Diabetes Mellitus Overview

Diabetes Mellitus

• Diabetes mellitus is a metabolic disease characterized by high blood glucose levels.
• It is one of the most common chronic diseases and a leading cause of disability and mortality.
• It reduces lifespan by 5-15 years with a mortality rate twice as high as those without diabetes.
• Globally, 1 in 11 adults between 20-79 years old is diagnosed with diabetes.
• In the U.S., an estimated 34.2 million (10.5%) adults have diabetes.

Type 2 Diabetes: Signs and Symptoms

• Weight gain, including overweight or obesity.
• Centripetal fat distribution (excess fat around the waist).
• Waist circumference greater than 40 inches for men and 35 inches for women.
• Obstetrical complications such as delivering babies over 9 lb, polyhydramnios, preeclampsia, or unexplained fetal losses.

Type 2 Diabetes: Screening Recommendations

• Screening is recommended for Type 2 diabetes.
• Lifestyle changes and medications can reduce disease progression and adverse sequelae, even in asymptomatic patients.
• Screening for asymptomatic adults with a body mass index (BMI) ≥25 kg/m2, and one or more additional risk factors:
  • A1c > 5.7%
  • Impaired glucose tolerance
  • Impaired fasting glucose

Clinical Features of Diabetes at Diagnosis

"Metabolic Syndrome" / Insulin Resistance Syndrome

• Identifies individuals at higher risk for developing diabetes and cardiovascular disease.
• Not clear whether it is a useful diagnostic or management tool.
• Gestational diabetes screening recommendations:
  • Screen women in their first trimester if risk factors are present (obesity, advanced maternal age, history of gestational diabetes, family history of diabetes, high-risk ethnicity).
  • Screen asymptomatic patients at or after 24 weeks' gestation.

Gestational Diabetes: Complications

• Increases the risk of maternal complications including gestational hypertension, preeclampsia, Cesarean delivery, shoulder dystocia, macrosomia, and birth defects.
• 7 times greater maternal risk of developing Type 2 diabetes later in life.
• 1.5 times greater risk of the child being overweight in childhood/adolescence.
• In high-risk populations, diabetes develops in up to 50% of women with gestational diabetes.

Gestational Diabetes: Management

• Short- and long-term follow-up is critical.
• Screening at 6-12 weeks postpartum with a fasting glucose measurement or a 75g 2-hour glucose tolerance test.
• Women with history of gestational diabetes should be screened every 3 years for overt diabetes.

Diabetes in Children and Adolescents

• Includes Type 1 diabetes, Type 2 diabetes, and Maturity-Onset Diabetes of the Young (MODY).
• In 2018, an estimated 210,000 children and adolescents in the U.S. had diabetes (2.5 per 1000).
• Approximately 23,000 had Type 2 diabetes (0.24 per 1000).

Type 2 Diabetes in Children and Adolescents

• Risk factors include obesity, excess adipose tissue, and family history.
• Prevalence is highest in Native American, Black, Latin American, and Atlantic/Pacific Islander youth.
• Socioeconomic position, area of residence, and environmental factors may contribute.

Type 2 Diabetes in Children and Adolescents: Complications

• Major acute complications include diabetic ketoacidosis and hyperglycemic hyperosmolar state.
• Long-term morbidity is due to macrovascular and microvascular diseases.
• Increased prevalence of associated chronic comorbid conditions: hypertension, dyslipidemia, and nonalcoholic fatty liver disease.

Type 2 Diabetes in Children and Adolescents: Screening Recommendations

• Evidence is insufficient to assess the benefits versus harms of screening for Type 2 diabetes.
• Screening is recommended for age ≤18 who are overweight and have any two of the following risk factors:
  • History of Type 2 diabetes in a first- or second-degree relative
  • Belonging to a high-risk ethnic group
  • Acanthosis nigricans
  • Hypertension
  • Hyperlipidemia
  • Polycystic ovarian syndrome
• Screening recommended for at-risk patients every 2 years, starting at age 10, or at onset of puberty if under age 10.

