually, neuroglycopenic symptoms occur at a lower blood-glucose concentration. Patients with hypoglycemic unawareness are at risk of more-severe complications. Hypoglycemic unawareness can potentially be corrected by strict avoidance of hypoglycemia for 2 to 3 months.

Treatment

• Nonsevere hypoglycemia (patient is conscious and capable of self-management) can be treated with fast-acting oral glucose (15 g) such as fruit juice or glucose gel.

• Severe hypoglycemia (patient is unconscious or unable to perform self-management) needs to be treated with intramuscular or nasal glucagon and potentially intravenous glucagon.

• All patients should be encouraged to consume sources of long-acting carbohydrates when able and acute hypoglycemia has been corrected.

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