Maturity-Onset Diabetes of the Young (MODY)

• A non-insulin-dependent form of diabetes typically diagnosed at ≤25 years of age.
• 1-5% of all patients with diabetes have the MODY type, often misdiagnosed as Type 1 or 2 diabetes.
• Suspect MODY in patients who are/have:
  • Non-obese and diagnosed with diabetes at a young age (< 144 mg/dL or 8.0 mmol/L, and no laboratory evidence of beta cell autoimmunity)
• Autosomal dominant disease, with 50% of offspring affected.
• Divided into 14 subtypes (MODY1 to MODY14) with MODY1 to MODY3 accounting for 95% of cases.
• Subtypes distinguished by gene mutations:
  • MODY1 (HNF4A): rare
  • MODY2 (GCK): less rare
  • MODY3 (HNF1A): most common, 30-50% of cases
  • Remaining subtypes are very rare.
• MODY1 and MODY3 have progressive hyperglycemia and vascular complication rates similar to Type 1 and 2 diabetes.
• MODY2 has mild stable fasting hyperglycemia with low risk of diabetes related complications.

Maturity-Onset Diabetes of the Young (MODY): Screening Recommendations

• Consider genetic testing and referral to an endocrinologist and/or clinical genetics consultant.
• Accurate diagnosis of MODY will determine treatment and management plan.
• Lack of evidence from randomized trials to show that early diagnosis and appropriate therapy improve patient outcomes.

Diabetes in Older Adults

• The definition of "older" varies but generally accepted as >65 years of age.
• Between 1997-2010, U.S. prevalence of diabetes in older adults increased by 62%.
• In the U.S., 21.4% of adults aged ≥65 years have a known diagnosis of diabetes and 16% are unaware.
• Most commonly affected by Type 2 diabetes.
• Older diabetic population is highly heterogeneous, complicating development of standard guidelines of care.
• Diabetes increases the risk of mortality, cardiovascular and microvascular complications, and other geriatric conditions.

Diabetes in Older Adults: Screening Recommendations

• No current recommendations for routine screening.
• Screening considerations: whether treatment would improve overall quality of life or life expectancy.
• Treatment decisions should be made based on age, life expectancy, functional status, and co-morbid diseases.

Secondary Causes of Diabetes

• Secondary causes include:
  • Exocrine pancreas diseases
  • Endocrinopathies
  • Drug- or chemical-induced insulin resistance
  • Genetic diseases
• Any disorder that damages the pancreas can result in diabetes (e.g., liver cirrhosis, hemochromatosis, hemosiderosis).

Secondary Causes of Diabetes: Examples

Diagnostic Tests

• Fasting plasma glucose levels (FPG)
• Oral glucose tolerance test (OGTT)
• Glycated hemoglobin (HbA1c)
• Additional tests (urine, self-monitoring, continuous glucose monitoring, autoantibody, genetic)

Fasting Plasma Glucose (FPG)

• 100-125 mg/dL (5.6-6.9 mmol/L) = impaired fasting glucose tolerance (increased risk of diabetes, "pre-diabetes").
• ≥126 mg/dL (7.0 mmol/L) on more than one occasion, after at least 8-hour fasting = Diagnostic.
• Diagnosis may be made with hyperglycemia signs and symptoms, PLUS >200 mg/dL (11.1 mmol/L) - and testing should be repeated to confirm.
• Pros: may identify one-third more undiagnosed cases than A1c.
• Cons: fasting is required.

Oral Glucose Tolerance Test (OGTT)

• Perform if FPG is:
  • 100-125 mg/dL (5.6-6.9 mmol/L)
  • Or if the patient has symptoms of hyperglycemia.
• A 2-hour post-load glucose level of >200 mg/dL (11.1 mmol/L) is diagnostic.

Glycated Hemoglobin (HbA1c)

• Reflects average blood glucose levels over the past 2-3 months.
• HbA1c of 6.5% or higher is diagnostic of diabetes.
• HbA1c of 5.7-6.4% is considered pre-diabetes.

Additional Tests

• Urine Tests:
  • Urinary glucose and ketones can be used for initial screening and monitoring.
  • Proteinuria and microalbuminuria can detect kidney damage.
• Self-Monitoring of Blood Glucose (SMBG):
  • Used by patients with Type 1 and Type 2 diabetes to manage their blood glucose levels.
• Continuous Glucose Monitoring (CGM):
  • Provides real-time blood glucose readings.
  • Used for tight blood glucose control and to identify patterns of hypoglycemia and hyperglycemia.
• Autoantibody Testing:
  • Can identify Type 1 diabetes by detecting autoantibodies against pancreatic beta cells.
• Genetic Testing:
  • For MODY or other genetic forms of diabetes.

### Diabetes in Canada

• 14% of Canadians have diabetes (5.7 million people)
• Since 2000, the prevalence rate has increased by an average of 3.3% each year
• Those with diabetes are living longer

Diabetes Mellitus

• Diabetes can be influenced by both genetics and environmental factors
• The two major subtypes of diabetes are type 1 and type 2
• Other subtypes include maturity-onset diabetes of the young (MODY), gestational diabetes, and secondary causes

### Type 1 Diabetes

• Results from the destruction of pancreatic islet beta cells, often due to an autoimmune reaction
• More common in children and young adults, with peak incidence between ages 4-6 and 10-14
• The global incidence of type 1 diabetes is rising by approximately 3% annually

### Type 1 Diabetes: Epidemiology

• Genetic Factors:
  • The HLA locus (HLA-DR3, -DR4, -DQ) accounts for around 40% of the genetic risk for developing type 1 diabetes
  • Most patients with type 1 diabetes have circulating antibodies to islet cells, glutamic acid decarboxylase 65, insulin, tyrosine phosphatase IA2, and zinc transporter 8
• Environmental Factors:
  • The highest incidence of type 1 diabetes is found in Scandinavia and northern Europe (e.g., Finland, with an annual incidence of 40 per 100,000 children aged ≤14 years)
  • The lowest incidence is observed in China and parts of South America (annual incidence is 9 per 100,000 children aged ≤14 years)

Type 2 Diabetes: Epidemiology

• Genetic Factors:

  • Epidemiological studies of monozygotic twins over 40 years of age show that if one twin develops type 2 diabetes, the other twin has a 70% chance of developing it within a year
  • Genome studies have identified 143 risk variants and regulatory mechanisms for type 2 diabetes, including loci related to:
    • Beta cell function/development (TCF7L2)
    • Insulin secretion (e.g., CDKAL1, SLC30A8)
    • Fat mass and obesity risk (FTO, MC4R)
    • Insulin resistance (PPARG)

• Environmental Factors:

  • Obesity, particularly visceral obesity, is the primary environmental factor contributing to insulin resistance

Type 2 Diabetes: Signs and Symptoms

• Weight gain:
  • Overweight or obese
  • Centripetal fat distribution
  • Waist circumference >40 inches for men, >35 inches for women
• Obstetrical complications:
  • Consider type 2 diabetes in women who have delivered babies over 9 lb (4.1 kg) or have experienced polyhydramnios, preeclampsia, or unexplained fetal losses

Type 2 Diabetes: Screening Recommendations

• The USPSTF recommends screening for type 2 diabetes

• Reliable tests are available, and lifestyle changes and medications can reduce disease progression and adverse consequences even in asymptomatic individuals

• Studies show that while screening may not improve mortality at 10-year follow-up, interventions like lifestyle modifications and pharmacologic treatments can delay the development of type 2 diabetes

• Some studies suggest that screening may have mortality benefits at 23- to 30-year follow-up

• Screen asymptomatic adults who have a body mass index (BMI) ≥25 kg/m2 and one or more of the following risk factors from previous lab results:

  • A1c > 5.7%
  • Impaired glucose tolerance
  • Impaired fasting glucose

Clinical Features of Diabetes at Diagnosis

“Metabolic Syndrome”

• Also known as Insulin Resistance Syndrome
• Identifies individuals at increased risk for developing diabetes and cardiovascular disease
• Its usefulness as a diagnostic or management tool is debated
• Screening recommendations for gestational diabetes:
  • Screen women in their first trimester if risk factors such as obesity, advanced maternal age (>35 years), history of gestational diabetes, family history of diabetes, or high-risk ethnicity are present
  • Screen asymptomatic patients at or after 24 weeks’ gestation

Gestational Diabetes: Complications

• Adverse outcomes include:
  • Gestational hypertension (RR=1.6)
  • Preeclampsia (RR=1.5)
  • Cesarean delivery (RR=1.3)
  • Shoulder dystocia (RR=2.9)
  • Macrosomia (RR=1.6)
  • Birth defects (RR=1.2)
• Women with gestational diabetes have a 7 times greater risk of developing type 2 diabetes later in life (RR=7.4) and a 1.5 times greater risk of their child being overweight in childhood/adolescence (RR=1.5)
• In high-risk populations (BMI >25 kg/m2 plus physical inactivity, first-degree relative with diabetes, high-risk ethnicity, previous gestational diabetes, or hypertension), diabetes develops in up to 50% of women with gestational diabetes

### Gestational Diabetes: Management

• Short- and long-term follow-up is crucial
• Screening should be done at 6-12 weeks postpartum with a fasting glucose measurement or a 75g 2-hour glucose tolerance test.
• Up to 36% of women with gestational diabetes may have persistently abnormal glucose tolerance.
• Women with a history of gestational diabetes should be screened every 3 years for overt diabetes

### Diabetes in Children and Adolescents

• Type 1 diabetes
• Type 2 diabetes
• Maturity-onset diabetes of the young (MODY)

Diabetes in Children and Adolescents

• In 2018, an estimated 210,000 children and adolescents in the U.S. (2.5 per 1000) had diabetes
  • Approximately 23,000 had type 2 diabetes (0.24 per 1000)
• From 2005-2016, nearly 20% of youth aged 12-18 years had prediabetes
• Most cases occur after age 10, with peak occurrence at mid-puberty

### Type 2 Diabetes in Children and Adolescents

• Risk factors include: obesity, excess adipose tissue (especially when centrally distributed), and family history
• The prevalence is highest in Native American, Black, Latin American, and Atlantic/Pacific Islander youth (U.S.)
• Socioeconomic position, area of residence, and environmental factors may also play a role (e.g., quality of and access to health care, toxic stress, structural racism)

### Type 2 Diabetes in Children and Adolescents

• Major acute complications of type 2 diabetes in youth are diabetic ketoacidosis (10% at diagnosis) and hyperglycemic hyperosmolar state
• Long-term morbidity is due to macrovascular (atherosclerosis) and microvascular diseases (retinopathy, nephropathy, neuropathy)
• Complications like renal disease, retinopathy (13.7%), and peripheral neuropathy (17.7%) may develop during teenage and young adulthood years
• An increased prevalence of associated chronic comorbid conditions exists:
  • Hypertension (11.6-33.8%)
  • Dyslipidemia (4.5-10.7%)
  • Nonalcoholic fatty liver disease (22.2%)

Type 2 Diabetes in Children and Adolescents: Screening

• The USPSTF considers the evidence insufficient to assess the benefits versus harms of screening for type 2 diabetes in children and adolescents
• The USPSTF concludes there is insufficient evidence to recommend for or against screening for type 2 diabetes in children and adolescents without symptoms of diabetes or prediabetes
• There is inadequate evidence to demonstrate that screening and early intervention lead to improvements in health outcomes such as preventing:
  • Progression to type 2 diabetes
  • Renal impairment
  • Cardiovascular morbidity and mortality
  • Improvement in quality of life

Type 2 Diabetes in Children and Adolescents: Screening Recommendations

• Screening is recommended for individuals aged ≤18 who are overweight and have any two of the following risk factors:
  • History of type 2 diabetes in a first- or second-degree relative
  • Belonging to a high-risk ethnic group
  • Acanthosis nigricans
  • Hypertension
  • Hyperlipidemia
  • Polycystic ovarian syndrome
• Screening is recommended every 2 years, starting at age 10, or at the onset of puberty if under age 10

Maturity-Onset Diabetes of the Young (MODY)

• A non-insulin-dependent form of diabetes, typically diagnosed at ≤25 years of age
• 1-5% of all patients with diabetes have MODY
• Often misdiagnosed as type 1 or 2 diabetes

### Maturity-Onset Diabetes of the Young (MODY)

• MODY should be suspected in patients who:
  • Are non-obese and were diagnosed with diabetes at a young age (144 mg/dL or 8.0 mmol/L fasting glucose, with no laboratory evidence of pancreatic beta cell autoimmunity)

### Maturity-Onset Diabetes of the Young (MODY)

• Most often an autosomal dominant disease, affecting 50% of offspring
• Divided into 14 subtypes (MODY1 to MODY14), with MODY1 to MODY3 accounting for 95% of cases
• The subtypes are distinguished by their gene mutations:
  • MODY1 (HNF4A): rare
  • MODY2 (GCK): less rare
  • MODY3 (HNF1A): most common, 30-50% of cases
  • The remaining subtypes are very rare

### Maturity-Onset Diabetes of the Young (MODY)

• MODY1 and MODY3 exhibit progressive hyperglycemia and vascular complication rates similar to patients with type 1 and type 2 diabetes
• MODY2 typically presents with mild, stable fasting hyperglycemia and a low risk of diabetes-related complications. These patients generally do not require treatment, except during pregnancy.

Maturity-Onset Diabetes of the Young (MODY): Screening Recommendations

• Consider genetic testing and referral to an endocrinologist and/or clinical genetics consultant
• Accurate diagnosis of MODY is essential for determining the appropriate treatment and management plan
• However, there is a lack of evidence from randomized trials to show that early diagnosis and therapy improve patient-oriented outcomes

Diabetes in Older Adults

• The definition of "older" varies across studies; generally accepted as >65 years of age
• From 1997-2010, the U.S. prevalence of diabetes in older adults increased by 62%
• In the U.S., 21.4% of adults aged ≥65 years have a known diagnosis of diabetes; 16% are unaware they have diabetes

Diabetes in Older Adults

• Most commonly affected by type 2 diabetes
• The older diabetic population is highly heterogeneous in terms of race/ethnicity, duration of diabetes, comorbidity, and functional status, making it challenging to develop standard guidelines for care
• Diabetes increases the risk of mortality, cardiovascular and microvascular complications, and other geriatric conditions (e.g., cognitive impairment, frailty, unintentional weight loss, polypharmacy, and functional impairment)

### Diabetes in Older Adults: Screening Recommendations

• No current recommendations for routine screening
• Screening should be considered if treatment would improve overall quality of life or life expectancy
  • Consider screening to prevent complications that may lead to functional impairment
• Treatment decisions should be made based on:
  • Age
  • Life expectancy
  • Functional status
  • Presence of chronic co-morbid diseases

Secondary Causes of Diabetes

• Secondary causes include:
  • Exocrine pancreas diseases
  • Endocrinopathies
  • Drug- or chemical-induced insulin resistance
  • Other genetic diseases
• Any disorder that damages the pancreas can lead to diabetes (e.g., liver cirrhosis, hemochromatosis, hemosiderosis)

### Secondary Causes of Diabetes

Diagnostic Tests

Testing for Diabetes

• Fasting plasma glucose levels (FPG)
• Oral glucose tolerance test (OGTT)
• Glycated hemoglobin (HbA1c)
• Additional tests:
  • Urine
  • Self-monitoring
  • Continuous glucose monitoring
  • Autoantibody
  • Genetic

### Fasting Plasma Glucose (FPG)

• 100-125 mg/dL (5.6-6.9 mmol/L) = impaired fasting glucose tolerance - increased risk of diabetes (“pre-diabetes”)
• ≥126 mg/dL (7.0 mmol/L) on more than one occasion, after at least 8-hour fasting = Diagnostic
• Diagnosis may be made with hyperglycemia signs and symptoms, PLUS >200 mg/dL (11.1 mmol/L) – and testing should be repeated to confirm
• Pros: may identify one-third more undiagnosed cases than A1c
• Cons: fasting is required

Oral Glucose Tolerance Test (OGTT)

• Performed if FPG is:
  • Normal (less than 100 mg/dL) but there is a high suspicion of diabetes
  • Between 100-125 mg/dL (impaired fasting glucose)
• Involves drinking a sugary drink and having your blood sugar levels checked at intervals

Factors that Falsely Lower A1c

• Acute blood loss can cause a temporary decrease in A1c levels
• Chronic liver disease can interfere with HbA1c production and lead to inaccurate readings
• Hemolytic anemias can lower A1c by shortening the lifespan of red blood cells
• Antiretroviral treatment for HIV can affect A1c levels and sometimes cause false decreases
• Pregnancy can influence A1c levels, leading to lower readings compared to normal circumstances
• Vitamin E and C are thought to potentially reduce A1c levels

Factors that Lower or Elevate A1c

• Hemoglobinopathies or hemoglobin variants can affect A1c accuracy, sometimes lowering and sometimes elevating it
• Malnutrition can result in both increased and decreased A1c values, making interpretation challenging

Factors that Falsely Elevate A1c

• Aplastic anemias can interfere with A1c measurements, leading to falsely high readings
• Hyperbilirubinemia, high levels of bilirubin in the blood, can lead to falsely high A1c readings
• Hypertriglyceridemia, elevated levels of triglyceride in the blood, can contribute to inaccurate A1c results
• Iron deficiency anemias can cause falsely high A1c values.
• Renal failure can influence A1c levels, often leading to higher readings
• Splenectomy can cause elevation in A1c levels due to changes in red blood cell lifespan.

Diabetes Mellitus

• A metabolic disorder characterized by persistently elevated blood glucose levels.
• A leading cause of disability and mortality worldwide.
• Reduces life expectancy by 5-15 years.
• Prevalence in adults ages 20-79 is 1 in 11 globally.
• Both genetic and environmental factors contribute to its development.
• The two main types are Type 1 and Type 2.

Type 1 Diabetes

• Characterized by destruction of pancreatic beta cells, typically due to an autoimmune reaction.
• More common in children and young adults, with peak incidence at ages 4-6 & 10-14.
• Global incidence is increasing by approximately 3% each year.
• Genetic factors account for one-third of disease susceptibility, with HLA locus (HLA-DR3, -DR4, -DQ) conferring about 40% of the genetic risk.
• Environmental factors account for two-thirds of disease susceptibility, with highest incidence in Scandinavia and northern Europe.

Type 2 Diabetes

• The most prevalent type of diabetes.
• Characterized by insulin resistance and a relative deficiency of insulin secretion.
• Strongly associated with obesity, especially visceral obesity.
• Genetic factors contribute to 70% of cases when one monozygotic twin develops Type 2 diabetes after age 40.
• Environmental factors include obesity, sedentary lifestyle, and family history.

Gestational Diabetes

• Develops during pregnancy and typically resolves after delivery.
• Represents 7.8% of all pregnancies in 2020, increasing since 2016.
• Prevalence increases with advancing maternal age and higher pre-pregnancy BMI.
• Screening typically involves a 50g glucose challenge test between 24-28 weeks' gestation.
• Diagnostic criteria involve a 3-hour fasting 100g glucose challenge test with abnormal values ≥180, 155, 140 mg/dL for 1-, 2-, and 3-hour fasting glucose levels, respectively.

Diabetes in Children and Adolescents

• Represents 2-5% of all diagnosed cases of diabetes.
• Prevalence is highest in Native American, Black, Latin American, and Atlantic/Pacific Islander youth.
• Risk factors include obesity, excess adipose tissue, and family history.
• The presence of diabetic ketoacidosis (10% at diagnosis) and hyperglycemic hyperosmolar state represents major acute complications.
• Long-term morbidity is due to macrovascular and microvascular diseases.

Maturity-Onset Diabetes of the Young (MODY)

• A non-insulin-dependent form of diabetes, typically diagnosed at ≤25 years of age.
• Occurs in 1-5% of all patients with diabetes.
• Often misdiagnosed as Type 1 or 2 diabetes.
• Characterized by autosomal dominant inheritance with 50% of offspring affected.
• Divided into 14 subtypes, with MODY1 to MODY3 accounting for 95% of cases.